Abstract:
The present application provides the medicaments comprising the antibodies binding to phospholipase D4 (PLD4) as well as a method using said medicaments for detecting and suppressing activated B cells. The present application is further directed to therapy of auto-immune diseases and allergosis, resulting from the active-repressing function. In order to solves these problems, the present application provides that a monoclonal antibody binding to the extracellular domain of phospholipase D4 (PLD4) protein, or a fragment containing an antigen-binding region thereof as an active ingredient.

Description:
TECHNICAL FIELD 
       [0001]    The present invention relates to a use of an antibody binding to phospholipase D4. Hereinafter, “phospholipase D” may be abbreviated as PLD and “phospholipase D4” and the like may be abbreviated as PLD4 and the like. 
       BACKGROUND ART 
       [0002]    PLD is an enzyme which catalyzes a reaction to produce phosphatidic acid and choline by hydrolyzing phosphatidyl choline and causes various intracellular signaling. It has been believed that the produced phosphatidic acid functions as a lipid signal molecule. 
         [0003]    PLD1 and PLD2 have been known as two types of mammal PLD, which have been previously known, and contain a phosphatidyl inositide-binding Phox homology domain (PX domain) and a phosphatidyl inositide-binding pleckstrin homology domain (PH domain) in the N-terminal region thereof. Both domains are involved in membrane localization of PLD. 
         [0004]    PLD1 and PLD2 further contain two His-x-Lys-x-x-x-x-Asp sequences (HKD motifs). The HKD motifs are essential domains for PLD activity. 
         [0005]    Phosphatidic acid produced by PLD1 and PLD2 has been suggested to be involved in cytoskeleton reconstruction, exocytosis, phagocytosis, canceration, cell adhesion, chemotaxis and the like, and mainly acts on nervous systems, immune systems and the like. 
         [0006]    Human Hu-K4 and mouse SAM9, which are now officially named PLD3, lack the PX and PH domains and do not show PLD activity despite having two HKD motifs. Although there are further three PLD family members, PLD4, PLD5 and PLD6, little has been known about these non-classical PLDs. 
         [0007]    As a result of searching a gene expression pattern in mouse cerebellar development in Cerebellar Development Transcriptome Database (CDT-DB), a transcription product, PLD4, controlled during the development was identified (see Non Patent Literature 1). Basic characteristics of PLD4 have not been reported. Enzymatic activity of PLD4 with or without glycosylation needs to be determined. 
         [0008]    PLD4 has a 506 amino acid sequence shown in SEQ ID NO: 1 and is encoded by a cDNA base sequence of SEQ ID NO: 44 (Non Patent Literatures 1 and 2). The PLD4 protein has two tentative PDE regions (phosphodiesterase motifs) constituted of two HKD motifs (His-x-Lys-x-x-x-x-Asp amino acid sequence, x represents other amino acids) conserved in the C-terminal region, and a putative phosphorylation site (Thr 472). The structure of the PLD4 protein is estimated as a type II transmembrane protein. In addition, PLD4 does not have PX and PH domains, which PLD1 and PLD2 in a classical PLD family have them, in the N-terminal region. 
         [0009]    On the other hand, PLD4 belongs to the PLD family because of having two HKD motifs, but lacks the PX domain and the PH domain and has a putative transmembrane domain instead (Non Patent Literature 3). 
         [0010]    The expression of PLD4 mRNA has been found at low to medium levels in small cell clusters preferentially localized around white matter regions including corpus callosum and cerebellar white matter of 1 week old mice. These PLD4 mRNA-expressing cells have been identified as Iba1-positive microglia (Non Patent Literature 3). However, the PLD4-positive cells in mouse cerebellum is dispersed 10-day-old mice. It suggested that PLD4 expression is temporarily restricted during early postnatal development in mouse cerebellum. 
         [0011]    Myelin formation in mouse begins in the corpora callosa and the cerebellar white matter at one week after birth. At this time, PLD4 is highly expressed in amoeboid (an activated state) microglia existing in the white matter, and thus it has been also believed that there is a possibility that PLD4-expressing cells in the white matter in this time are involved in myelin formation. In particular, it has also been revealed that PLD4 accumulates in food vacuoles, and it has been suggested that there is a possibility that PLD4 is involved in phagocytosis. In amoeboid microglia which is in an activated state, various cytokines and growth factors are secreted and simultaneously phagocytosis is activated. It has been believed that in the brain white matter of mouse in a developmental period, surplus oligodendrocytes (central nervous system glial cells, which formmyelin by wrapping around axons) undergo apoptosis. There is a possibility that the oligodendrocytes are decomposed and removed in amoeboid microglia to secrete signal molecules and thereby adjust a myelin-forming environment in the white matter. It has been suggested that PLD4 is involved in these processes including the myelin formation. 
         [0012]    Expression of mouse PLD4 mRNA is also observed in non-neuronal tissues and mainly distributed in the spleen. Strong expression of PLD4 protein is detected around a marginal zone of the splenic red pulp, and splenic PLD4 protein collected from subcellular membrane fractions is highly N-glycosylated. When PLD4 was expressed in a heterologous cell system, PLD4 was localized in the endoplasmic reticulum and Golgi apparatus. The heterologously expressed PLD4 did not show PLD enzyme activity (Non Patent Literature 3). 
         [0013]    From the expression pattern of PLD4, which is spatiotemporally restricted, it has been suggested that PLD4 may play a role in common functions among the microglia and splenic marginal zone cells during early postnatal brain development. 
         [0014]    On the other hand, the present inventors have found that PLD4 is specifically highly expressed in pDC (plasmacytoid Dendritic Cell) in a resting period (resting pDC) (Patent Literature 1). The present inventors further have reported that a PLD4-specific antibody can be utilized for suppression of pDC activity. 
         [0015]    Further, PLD4 has been reported as one of novel susceptibility genes of Systemic Sclerosis in Japanese (Non Patent Literature 4). As a result of the same analysis in Europe, however, significant correlation with PLD4 has not been found and strong results showing a relationship between PLD4 and autoimmune diseases such as Systemic Sclerosis have not been obtained. 
         [0016]    An immune mechanism is roughly classified into two groups. One is “natural immunity (innate immunity)” which detects foreign substances such as pathogens and carries out an initial attack, and the other is “acquired immunity” through information exchange which is presentation of antigen peptides and the like derived from foreign substances. Neutrophils, macrophage, dendritic cells (DC), NK (Natural Killer) cells and the like are mainly involved in the “natural immunity”, and T cells and B cells to which information of antigen peptides and the like presented by the above dendritic cells and the like is transmitted are involved in the “acquired immunity”. T cells activated by transmission of information of antigen peptides are capable of specifically recognizing and attacking pathogens in a direct manner as the cell-mediated immunity, and B cells activated in the same manner as above are capable of specific recognition and attack against pathogens in an indirect manner by producing antibodies (hormonal immunity). 
         [0017]    In the “natural immunity”, pathogen-associated molecular patterns (PAMPs) universally existing in pathogens (LPS, CpG DNA, lipoproteins, RNA etc.) are recognized through Toll-like receptors (TLR), and secretion of inflammatory cytokines is promoted via NF-kB, or secretion of interferon (IFN) is promoted via IRF (Interferon regulatory factor). TLR is roughly classified into two groups by subcellular localization sites: a group expressed on cell surfaces and a group expressed in endosomes and endoplasmic reticula (ER). In pDC, IRF7 is activated via TLR7 and TLR9 localized in endosomes and endoplasmic reticula to induce IFN-α production. The reason why these TLRs are not expressed on cell surfaces but in cells has been suggested to decrease a risk of onset of autoimmune diseases. TLR7 and TLR9 recognize single-stranded RNA and DNA respectively as a ligand. Not only foreign pathogenic bacteria but also hosts hold these nucleic acids, and thus it has been suggested that receptors, which recognize nucleic acids and activate immune cells, always induce the autoimmune diseases. 
         [0018]    On the other hand, B cells (B lymphocytes) showing an important role in the “acquired immunity” are lymphocytes which express immunoglobulin Ig receptors on the surface thereof. B cells are produced from hematopoietic stem cells in the bone marrow, and are differentiated into pre-B cells and immature B cells, and then mature into naive B cells (mature, unprimed B cells). The naive B cells are activated by not only the stimulation through the above T cells but also the direct antigen stimulation, and further become antibody-producing cells by differentiation and proliferation to produce and secrete antibodies such as IgM, IgD, IgA, IgE, IgG (including subclasses such as IgG1, IgG2, IgG2b, IgG3 and the like). It has been known that in addition to B cell receptors (BCR) recognizing specific foreign antigens, the above TLRs are expressed in B cells. It has been previously known, for example, that LPS which has been known to cause the proliferation and antibody production of B cells is a ligand of TLR4 and the above TLR7 and TLR9 are also expressed in B cells. Such B cells have been suggested to have a possibility to induce not only the above autoimmune diseases but also allergic diseases due to the overreaction of the antibody-producing ability thereof. 
         [0019]    IgG, immunoglobulin G, is an antibody isotype consisting of four peptide chains-two identical heavy chains and two identical light chains. IgG is produced by B cells and plays a critical role for adaptive immunity. Naive B cells which do not produce IgG, differentiate into plasmablasts, and eventually into plasma cells. Plasmablasts and plasma cells can produce a large amount of antibodies. Conventionally, myeloid dendritic cells (DCs) have been shown to trigger B cell growth and differentiation by stimulating with IL-12 and IL-6 and/or membrane molecules such as BAFF/APRIL (Non Patent Literatures 5, 6 and 7). In addition, plasmacytoid DCs (pDCs) induce maturation and differentiation of naive B cells into antibody-secreting plasmablasts and plasma cells producing IFN-α and IL-6 (Non Patent Literature 8). The variable region of IgG captures various pathogens such as viruses, bacteria, and fungi, resulting in protection of the body from such infections. 
         [0020]    SLE is regarded as a classic immune complex-mediated autoimmune disease. Immune complexes (ICs) are formed in circulation or in situ as a result of produced auto-antibodies against nucleic acids and their associated proteins, such as dsDNA, ribonucleoprotein, and histone. Such ICs cause inflammation with disease-characteristic clinical symptoms such as nephritis, arthritis, skin rashes, and vasculitis. Blood from SLE patient is characterized by reduction of naive B cells and increased memory B cells, plasmablasts and plasma cells (Non Patent Literatures 9, 10 and 11). Therefore, suppression of differentiation into plasma cells and antibody production through manipulation of auto-reactive antibody-secreting plasmablasts would result in a promising strategy to cure autoimmune diseases. 
         [0021]    In PBMCs, there are various subsets of B cells, such as naive B cells, memory B cells, and plasmablasts. Most of B cell subset in PBMCs is naive B cells. Naive B cells are the one who are not exposed by foreign antigen. Memory B cells are the one who are formed by primary infection and are critical in quick antibody-mediated immune response by differentiation into plasmablasts. Plasmablasts are the one who secrete a large amount of antibody and marked by CD19+CD27+IgD-CD38+. 
         [0022]    Once exposed by foreign antigen, naive B cells become activated B cells. The activated B cells are further differentiated in to memory B cell and/or also plasmablasts that secrete antibodies. This change is called “maturation”. 
         [0023]    B cell maturation occurs in multiple phases. The initial, antigen-independent phase induces mature B cells that can bind to a unique antigen. This stage of maturation happens in the bone marrow and the spleen in living body. The antigen-dependent phase of B cell maturation happens following B cell activation by antigen binding and co-stimulation. These signals promote B cell maturation into either memory B cells or antibody-secreting plasmablasts. The antigen-dependent phase of B cell maturation involves activated B cell proliferation, antibody affinity maturation, and antibody class switching. Those maturations occur in the germinal centers of secondary lymphoid tissues. 
         [0024]    It has been reported that, in vitro experimental condition, pDCs induce the maturation of activated B cells into Ig-secreting plasmablasts through release of IFN-α and IL-6. CpG2216 activates pDCs to induce IFN-α production and B cells to initiate maturation. IFN-α from pDCs further supports maturation of activated B cells into plasmablasts in the presence of IL-6. 
       CITATION LIST 
     Patent Literature 
       [0000]    
       
         [PTL 1] PCT/JP2013/052781 
       
     
       Non Patent Literature 
       [0000]    
       
         [NPL 1] Tao et al., Nat. Methods 2(8), pp 591-598 (2005) 
         [NPL 2] Clark et al., Genome Res. 13(10), pp 2265-2270 (2003) 
         [NPL 3] Plos ONE www.plosone.org, November 2010, Volume 5, Issue 11, e13932 
         [NPL 4] ARTHRITIS &amp; RHEUMATISM Vol. 65, No. 2, February 2013, pp 472-480 
         [NPL 5] Balazs et al., 2002, Immunity, 17, 341-352 
         [NPL 6] Litinskiy et al., 2002, Nat Immunol, 3, 822-829 
         [NPL 7] MacLennan and Vinuesa, 2002, Immunity, 17, 235-238 
         [NPL 8] Jego et al, 2003, Immunity, 19, 225-234 
         [NPL 9] Odendahl et al., 2000, JI, 165, 5970-5979 
         [NPL. 10] Arce et al., 2001, JI, 167, 2361-2369 
         [NPL 11] Wei et al., 2007, JI, 178, 6624-6633 
       
     
       SUMMARY 
     Technical Problem 
       [0037]    A problem to be solved by the present invention is to regulate activated B cells using an antibody binding to PLD4 and to improve symptoms of diseases caused thereby. 
       Solution to Problem 
       [0038]    Through research on PLD4, the present inventors verified that in addition to pDC cells in a resting period which have been previously reported, PLD4 expression was also induced in activated B cells. The present inventors therefore examined influence of PLD4 antibodies on activated B cells. A method for producing and purifying anti-PLD4 antibodies is carried out by a method in Patent Literature 1. 
         [0039]    That is, the present invention relates to a second use using anti-PLD4 antibodies described below. 
         [0000]    (1) A pharmaceutical composition for suppressing activated B cells, wherein the pharmaceutical composition comprises a monoclonal antibody binding to a phospholipase D4 (PLD4) protein, or a fragment containing an antigen-binding region thereof as an active ingredient.
 
(2) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence SYWMH (SEQ ID NO: 2) as CDR1, a sequence DIYPGSDSTNYNEKFKS (SEQ ID NO: 3) as CDR2 and GGWLDAMDY (SEQ ID NO: 4) as a sequence CDR3 in a variable region of a heavy chain.
 
(3) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence RASQDISNYLN (SEQ ID NO: 5) as CDR1, a sequence YTSRLHS (SEQ ID NO: 6) as CDR2 and a sequence QQGNTLPW (SEQ ID NO: 7) as CDR3 in a variable region of a light chain.
 
(4) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has the sequence SYWMH as CDR1, the sequence DIYPGSDSTNYNEKFKS as CDR2 and the sequence GGWLDAMDY as CDR3 in the variable region of the heavy chain, and has the sequence RASQDISNYLN as CDR1, the sequence YTSRLH as CDR2 and the sequence QQGNTLPW as CDR3 in the variable region of the light chain.
 
(5) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence TYWMH (SEQ ID NO: 8) as CDR1, a sequence AIYPGNSETSYNQKFKG (SEQ ID NO: 9) as CDR2 and GYSDFDY (SEQ ID NO: 10) as a sequence CDR3 in the variable region of the heavy chain.
 
(6) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence HASQGIRSNIG (SEQ ID NO: 11) as CDR1, a sequence HGTNLED (SEQ ID NO: 12) as CDR2 and a sequence VQYVQFP (SEQ ID NO: 13) as CDR3 in the variable region of the light chain.
 
(7) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has the sequence TYWMH as CDR1, the sequence AIYPGNSETSYNQKFKG as CDR2 and the sequence GYSDFDY as CDR3 in the variable region of the heavy chain, and has the sequence HASQGIRSNIG as CDR1, the sequence HGTNLED as CDR2 and the sequence VQYVQFP as CDR3 in the variable region of the light chain.
 
(8) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence DYNLH (SEQ ID NO: 14) as CDR1, a sequence YIYPYNGNTGYNQKFKR (SEQ ID NO: 15) as CDR2 and GGIYDDYYDYAIDY (SEQ ID NO: 16) as a sequence CDR3 in the variable region of the heavy chain.
 
(9) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence RASENIYSHIA (SEQ ID NO: 17) as CDR1, a sequence GATNLAH (SEQ ID NO: 18) as CDR2 and a sequence QHFWGTP (SEQ ID NO: 19) as CDR3 in the variable region of the light chain.
 
(10) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has the sequence DYNLH as CDR1, the sequence YIYPYNGNTGYNQKFKR as CDR2 and the sequence GGIYDDYYDYAIDY as CDR3 in the variable region of the heavy chain, and has the sequence RASENIYSHIA as CDR1, the sequence GATNLAH as CDR2 and the sequence QHFWGTP as CDR3 in the variable region of the light chain.
 
(11) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence SYYLY (SEQ ID NO: 20) as CDR1, a sequence LINPTNSDTIFNEKFKS (SEQ ID NO: 21) as CDR2 and EGGYGYGPFAY (SEQ ID NO: 22) as a sequence CDR3 in the variable region of the heavy chain.
 
(12) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence TSSQTLVHSNGNTYLH (SEQ ID NO: 23) as CDR1, a sequence KVSNRFS (SEQ ID NO: 24) as CDR2 and a sequence HSTHVP (SEQ ID NO: 25) as CDR3 in the variable region of the light chain.
 
(13) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has the sequence SYYLY as CDR1, the sequence LINPTNSDTIFNEKFKS as CDR2 and the sequence EGGYGYGPFAY as CDR3 in the variable region of the heavy chain, and has the sequence TSSQTLVHSNGNTYLH as CDR1, the sequence KVSNRFS as CDR2 and the sequence HSTHVP as CDR3 in the variable region of the light chain.
 
(14) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence SYGMS (SEQ ID NO: 26) as CDR1, a sequence TISSGGSYIYYPESVKG (SEQ ID NO: 27) as CDR2 and LYGGRRGYGLDY (SEQ ID NO: 28) as a sequence CDR3 in the variable region of the heavy chain.
 
(15) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence RSSKSLLHSDGITYLY (SEQ ID NO: 29) as CDR1, a sequence QMSNLAS (SEQ ID NO: 30) as CDR2 and a sequence AQNLEL (SEQ ID NO: 31) as CDR3 in the variable region of the light chain.
 
(16) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has the sequence SYGMS as CDR1, the sequence TISSGGSYIYYPESVKG as CDR2 and the sequence LYGGRRGYGLDY as CDR3 in the variable region of the heavy chain, and has the sequence RSSKSLLHSDGITYLY as CDR1, the sequence QMSNLAS as CDR2 and the sequence AQNLEL as CDR3 in the variable region of the light chain.
 
(17) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence SHYYWT (SEQ ID NO: 32) as CDR1, a sequence YISYDGSNNYNPSLKN (SEQ ID NO: 33) as CDR2 and EGPLYYGNPYWYFDV (SEQ ID NO: 34) as a sequence CDR3 in the variable region of the heavy chain.
 
(18) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence RASQDIDNYLN (SEQ ID NO: 35) as CDR1, a sequence YTSRLHS (SEQ ID NO: 36) as CDR2 and a sequence QQFNTLP (SEQ ID NO: 37) as CDR3 in the variable region of the light chain.
 
(19) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has the sequence SHYYWT as CDR1, the sequence YISYDGSNNYNPSLKN as CDR2 and the sequence EGPLYYGNPYWYFDV as CDR3 in the variable region of the heavy chain, and has the sequence RASQDIDNYLN as CDR1, the sequence YTSRLHS as CDR2 and the sequence QQFNTLP as CDR3 in the variable region of the light chain.
 
(20) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence SHYYWS (SEQ ID NO: 38) as CDR1, a sequence YISYDGSNNYNPSLKN (SEQ ID NO: 39) as CDR2 and EGPLYYGNPYWYFDV (SEQ ID NO: 40) as a sequence CDR3 in the variable region of the heavy chain.
 
(21) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has a sequence RASQDIDNYLN (SEQ ID NO: 41) as CDR1, a sequence YTSRLHS (SEQ ID NO: 42) as CDR2 and a sequence QQFNTLP (SEQ ID NO: 43) as CDR3 in the variable region of the light chain.
 
(22) The pharmaceutical composition according to (1) above, wherein the monoclonal antibody or the fragment containing the antigen-binding region thereof has the sequence SHYYWS as CDR1, the sequence YISYDGSNNYNPSLKN as CDR2 and the sequence EGPLYYGNPYWYFDV as CDR3 in the variable region of the heavy chain, and has the sequence RASQDIDNYLN as CDR1, the sequence YTSRLHS as CDR2 and the sequence QQFNTLP as CDR3 in the variable region of the light chain.
 
(23) A pharmaceutical composition for suppressing activated B cells, wherein the pharmaceutical composition comprises a monoclonal antibody produced by any of hybridomas mp5B7, mp7B4, mp13D4 and mp13H11 of Deposit Nos. NITE BP-1211, NITE BP-1212, NITE BP-1213 and NITE BP-1214, or a fragment containing an antigen-binding region thereof as an active ingredient.
 
(24) The pharmaceutical composition according to any one of (1) to (23) above, further for preventing or treating autoimmune diseases.
 
(25) The pharmaceutical composition according to any one of (1) to (23) above, further for preventing or treating allergic diseases.
 
(26) A method for detecting activated B cells, the method including a step of bringing a monoclonal antibody binding to an extracellular domain of PLD4 or a fragment containing an antigen-binding region thereof into contact with cells to be tested and detecting the monoclonal antibody or the fragment containing the antigen-binding region thereof which binds to the cells.
 
(27) A reagent for detecting activated B cells, wherein the reagent comprises a monoclonal antibody binding to an extracellular domain of PLD4 or a fragment containing an antibody-binding region thereof.
 
(28) A method for suppressing activated B cells, the method including a step of bringing either of the following components into contact with activated B cells:
 
         [0040]    (a) a monoclonal antibody which binds to PLD4 and suppresses activated B cells, or a fragment containing an antigen-binding region thereof, and 
         [0041]    (b) immunoglobulin into which a 
         [0000]    complementarity-determining region of the monoclonal antibody in (a) is grafted, or a fragment containing an antigen-binding region thereof.
 
(29) A method for suppressing activated B cells in a living body, the method including a step of administering either of the following components to the living body:
 
         [0042]    (a) a monoclonal antibody which binds to PLD4 and suppresses an activity of activated B cells, or a fragment containing an antigen-binding region thereof, and 
         [0043]    (b) immunoglobulin into which a 
         [0000]    complementarity-determining region of the monoclonal antibody in (a) is grafted, or a fragment containing an antigen-binding region thereof.
 
(30) The method according to (28) above or (29) above, wherein the activity of the activated B cells is an antibody-producing activity.
 
(31) An agent for suppressing activated B cells, wherein the agent comprises either of the following components as an active component:
 
         [0044]    (a) a monoclonal antibody which binds to PLD4 and suppresses activated B cells, or a fragment containing an antigen-binding region thereof, and 
         [0045]    (b) immunoglobulin into which a 
         [0000]    complementarity-determining region of the monoclonal antibody in (a) is grafted, or a fragment containing an antigen-binding region thereof.
 
(32) The agent for suppressing activated B cells according to
 
(31) above, wherein an activity of the activated B cells is an antibody-producing activity.
 
         [0046]    The “activated B cells” may include B cells possessing the activity of proliferation and antibody production and secretion by not only direct stimulation through BCR and TLR but also stimulation through T cells. 
         [0047]    The “fragment containing an antigen-binding region” may include Fab, Fab′, F(ab′) 2  fragments and the like obtained by partial digestion with papain or pepsin, but is not limited thereto. In addition, the fragment containing an antigen-binding region also may include a fragment of immunoglobulin containing a variable region into which CDR (complementarily-determining region) of a monoclonal antibody is grafted. It is well known that these antibody fragments can be used as antibody molecules having binding affinity to antigens. Alternatively, insofar as required antigen-binding activity is maintained, antibodies constructed by gene recombination can be used. Examples of antibodies constructed by gene recombination can include chimeric antibodies, CDR-grafted antibodies, single chain Fv (scFv), diabody (diabodies), linear antibodies, and polyspecific antibodies formed from antibody fragments and the like. A method for obtaining these antibodies based on monoclonal antibodies or antibody-producing cells producing the monoclonal antibodies is known. 
         [0048]    The “autoimmune diseases” are diseases which are caused by attacks of immune functions by misunderstanding one&#39;s own body tissues as foreign substances. Organ-specific autoimmune diseases include Guillain-Barre syndrome, myasthenia gravis, chronic gastritis (chronic atrophic gastritis), autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune pancreatitis, aortitis syndrome, Goodpasture syndrome, rapidly progressive glomerulonephritis, megaloblastic anemia, autoimmune hemolytic anemia, autoimmune neutropenia, idiopathic thrombocytopenic purpura, Basedow disease, Hashimoto thyroiditis, primary hypothyroidism, idiopathic Addison&#39;s disease, type 1 diabetes, ulcerative colitis, Crohn&#39;s disease, celiac disease and the like; and systemic autoimmune diseases include articular rheumatism, systemic lupus erythematosus, anti-phospholipid antibody syndrome, polymyositis, scleroderma, Sjogren&#39;s syndrome, vasculitis syndrome, autoimmune lymphoproliferative syndrome (ALPS) and the like, but are not limited thereto. 
         [0049]    The “allergic diseases” are diseases caused by abnormal immune reactions against foreign substances, and include atopic dermatitis, bronchial asthma, pollinosis, allergic rhinitis, urticaria, infantile asthma, allergic gastroenteritis, contact dermatitis, serum sickness, vascular purpura and the like but are not limited thereto. 
       Advantageous Effects of Invention 
       [0050]    The present invention provides a therapeutic method attributable to suppression of activated B cells using an antibody specifically recognizing PLD4 and a fragment thereof, and a medicament having its therapeutic effect. 
         [0051]    The present invention can be further expected to have preventive and therapeutic effects on patients with autoimmune diseases or allergic diseases by using the activated B cell-suppressing activity. 
     
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         [0052]      FIG. 1  is a FACS analysis diagram which shows staining of human B cells (CD19+) with anti-PLD4 antibodies. PLD4 protein was induced on CD19+ B cells by stimulation with TLR9 ligand, CpG2006. Induction of PLD4 in activated B cells (CD19+) could be detected by a TLR9 ligand (CpG2006). Monoclonal antibodies 11G9.6 and 5B7 were used to detect PLD4. Mouse IgG2b, κ was used as a negative control. 
           [0053]      FIG. 2  is a FACS analysis diagram which shows staining of human PBMC with an anti-PLD4 antibody and an anti-CD19 antibody. PLD4+ cells were increased in activated B cells (CD19+) by stimulation with TLR9 ligand. Mouse IgG1, κ was used as a negative control. 
           [0054]      FIG. 3  is a FACS analysis diagram which shows staining of human PBMC with anti-PLD4 antibodies and an anti-CD19 antibody in the presence or absence of TLR9 ligand stimulation. A significant increase of PLD4+TLR9 ligand-stimulated B cells (CD19+) could be detected with anti-PLD4 antibodies (5B7, 13D4, 13H11 and 11G9.6). Mouse IgG2b, K was used as a negative control. 
           [0055]      FIG. 4  is a FACS analysis diagram which shows reduction of PLD4+ activated B cells by the indicated each anti-PLD4 chimeric antibody. Co-culture of PBMCs with the anti-PLD4 chimeric antibodies (ch3B4, ch13D4, ch13H11, ch5B7 and chG9.6) reduced PLD4+ activated B cells in the presence of TLR9 ligand. In a case in which an antibody was not added (NoAb) and a case in which a non-specific antibody was used (Control Ig), however, the activation of B cells by adding CpG2006 could not be suppressed. 
           [0056]      FIG. 5  is a diagram in which suppressive effect in  FIG. 4  is expressed in numbers. An activated B cell group which expresses PLD4 and was treated with control Ig is considered as 100% and changes in an activated B cell group which expresses PLD4 and was treated with each anti-PLD4 chimeric antibody are shown. 
           [0057]      FIG. 6  is a result of flow cytometry. PBMCs were cultured with the indicated chimeric PLD4 antibodies in the presence of TLR9 ligand and recombinant human IL-6. Plasmablast population (CD19+CD27+IgD-CD38+) was reduced by the treatment with ch3B4, ch5B7, ch13D4, ch13H11, or ch11G9.6 compared with control Ig treatment. 
           [0058]      FIG. 7  is a result of ELISA assay of the culture supernatant of  FIG. 6 . Human IgG production from plasmablasts was reduced by the treatment with ch3B4, ch5B7, ch13D4, ch13H11, or ch11G9.6 compared with control Ig treatment. 
       
    
    
     DESCRIPTION OF EMBODIMENTS 
       [0059]    The present inventors newly found that PLD4 was a molecule whose expression is induced with activation of B cells. 
         [0060]    The present inventors have previously reported expression, subcellular localization, structure and function of human PLD4 (Patent Literature 1). In the present invention, it further turned out that the expression of PLD4 is induced in not only pDC but also activated B cells. It was further newly found that anti-PLD4 antibodies suppressed activated B cells. Such findings not only strengthen a possibility that anti-PLD4 antibodies have a therapeutic effect on autoimmune diseases by suppression of pDC activity, which has been previously reported, but also B cell activity. 
         [0061]    Proteins such as CD19, CD20, CD22 and BAFF-R are expressed on the surface of B cells. CD19 is expressed on B cells from an early stage such as pro-B cells to antibody-secreting plasma cells, and functions as an auxiliary receptor controlling activation in mature B cells. CD20 is expressed from pre B cells to activated B cells, CD22 is expressed on the cell surface of mature B cells, and the expression of BAFF-R is observed in the extensive differentiation stage of B cells. Therefore, there is concern that antibodies recognizing these proteins suppress not only activated B cells but also unprimed naive B cells. The anti-PLD4 antibodies of the present invention are however characterized by suppressing activated B cells without influence on naive B cells. 
         [0062]    The anti-PLD4 antibodies used in the present invention are the same as those reported previously (Patent Literature 1). In short, using as an immunogen a recombinant PLD4-Ig fusion protein encoding an amino acid sequence containing an extracellular domain of PLD4 (the amino acid sequence corresponding to from position 54 to 50.6 in the amino acid sequence shown in SEQ ID NO: 1), an antibody against PLD4 was obtained as follows. 
       &lt;Creation of Anti-Human PLD4 Monoclonal Antibodies&gt; 
     1) Immunization 
       [0063]    As an immunogen, the above recombinant PLD4-Ig fusion protein was used. The PLD4-Ig fusion protein was administered to the dorsal hypodermis of three BALB/c mice. As adjuvants, Freund&#39;s Adjuvants, Complete and Incomplete (SIGMA), were used. The volume of first administration was 200 g/mouse, and the volume of second to fourth administration was 50 g/mouse. 
       2) Confirmation of Anti-Serum Titer 
       [0064]    Blood was collected after third and fourth immunization and anti-serum titer was evaluated by ELISA. 
         [0065]    The PLD4-Ig fusion protein was transformed into a solid phase on a 96 well microtiter plate. An antiserum was serially diluted in 3-fold increments from 1000-fold and a dilution series up to 729000-fold was prepared. To the antigen-coated plate, each 50 μl of each sample was added and a first-order reaction was carried out. After washing, a second-order reaction was carried out with the HRP-labeled anti-mouse IgG (κ, λ) antibody and color development was detected with OPD (orthophenylene diamine) (490 nm). 
       3) Cell Fusion 
       [0066]    Splenic cells were extracted from mice in which an increase in anti-serum titer was observed. The extracted splenic cells and mouse myeloma cells (P3U1) were fused by the PEG method and the fused splenic cells were selectively cultured in an HAT medium. 
       &lt;FACS Screening of Hybridomas Using CAL-1 Cells&gt; 
       [0067]    An antibody produced from each clone of the fused splenic cells obtained by HAT selective culture was evaluated by FACS. Consequently, 3B4, 5B7, 7B4, 8C11, 10C3, 11D10, 13D4, 13H11, 14C1 and 11G9.6 in hybridoma culture supernatant well reacted to human PLD4. 
         [0068]    In each monoclonal antibody produced from the above hybridomas, CDR regions (CDRs; CDR1, CDR2 and CDR3) and FW regions (Frame work regions) in a variable region and a sequence of the variable region were determined according to an analytical method of Kabat numbering system (Kabat et al, 1991, Sequences of Proteins of Immunological Interest, National Institutes of Health Publication No. 91-3242, 5th ed., United States Department of Health and Human Services, Bethesda, Md.) 
         [0069]    The nucleic acid sequence of the heavy chain variable region of the obtained mouse 11G9.6 antibody is SEQ ID NO: 74, and the amino acid sequence is SEQ ID NO: 75. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 11G9.6 antibody are SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, respectively. 
         [0070]    The nucleic acid sequence of the heavy chain variable region of the obtained mouse 3B4 antibody is SEQ ID NO: 76, and the amino acid sequence is SEQ ID NO: 77. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 3B4 antibody are SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, respectively. 
         [0071]    The nucleic acid sequence of the heavy chain variable region of the obtained mouse 5B7 antibody is SEQ ID NO: 78, and the amino acid sequence is SEQ ID NO: 79. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 5B7 antibody are SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, respectively. 
         [0072]    The nucleic acid sequence of the heavy chain variable region of the obtained mouse 7B4 antibody is SEQ ID NO: 80, and the amino acid sequence is SEQ ID NO: 81. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 7B4 antibody are SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, respectively. The 7B4 antibody is an antibody which has the same CDR sequences in the variable regions of the heavy and light chains as of the 5B7 antibody. 
         [0073]    The nucleic acid sequence of the heavy chain variable region of the obtained mouse 8C11 antibody is SEQ ID NO: 82, and the amino acid sequence is SEQ ID NO: 83. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 8C11 antibody are SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22, respectively. 
         [0074]    The nucleic acid sequence of the heavy chain variable region of the obtained mouse 10C3 antibody is SEQ ID NO: 84, and the amino acid sequence is SEQ ID NO: 85. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 10C3 antibody are SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, respectively. 
         [0075]    The nucleic acid sequence of the heavy chain variable region of the obtained mouse 11D10 antibody is SEQ ID NO: 86, and the amino acid sequence is SEQ ID NO: 87. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 11D10 antibody are SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, respectively. The 11D10 antibody is an antibody which has the same CDR sequences in the variable regions of the heavy and light chains as of the 10C3 antibody. Their heavy chain isotypes are, however, different (10C3 has the constant region of mouse IgG2a and 11D10 has the constant region of mouse IgG2b). 
         [0076]    The nucleic acid sequence of the heavy chain variable region of the obtained mouse 13D4 antibody is SEQ ID NO: 88, and the amino acid sequence is SEQ ID NO: 89. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 13D4 antibody are SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34, respectively. 
         [0077]    The nucleic acid sequence of the heavy chain variable region of the obtained mouse 13H11 antibody is SEQ ID NO: 90, and the amino acid sequence is SEQ ID NO: 91. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 13H11 antibody are SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, respectively. 
         [0078]    The nucleic acid sequence of the heavy chain variable region of the obtained mouse 14C1 antibody is SEQ ID NO: 92, and the amino acid sequence is SEQ ID NO: 93. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 14C1 antibody are SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, respectively. The 14C1 antibody is an antibody which has the same CDR sequences in the variable regions of the heavy and light chains as of the 13H11 antibody. Their heavy chain isotypes are, however, different (13H11 has the constant region of mouse IgG2b and 14C1 has the constant region of mouse IgG1). 
         [0079]    The nucleic acid sequence of the light chain variable region of the mouse 11G9.6 antibody is SEQ ID NO: 94, and the amino acid sequence is SEQ ID NO: 95. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 11G9.6 antibody are SEQ ID NO: 5, SEQ ID NO: 6 and SEQ ID NO: 7, respectively. 
         [0080]    The nucleic acid sequence of the light chain variable region of the mouse 3B4 antibody is SEQ ID NO: 96, and the amino acid sequence is SEQ ID NO: 97. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 3B4 antibody are SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, respectively. 
         [0081]    The nucleic acid sequence of the light chain variable region of the mouse 5B7 antibody is SEQ ID NO: 98, and the amino acid sequence is SEQ ID NO: 99. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 5B7 antibody are SEQ ID NO: 17, SEQ ID NO: 18 and SEQ ID NO: 19, respectively. 
         [0082]    The nucleic acid sequence of the light chain variable region of the mouse 7B4 antibody is SEQ ID NO: 100, and the amino acid sequence is SEQ ID NO: 101. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 7B4 antibody are SEQ ID NO: 17, SEQ ID NO: 18 and SEQ ID NO: 19, respectively. 
         [0083]    The nucleic acid sequence of the light chain variable region of the mouse 8C11 antibody is SEQ ID NO: 102, and the amino acid sequence is SEQ ID NO: 103. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 8C11 antibody are SEQ ID NO: 23, SEQ ID NO: 24 and SEQ ID NO: 25, respectively. 
         [0084]    The nucleic acid sequence of the light chain variable region of the mouse 10C3 antibody is SEQ ID NO: 104, and the amino acid sequence is SEQ ID NO: 105. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 10C3 antibody are SEQ ID NO: 29, SEQ ID NO: 30 and SEQ ID NO: 31, respectively. 
         [0085]    The nucleic acid sequence of the light chain variable region of the mouse 11D10 antibody is SEQ ID NO: 106, and the amino acid sequence is SEQ ID NO: 107. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 11D10 antibody are SEQ ID NO: 29, SEQ ID NO: 30 and SEQ ID NO: 31, respectively. 
         [0086]    The nucleic acid sequence of the light chain variable region of the mouse 13D4 antibody is SEQ ID NO: 108, and the amino acid sequence is SEQ ID NO: 109. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 13D4 antibody are SEQ ID NO: 35, SEQ ID NO: 36 and SEQ ID NO: 37, respectively. 
         [0087]    The nucleic acid sequence of the light chain variable region of the mouse 13H11 antibody is SEQ ID NO: 100, and the amino acid sequence is SEQ ID NO: 111. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 13H11 antibody are SEQ ID NO: 41, SEQ ID NO: 42 and SEQ ID NO: 43, respectively. 
         [0088]    The nucleic acid sequence of the light chain variable region of the mouse 14C1 antibody is SEQ ID NO: 112, and the amino acid sequence is SEQ ID NO: 113. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 14C1 antibody are SEQ ID NO: 41, SEQ ID NO: 42 and SEQ ID NO: 43, respectively. 
         [0089]    Examples of more preferred monoclonal antibodies in the present invention can include monoclonal antibodies produced by 
         [0090]    hybridomas mp5B7, mp7B4, mp13D4 and mp13H11. 
         [0091]    Hybridomas mp5B7, mp7B4, mp13D4 and mp13H11 were accepted by National Institute of Technology and Evaluation, International Patent Organism Depositary, 
         [0092]    under accession No. NITE ABP-1211, NITE ABP-1212, NITE ABP-1213 and NITE ABP-1214 
         [0000]    as of Jan. 27, 2012. The details specifying the deposition will be described as follows. 
       (1) Name and Address of Depositary Authority 
     Name: National Institute of Technology and Evaluation, Advanced Industrial Science and Technology, International Patent Organism Depositary 
     Address: 2-5-8 Kazusa Kamatari Kisarazu-shi, Chiba Ibaraki, 292-0818, Japan 
     (2) Deposit Date: Jan. 27, 2012 
       [0093]    (3) Deposit number NITE BP-1211 (hybridoma mp5B7) 
         [0094]    NITE BP-1212 (hybridoma mp7B4) 
         [0095]    NITE BP-1213 (hybridoma mp13D4) 
         [0096]    NITE BP-1214 (hybridoma mp13H11) 
         [0097]    In particular, more preferred antibodies are an antibody having a combination of 
         [0000]    the heavy chain CDR1: DYNLH, CDR2: YIYPYNGNTGYNQKFKR, and CDR3: GGIYDDYYDYAIDY, and
 
the light chain CDR1: RASENIYSHIA, CDR2: GATNLAH, and CDR3: QHFWGTP
 
as the sequences of CDRs constituting its variable regions;
 
an antibody having a combination of
 
the heavy chain CDR1: SHYYWT, CDR2: YISYDGSNNYNPSLKN, and CDR3: EGPLYYGNPYWYFDV, and
 
the light chain CDR1: RASQDIDNYLN, CDR2: YTSRLHS, and CDR3: QQFNTLP
 
as the sequences of CDRs constituting its variable regions; and
 
an antibody having a combination of
 
the heavy chain CDR1: SHYYWS, CDR2: YISYDGSNNYNPSLKN, and CDR3: EGPLYYGNPYWYFDV, and
 
the light chain CDR1: RASQDIDNYLN, CDR2: YTSRLHS, and CDR3: QQFNTLP,
 
as the sequences of CDRs constituting its variable regions.
 
         [0098]    A chimeric antibody or a humanized antibody recognizing PLD4 can be produced by genetic engineering using a polynucleotide encoding it. As described in Patent Document 1, for example, each active chimeric antibody (ch3B4Ab, ch5B7Ab, ch7B4Ab, ch8C11Ab, ch10C3Ab, ch11D10Ab, ch13D4Ab, ch13H11Ab, ch14C1Ab, ch11G9.6Ab etc.) can be easily produced using each CDR region of the above mouse monoclonal antibodies (3B4, 5B7, 7B4, 8C11, 10C3, 11D10, 13D4, 13H11, 14C1, 11G9.6 etc.) by those of skill in the art. 
         [0099]    The present inventors have verified that monoclonal antibodies against PLD4 have CDC (Complement Dependent Cytotoxicity) activity and ADCC (Antibody-dependent cellular cytotoxicity) activity against the PLD4-expressing cells. Therefore, the anti-PLD4 monoclonal antibodies according to the present invention have cytotoxicity action against PLD4-expressing cells. 
         [0100]    That is, the present invention relates to an agent for suppressing activated B cells, wherein the agent comprises an antibody binding to an extracellular domain of PLD4 as an active component. Alternatively, the present invention provides a method for suppressing antibody production, the method including a step of administering an antibody binding to an extracellular domain of PLD4. The present invention further relates to use of an antibody binding to an extracellular domain of PLD4 in production of a pharmaceutical composition for suppressing activated B cells. 
         [0101]    In the present invention, an antibody modified as needed can be used. According to the present invention, an antibody recognizing the extracellular domain of PLD4 has the activated B cell-suppressing action. That is, it has been believed that there is a possibility that an antibody itself have cytotoxicity action against activated B cells. The subclass of an antibody showing intense effector action is known. Alternatively, suppressive effect on activated B cells can be further increased by modifying an antibody with a cytotoxic agent. As the cytotoxic agents, the following substances can be mentioned. Toxins:  Pseudomonas  Endotoxin (PE), diphtheria toxin, lysine Radioisotopes: Tc99m, Sr89, I131, Y90 
         [0000]    Anticancer agents: calicheamicin, mitomycin, paclitaxel 
         [0102]    The toxins containing proteins can be bound to an antibody or a fragment thereof or the like by a bifunctional reagent. Alternatively, by conjugating a gene encoding an antibody with a gene encoding a toxin, a fusion protein of the two can be also obtained. A method for binding a radioisotope to an antibody is also known. A method for labeling an antibody with a radioisotope, for example, using a chelating agent is known. Further, an anticancer agent can be bound to an antibody, using glycan or a bifunctional reagent or the like. 
         [0103]    In the present invention, an antibody whose structure is artificially modified can be used as an active component. For example, various modification methods for improving the cytotoxicity action and stability of antibodies are known. 
         [0104]    Concretely, immunoglobulin in which the glycan of its heavy chain is modified is known (Shinkawa, T. et al. J. Biol. Chem. 278:3466-3473. 2003). By modification of glycan, the ADCC (Antibody Dependent Cell-mediated Cytotoxicity) activity of immunoglobulin was increased. 
         [0105]    In the present invention, one or more monoclonal antibodies can be used. For example, several types of monoclonal antibodies recognizing the extracellular domain of PLD4 can be combined and used for the present invention. 
         [0106]    As described below, it can be verified that anti-PLD4 antibodies have suppressive action on the acquired immune antibody-producing activity of activated B cells. B cells produce a large amount of antibodies by stimulation of a BCR ligand or a TLR ligand (preferably TLR4 ligand, TLR7 ligand or TLR9 ligand). An anti-PLD4 antibody is provided before and after stimulation of the above ligand on B cells or simultaneously with stimulation of the ligand, and using B cells for which an anti-PLD4 antibody is not provided as a control, ability to produce acquired immune antibodies derived from B cells is compared. The antibody-producing ability can be evaluated by measuring secretory immunoglobulin contained in a culture supernatant of B cells. As a result of the comparison, when the amount of the acquired immune antibody derived from B cells in the supernatant significantly declines by adding an anti-PLD4 antibody, it can be verified that the tested anti-PLD4 antibody has suppressive action on the antibody-producing ability of B cells. A method for measuring the antibodies is known. B cells are cells which produce hormonal immunity (secretory antibody) in a living body. Therefore, hormonal immunity can be adjusted by suppressing the antibody-producing ability of B cells. 
         [0107]    When an antibody recognizing the extracellular domain of PLD4 is administered to a host different from an organism species from which the antibody is derived, it is desired to process into a form which is difficult to be recognized as a foreign substance by such a host. By processing into molecules described below, for example, it can be difficult that immunoglobulin is recognized as a foreign substance. 
         [0108]    Techniques for processing immunoglobulin molecules as described below are known: 
         [0109]    a fragment containing an antigen-binding region which lacks a constant region (Monoclonal Antibodies: Principles and Practice. third edition, Academic Press Limited. 1995; Antibody Engineering, A Practical Approach, IRL PRESS, 1996); 
         [0110]    a chimeric antibody constituted of an antigen-binding region of a monoclonal antibody and a constant region of host immunoglobulin (Experimental manual for genetic expression, Kodansha Ltd. 1994 (edited by Isao Ishida and Tamie Ando)); and 
         [0111]    a CDR-substituted antibody in which a complementarity-determining region (CDR) in host immunoglobulin is substituted by the CDR of a monoclonal antibody (Experimental manual for genetic expression, Kodansha Ltd. 1994 (edited by Isao Ishida and Tamie Ando)). 
         [0112]    Alternatively, a variable region gene of human immunoglobulin can be also obtained by the phage display method (McCafferty J. et al., Nature 348:552-554, 1990; Kretzschmar T et. al., Curr Opin Biotechnol. 2002 December; 13(6):598-602.). In the phage display method, a gene encoding a variable region of human immunoglobulin is incorporated into a phage gene. Using various types of immunoglobulin genes as sources, a phage library can be also created. A phage expresses such a variable region as a fusion protein of a protein constructing the phage itself. The variable region expressed by the phage on the phage surface maintains binding activity to antigens. Therefore, by selecting a phage binding to an antigen or cells expressing the antigen or the like, a phage expressing a variable region having target binding activity can be screened from a phage library. Further, a gene encoding a variable region having target binding activity is maintained in the phage particle selected as above. That is, in the phage display method, using the binding activity of a variable region as an index, a gene encoding a variable region having target binding activity can be obtained. 
         [0113]    In the agent for suppressing B cell activity or the method for suppressing B cell activity according to the present invention, an antibody recognizing the extracellular domain of PLD4 or an antibody fragment containing at least the antigen-binding region thereof can be administered as a protein or a polynucleotide encoding it. In order to administer a polynucleotide, it is desired that a vector in which a polynucleotide encoding a target protein is arranged be used under control of a proper promoter so that the target protein can be expressed. In a vector, an enhancer and a terminator can be also arranged. Vectors which maintain the genes of heavy and light chains constituting immunoglobulin and in which an immunoglobulin molecule can be expressed are known. A vector in which immunoglobulin can be expressed can be administered by introduction into cells. For administration to a living body, a vector which can infect cells by administration to the living body can be directly administered. Alternatively, a vector is introduced into a lymphocyte separated from a living body and then the vector can be returned into the living body (ex vivo) 
         [0114]    In the agent for suppressing B cell activity or the method for suppressing B cell activity based on the present invention, the amount of monoclonal antibody to be administered to a living body is normally 0.5 mg to 10 mg, for example 1 mg to 50 mg, preferably 2 mg to 10 mg as immunoglobulin per kg of body weight. An interval of administration of an antibody to a living body can be properly adjusted in order that an effective concentration of immunoglobulin in the living body during treatment period can be maintained. Concretely, for example, an antibody can be administered at intervals of 1 to 2 weeks. Any administration route can be used. Those of skill in the art can properly select an effective administration route for treatment. Concretely, oral or parenteral administration can be mentioned. By an intravenous injection, an intramuscular injection, an intraperitoneal injection or a subcutaneous injection or the like, for example, an antibody can be systemically or locally administered. The formulations suitable for parenteral administration in the present invention include injections, suppositories, sprays and the like. In addition, when provided to cells, immunoglobulin is provided in a culture fluid in an amount of normally 1 μg/ml, preferably 10 μg/mL or more, more preferably 50 μg/mL or more, and further preferably 0.5 mg/mL or more. 
         [0115]    In the agent for suppressing B cell activity or the method for suppressing B cell activity based on the present invention, a monoclonal antibody can be administered to a living body by any method. A monoclonal antibody is normally combined with a pharmaceutically acceptable carrier. A monoclonal antibody can be combined with additives as needed, such as a thickener, a stabilizer, an antiseptic and a solubilizing agent. Such carriers or additives include lactose, a citric acid, a stearic acid, magnesium stearate, sucrose, starch, talc, gelatin, agar, plant oil, ethylene glycol and the like. The term “pharmaceutically acceptable” means to be approved by government authorities of various countries, or that its use for animals, mammals and, in particular, human is listed in pharmacopoeias of various countries or pharmacopoeias commonly acknowledged. The agent for suppressing B cell activity in the present invention can be also supplied in the form of freeze-drying powders or tablets at one or more doses. Further, sterilized water for injections, a physiological salt solution or a buffer solution, which are used for dissolution, can be combined with freeze-drying powders or tablets in order that the composition will obtain a desired concentration before administration. 
         [0116]    Further, for administration as a vector expressing immunoglobulin, a heavy chain and a light chain are cotransfected as different plasmids and each plasmid can be administered at 0.1 to 10 mg, for example 1 to 5 mg per kg of body weight. In addition, 1 to 5 g vectors/10 6  cells are used to introduce into cells in vitro. The present invention will be now described in more detail by way of examples. 
         [0117]    All of the related art literatures cited in the present description are incorporated by reference herein. 
         [0118]    The present invention will be now described in more detail by way of examples. It should be noted, however, that the present invention is not limited to the examples. 
       EXAMPLES 
     Example 1 
       [0119]    Human PBMC (1×10 7  cells/ml) was stimulated by CpG2006, a ligand of TLR9, (a final concentration of 1 LM) and incubated in a 24 well plate in a CO 2  incubator (37° C., 5% CO 2 ) for about 20 hours. In parallel, human PBMC (1×10 7  cells/ml) which was not stimulated was also cultured in a CO 2  incubator (37° C., 5% CO 2 ) for about 20 hours. 
         [0120]    Human PBMC was treated with FcR Blocking Reagent (Miltenyi), which was diluted 5-fold with FACS buffer (1% FBS/PBS), at 4° C. for 20 minutes. After washing, staining was carried out with 5B7, 11G9.6 or mouse IgG2b, κ, a primary antibody, (each 10 μg/ml) at 4° C. for 15 minutes. A secondary antibody and subsequent antibodies were diluted with FACS buffer so that FcR Blocking Reagent would be diluted 25-fold. PE-labeled anti-mouse Ig (BD), a secondary antibody, was diluted 100-fold and the solution was added thereto and mixed. Besides, to fractionate B cells on FACS, an APC-labeled anti-human CD 19 antibody (Biolegend) was diluted 30-fold with FACS buffer containing FcR Blocking Reagent and staining was carried out at 4° C. for 15 minutes. Using FACS Calibur (BD), data was incorporated. Living cells were gated on a dot plot of the X axis: FSC and the Y axis: SSC. Data was incorporated until the number of cells in the living cell gate became 100,000 counts. B cells: anti-marker molecule antibody-positive cells were gated. The gated cells were analyzed on the histogram with the X axis: PLD4, and the results of staining with mouse IgG2b, K were overlaid thereon. Consequently, anti-PLD4 antibodies were hardly bound to non-stimulated, but were selectively bound to activated B cells by stimulation with TLR9 ligand ( FIG. 1 ) This shows that PLD4 is expressed on activated B cells. 
       Example 2 
     Binding Test to B Cells by Each Monoclonal Antibody 
       [0121]    Human PBMC was stimulated with CpG2006 with a final concentration of 1 μM for about 20 hours. Cells were collected and treated with FcR Blocking Reagent at 4° C. for 20 minutes. After washing, staining was carried out with each 10 μg/ml of 3B4, 5B7, 13D4, 13H11, 11G9.6, mouse IgG1, K or mouse IgG2b, κ, a primary antibody, at 4° C. for 15 minutes. Staining was carried out with PE-labeled anti-mouse Ig, a secondary antibody, at 4° C. for 15 minutes. For gating of a B cell group, double staining was carried out with an APC-labeled anti-human CD19 antibody at 4° C. for 15 minutes. A living cell group on the dot plot of the X axis: FSC and the Y axis: SSC was analyzed by binding of anti-PLD4 antibody to CD19+ B cells ( FIG. 2  and  FIG. 3 ) Consequently, all of the tested anti-PLD4 monoclonal antibodies were bound to B cells stimulated by TLR9. That is, it was verified that by all anti-PLD4 monoclonal antibodies, expression of PLD4 was induced in B cells in an activation-dependent manner. 
       Example 3 
     Cytotoxic Activity of Anti-PLD4 Chimeric Antibodies Against Activated B Cells 
       [0122]    Frequency of PLD4+ activated B cells induced by stimulation with TLR9 ligand (1 μM) was used as an index. Human PBMC was cultured with CpG2006 and each anti-PLD4 chimeric antibody or control Ig for about 16 hours. As a medium, RPM11640 (SIGMA) was used (including 10% FBS (Equitech-bio), 5 ml of 200 mML-Glutamine (GIBCO), 5 ml of Pen-Strep (GIBCO), 5 ml of Sodium Pyruvate (GIBCO), and 0.5 ml of 50 mM 2-ME (SIGMA)). The cells were collected and treated with FcR Blocking Reagent at 4° C. for 20 minutes. After washing, the cells were further stained by 5B7 or 13D4, 3B4 or mouse IgG2b, K, a primary antibody, at 4° C. for 15 minutes (each 10 g/ml). A sample in which PBMC was treated with a chimeric 3B4 antibody (ch3B4), a chimeric 3D4 antibody (ch3D4), or a chimeric 13H11 antibody (ch13H11) was stained with 5B7, and a sample in which PBMC was treated with a chimeric 5B7 antibody (ch5B7) or a chimeric 11G9.6 antibody (ch11G9.6) was stained with 13D4. It has been verified that an anti-PLD4 antibody clone treated for ADCC and an anti-PLD4 antibody clone used for staining do not compete with each other. The binding of the anti-PLD4 was found by PE-labeled anti-mouse Ig, a secondary antibody, at 4° C. for 15 minutes. For gating of B cells, double staining was carried out with an APC-labeled anti-human CD19 antibody at 4° C. for 15 minutes ( FIG. 4 ). The population of PLD4+ activated B cells treated with each chimeric anti-PLD4 antibody was compared with that of PLD4+ activated B cells treated with the control antibody ( FIG. 5 ). Consequently, all of the chimeric anti-PLD4 antibodies reduced activated PLD4+ B cells compared to the treatment with control Ig (when a case of treating with control Ig was considered as 100%, ch3B4: 70.2%, ch13D4: 56.0%, ch13H11: 55.3%, ch5B7: 25.8%, ch11G9.6: 66.4%). 
       Example 4 
     Inhibitory Effects of the Chimeric Anti-PLD4 Antibodies Against Activated B Cells 
       [0123]    To determine the effect of anti-human PLD4 antibody on B cells maturation and Ig production through B cell activation, whole human PBMCs were treated with ch3B4, ch5B7, ch13D4, ch13H11, ch11G9.6, or control Ig for 24 h. Then, the PBMCs were further cultured in the presence of CpG2216 (1 μM) and recombinant human IL-6 to induce B cell activation, resulting in B cell maturation. In the result of culture of activated B cells for 7 days, Plasmablasts, CD19+CD27+IgD-CD38+, in the activated B cells was analyzed by flow cytometry with a PE-labeled anti-human CD19 antibody. In order to measure human IgG production, the cultured activated B cells were re-stimulated with 50 ng/ml of PMA (Phorbol myristate acetate) after washed with PBS 2 times. Two days later, human IgG production was measured in the culture supernatants by ELISA. Plasmablasts in the activated B cells were reduced by the treatment with ch3B4, ch5B7, ch13D4, ch13H11, or ch11G9.6 compared with control Ig treatment ( FIG. 6 ). Also, human IgG production was reduced by the treatment with ch3B4, ch5B7, ch13D4, ch13H11, or ch11G9.6 compared to control Ig treatment ( FIG. 7 ). These results indicated that the treatment with the chimeric anti-human PLD4 Abs reduced Ab-secreting activated human B cells. 
       INDUSTRIAL APPLICABILITY 
       [0124]    As shown in the above examples, anti-PLD4 antibodies recognize and suppress activated B cells. Therefore, the antibodies are useful for prevention and treatment of diseases involved in immune function (autoimmune diseases and allergic diseases). 
       &lt;Explanation of Sequence Information of Anti-PLD4 Monoclonal Antibodies According to the Present Invention&gt; 
     1. Anti-PLD4 Mouse 11G9.6 Antibody 
       [0125]    The nucleic acid sequence of the heavy chain variable region of the obtained anti-PLD4 mouse 11G9.6 antibody is SEQ ID NO: 74, and the amino acid sequence is SEQ ID NO: 75. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 11G9.6 antibody are SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, respectively. 
         [0126]    The nucleic acid sequence of the heavy chain variable region of the anti-PLD4 mouse 11G9.6 antibody (504 bp) [capital letters: mouse 11G9.6 VH variable region, small letters: mouse IgG2b heavy chain constant region](SEQ ID NO: 74) 
         [0000]    
       
         
               
             
           
               
                 ATGAGATCACAGTTCTCTATACAGTTACTGAGCACACAGAACCTCACCTT 
               
               
                   
               
               
                 GGGATGGAGCTGTATCATCCTCTTCTTGGTAGCAACAGCTACAGGTGTCC 
               
               
                   
               
               
                 ACTCCCAGGTCCAACTGCAGCAGCCTGGGGCTGAACTGGTGAAGCCTGGG 
               
               
                   
               
               
                 ACTTCAGTGAAAATGTCCTGCAAGGCTTCTGGCTACACCTTCACCAGCTA 
               
               
                   
               
               
                 CTGGATGCACTGGGTGAAGCAGAGGCCGGGACAAGGCCTTGAGTGGATTG 
               
               
                   
               
               
                 GAGATATTTATCCTGGTAGTGATAGTACTAACTACAATGAGAAGTTCAAG 
               
               
                   
               
               
                 AGCAAGGCCACACTGACTGTAGACACATCCTCCAGCACAGCCTACATGCA 
               
               
                   
               
               
                 ACTCAGCAGCCTGACATCTGAGGACTCTGCGGTCTATTACTGTGCAAGAG 
               
               
                   
               
               
                 GAGGGTGGTTGGATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACC 
               
               
                   
               
               
                 GTCTCCTCAgccaaaacaacacccccatcagtctatccactggcccctaa 
               
               
                   
               
               
                 gggc 
               
             
          
         
       
     
         [0127]    The amino acid sequence of the heavy chain variable region of the mouse 11G9.6 antibody (168 a. a.) [capital letters: mouse 11G9.6 VH variable region, small letters: mouse IgG2b heavy chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3) (SEQ ID NO: 75). 
         [0000]                      MRSQFSIQLLSTQNLTLGWSCIILFLVATATGVIIS QVQLQQPGAELVKP               GTSVKMSCKASGYTFT SYWMH WVKQRPGQGLEWIG DIYPGSDSTNYNEKF                   KS KATLTVDTSSSTAYMQLSSLTSEDSAVYYCAR GGWLDAMDY WGQGTSV               TVSSakttppsvyplapkg            
CDR1 in the heavy chain variable region of the 11G9.6 antibody (SEQ ID NO: 2)
 
CDR2 in the heavy chain variable region of the 11G9.6 antibody (SEQ ID NO: 3)
 
CDR3 in the heavy chain variable region of the 11G9.6 antibody (SEQ ID NO: 4)
 
         [0128]    The nucleic acid sequence of the light chain variable region of the obtained anti-PLD4 mouse 11G9.6 antibody is SEQ ID NO: 38, and the amino acid sequence is SEQ ID NO: 39. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 11G9.6 antibody are SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, respectively. 
         [0129]    The nucleic acid sequence of the light chain variable region of the anti-PLD4 mouse 11G9.6 antibody (421 bp) [capital letters: mouse 11G9.6 VL variable region, small letters: mouse Ig κ light chain constant region](SEQ ID NO: 94) 
         [0000]    
       
         
               
             
           
               
                 ATGATGTCCTCTGCTCAGTTCCTTGGTCTCCTGTTGCTCTGTTTTCAAGG 
               
               
                   
               
               
                 TACCAGATGTGATATCCAGATGACACAGACTACATCCTCCCTGTCTGCCT 
               
               
                   
               
               
                 CTCTGGGAGACAGAGTCACCATCAGTTGCAGGGCAAGTCAGGACATTAGC 
               
               
                   
               
               
                 AATTATTTAAACTGGTATCAGCAGAAACCAGATGGAACTGTTAAACTCCT 
               
               
                   
               
               
                 GATCTACTACACATCAAGATTACACTCAGGAGTCCCATCAAGGTTCAGTG 
               
               
                   
               
               
                 GCAGTGGGTCTGGAACAGATTATTCTCTCACCATTAGCAACCTGGAGCAA 
               
               
                   
               
               
                 GAAGATATTGCCACTTACTTTTGCCAACAGGGTAATACGCTTCCGTGGAC 
               
               
                   
               
               
                 GTTCGGTGGAGGCACCAAGCTGGAAATCAAAcgggctgatgctgcaccaa 
               
               
                   
               
               
                 ctgtatccatcaagggcgaat 
               
             
          
         
       
     
         [0130]    The amino acid sequence of the light chain variable region of the mouse 11G9.6 antibody (140 a. a.) [capital letters: mouse 11G9.6 VL variable region, small letters: mouse Ig κ light chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3) (SEQ ID NO: 95). 
         [0000]                      MMSSAQFLGLLLLCFQGTRC DIQMTQTTSSLSASLGDRVTISC RASQDIS                   NYLN WYQQKPDGTVKLLIY YTSRLHS GVPSRFSGSGSGTDYSLTISNLEQ               EDIATYFC QQGNTLPW TFGGGTKLEIKradaaptvsikge            
CDR1 in the light chain variable region of the 11G9.6 antibody (SEQ ID NO: 5)
 
CDR2 in the light chain variable region of the 11G9.6 antibody (SEQ ID NO: 6)
 
CDR3 in the light chain variable region of the 11G9.6 antibody (SEQ ID NO: 7)
 
       2. Anti-PLD4 Mouse 3B4 Antibody 
       [0131]    The nucleic acid sequence of the heavy chain variable region of the obtained anti-PLD4 mouse 3B4 antibody is SEQ ID NO: 76, and the amino acid sequence is SEQ ID NO: 77. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 3B4 antibody are SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, respectively. 
         [0132]    The nucleic acid sequence of the heavy chain variable region of the anti-PLD4 mouse 3B4 antibody (437 bp) [capital letters: mouse 3B4 VH variable region, small letters: mouse IgG1 heavy chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGGAATGTAACTGGATACTTCCTTTTATTCTGTCGGTAATTTCAGGGGT 
               
               
                   
               
               
                 CTCCTCAGAGGTTCAGCTCCAGCAGTCTGGGACTGTGCTGTCAAGGCCTG 
               
               
                   
               
               
                 GGGCTTCCGTGACGATGTCCTGCAAGGCTTCTGGCGACAGCTTTACCACC 
               
               
                   
               
               
                 TACTGGATGCACTGGGTAAAACAGAGGCCTGGACAGGGTCTAGAATGGAT 
               
               
                   
               
               
                 TGGTGCTATCTATCCTGGAAATAGTGAAACTAGCTACAACCAGAAGTTCA 
               
               
                   
               
               
                 AGGGCAAGGCCAAACTGACTGCAGTCACATCCGCCAGCACTGCCTATATG 
               
               
                   
               
               
                 GAGTTCACTAGCCTGACAAATGAGGACTCTGCGGTCTATTACTGTACGGG 
               
               
                   
               
               
                 GGGTTATTCCGACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCT 
               
               
                   
               
               
                 CCTCAgccaaaacgacacccccatctgtctatccact 
               
             
          
         
       
     
         [0133]    The amino acid sequence of the heavy chain variable region of the mouse 3B4 antibody (145 a. a.) [capital letters: mouse 3B4 VH variable region, small letters: mouse IgG1 heavy chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MECNWILPFILSVISGVSS EVQLQQSGTVLSRPGASVTMSCKASGDSFT T                   YWMH WVKQRPGQGLEWIG AIYPGNSETSYNQKFKG KAKLTAVTSASTAYM               EFTSLTNEDSAVYYCTG GYSDFDY WGQGTTLTVSSakttppsvyp            
CDR1 in the heavy chain variable region of the 3B4 antibody TYWMH
 
CDR2 in the heavy chain variable region of the 3B4 antibody AIYPGNSETSYNQKFKG
 
CDR3 in the heavy chain variable region of the 3B4 antibody GYSDFDY
 
         [0134]    The nucleic acid sequence of the light chain variable region of the obtained anti-PLD4 mouse 3B4 antibody is SEQ ID NO: 96, and the amino acid sequence is SEQ ID NO: 97. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 3B4 antibody are SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, respectively. 
         [0135]    The nucleic acid sequence of the light chain variable region of the anti-PLD4 mouse 3B4 antibody (459 bp) [capital letters: mouse 3B4 VL variable region, small letters: mouse Ig κ light chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGATGGTCCTTGCTCAGTTTCTTGCATTCTTGTTGCTTTGGTTTCCAGG 
               
               
                   
               
               
                 TGCAGGATGTGACATCCTGATGACCCAATCTCCATCCTCCATGTCTGTAT 
               
               
                   
               
               
                 CTCTGGGAGACACAGTCAGCATCACTTGCCATGCAAGTCAGGGCATTAGA 
               
               
                   
               
               
                 AGTAATATAGGGTGGTTGCAGCAGAAACCAGGGAAATCATTTAAGGGCCT 
               
               
                   
               
               
                 GATCTTTCATGGAACCAACTTGGAAGATGGAGTTCCATCAAGGTTCAGTG 
               
               
                   
               
               
                 GCAGAGGATCTGGAGCAGATTATTCTCTCACCATCAACAGCCTGGAATCT 
               
               
                   
               
               
                 GAAGATTTTGCAGACTATTACTGTGTACAGTATGTTCAGTTTCCTCCAAC 
               
               
                   
               
               
                 GTTCGGCTCGGGGACAAAGTTGGAAATAAGAcgggctgatgctgcaccaa 
               
               
                   
               
               
                 ctgtatccatcttcccaccatccagtgagcagttaacatctggaggtgcc 
               
               
                   
               
               
                 tcagtcgtg 
               
             
          
         
       
     
         [0136]    The amino acid sequence of the light chain variable region of the mouse 3B4 antibody (153 a. a.) [capital letters: mouse 3B4 VL variable region, small letters: mouse Ig κ light chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MMVLAQFLAFLLLWFPGAGC DILMTQSPSSMSVSLGDTVSITC HASQGIR                   SNIG WLQQKPGKSFKGLIF HGTNLED GVPSRFSGRGSGADYSLTINSLES               EDFADYYC VQYVQFP PTFGSGTKLEIRradaaptvsifppsseqltsgga               svv            
CDR1 in the light chain variable region of the 3B4 antibody HASQGIRSNIG
 
CDR2 in the light chain variable region of the 3B4 antibody HGTNLED
 
CDR3 in the light chain variable region of the 3B4 antibody VQYVQFP
 
       3. Anti-PLD4 Mouse 5B7 Antibody 
       [0137]    The nucleic acid sequence of the heavy chain variable region of the obtained anti-PLD4 mouse 5B7 antibody is SEQ ID NO: 78, and the amino acid sequence is SEQ ID NO: 79. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 5B7 antibody are SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, respectively. 
         [0138]    The nucleic acid sequence of the heavy chain variable region of the anti-PLD4 mouse 5B7 antibody (475 bp) [capital letters: mouse 5B7 VH variable region, small letters: mouse IgG2b heavy chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGGGATGGAGCTGGATCTTTCTCTTCCTCCTGTCAGGAACTGCAGGCGT 
               
               
                   
               
               
                 CCACTCTGAGGTCCAGCTTCAGCAGTCAGGACCTGAACTGGTGAAACCTG 
               
               
                   
               
               
                 GGGCCTCAGTGAAGATATCCTGCAAGGCTTCTGGATACACATTCACTGAC 
               
               
                   
               
               
                 TACAACTTGCACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGAT 
               
               
                   
               
               
                 TGGATATATTTATCCTTACAATGGTAATACTGGCTACAACCAGAAGTTCA 
               
               
                   
               
               
                 AGAGGAAGGCCACATTGACTGTAGACAATTCCTCCGGCACAGTCTACATG 
               
               
                   
               
               
                 GAGCTCCGCAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGCAAG 
               
               
                   
               
               
                 AGGAGGGATCTATGATGATTACTACGACTATGCTATCGACTATTGGGGTC 
               
               
                   
               
               
                 AAGGAACCTCAGTCACCGTCTCCTCAgccaaaacaacacccccatcagtc 
               
               
                   
               
               
                 tatccactggcccctaagggcgaat 
               
             
          
         
       
     
         [0139]    The amino acid sequence of the heavy chain variable region of the mouse 5B7 antibody (158 a. a.) [capital letters: mouse 5B7 VH variable region, small letters: mouse IgG2b heavy chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MGWSWIFLELLSGTAGVHS EVQLQQSGPELVKPGASVKISCKASGYTFT D                   YNLH WVKQSHGKSLEWIGY IYPYNGNTGYNQKFKR KATLTVDNSSGTVYM               ELRSLTSEDSAVYYCAR GGIYDDYYDYAIDY WGQGTSVTVSSakttppsv               yplapkge            
CDR1 in the heavy chain variable region of the 5B7 antibody DYNLH
 
CDR2 in the heavy chain variable region of the 5B7 antibody YIYPYNGNTGYNQKFKR
 
CDR3 in the heavy chain variable region of the 5B7 antibody GGIYDDYYDYAIDY
 
         [0140]    The nucleic acid sequence of the light chain variable region of the obtained anti-PLD4 mouse 5B7 antibody is SEQ ID NO: 98, and the amino acid sequence is SEQ ID NO: 99. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 5B7 antibody are SEQ ID NO: 17, SEQ ID NO: 18 and SEQ ID NO: 19, respectively. 
         [0141]    The nucleic acid sequence of the light chain variable region of the anti-PLD4 mouse 5B7 antibody (467 bp) [capital letters: mouse 5B7 VL variable region, small letters: mouse Ig κ light chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGAGTGTGCCCACTCAGGTCCTGGGGTTGCTGCTGCTGTGGCTTACAGA 
               
               
                   
               
               
                 TGCCAGATGTGACATCCAGATGACTCAGTCTCCAGCCTCCCTATCTGTAT 
               
               
                   
               
               
                 CTGTGGGAGAAACTGTCGCCATCACATGTCGAGCAAGTGAGAATATTTAC 
               
               
                   
               
               
                 AGTCATATAGCATGGTATCAGCAGAAAGAGGGAAAATCTCCTCAGCGCCT 
               
               
                   
               
               
                 GGTCTATGGTGCAACAAACTTAGCACATGGTGTGCCATCAAGGTTCAGTG 
               
               
                   
               
               
                 GCAGTGGATCAGGCACACAGTATTCCCTCAAGATCAACAGCCTTCAGTCT 
               
               
                   
               
               
                 GAAGATTTTGGGAGTTATTACTGTCAACATTTTTGGGGTACTCCGTGGAC 
               
               
                   
               
               
                 GTTCGGTGGAGGCACCAAGCTGGAAATCAAAcgggctgatgctgcaccaa 
               
               
                   
               
               
                 ctgtatccatcttcccaccatccagtgagcagttaacatctggaggtgcc 
               
               
                   
               
               
                 tcagtcgtgtgcttctt 
               
             
          
         
       
     
         [0142]    The amino acid sequence of the light chain variable region of the mouse 5B7 antibody (155 a. a.) [capital letters: mouse 5B7 VL variable region, small letters: mouse Ig κ light chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MSVPTQVLGLLLLWLTDARC DIQMTQSPASLSVSVGETVAITC RASENIY                   SHIA WYQQKEGKSPQRLVY GATNLAH GVPSRESGSGSGTQYSLKINSLQS               EDEGSYYC QHFWGTP WTEGGGTKLEIKradaaptvsifppsseqltsgga               svvef            
CDR1 in the light chain variable region of the 5B7 antibody RASENIYSHIA
 
CDR2 in the light chain variable region of the 5B7 antibody GATNLAH
 
CDR3 in the light chain variable region of the 5B7 antibody QHFWGTP
 
       4. Anti-PLD4 Mouse 7B4 Antibody 
       [0143]    The nucleic acid sequence of the heavy chain variable region of the obtained anti-PLD4 mouse 7B4 antibody is SEQ ID NO: 80, and the amino acid sequence is SEQ ID NO: 81. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 7B4 antibody are SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, respectively. 
         [0144]    The nucleic acid sequence of the heavy chain variable region of the anti-PLD4 mouse 7B4 antibody (470 bp) [capital letters: mouse 7B4 VH variable region, small letters: mouse IgG2b heavy chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGGGATGGAGCTGGATCTTTCTCTTCCTCCTGTCAGGAACTGCAGGCGT 
               
               
                   
               
               
                 CCACTCTGAGGTCCAGCTTCAGCAGTCAGGACCTGAACTGGTGAAACCTG 
               
               
                   
               
               
                 GGGCCTCAGTGAAGATATCCTGCAAGGCTTCTGGATACACATTCACTGAC 
               
               
                   
               
               
                 TACAACTTGCACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGAT 
               
               
                   
               
               
                 TGGATATATTTATCCTTACAATGGTAATACTGGCTACAACCAGAAGTTCA 
               
               
                   
               
               
                 AGAGGAAGGCCACATTGACTGTAGACAATTCCTCCGGCACAGTCTACATG 
               
               
                   
               
               
                 GAGCTCCGCAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGCAAG 
               
               
                   
               
               
                 AGGAGGGATCTATGATGATTACTACGACTATGCTATCGACTATTGGGGTC 
               
               
                   
               
               
                 AAGGAACCTCAGTCACCGTCTCCTCAgccaaaacaacacccccatcagtc 
               
               
                   
               
               
                 tatccactggcccctaaggg 
               
             
          
         
       
     
         [0145]    The amino acid sequence of the heavy chain variable region of the mouse 7B4 antibody (156 a. a.) [capital letters: mouse 7B4 VH variable region, small letters: mouse IgG2b heavy chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MGWSWIFLFLLSGTAGVHS EVQLQQSGPELVKPGASVKISCKASGYTFT D                   YNLH WVKQSHGKSLEWIG YIYPYNGNTGYNQKFKR KATLTVDNSSGTVYM               ELRSLTSEDSAVYYCAR GGIYDDYYDYAIDY WGQGTSVTVSSakttppsv               yplapk            
CDR1 in the heavy chain variable region of the 7B4 antibody DYNLH
 
CDR2 in the heavy chain variable region of the 7B4 antibody YIYPYNGNTGYNQKFKR
 
CDR3 in the heavy chain variable region of the 7B4 antibody GGIYDDYYDYAIDY
 
         [0146]    The nucleic acid sequence of the light chain variable region of the obtained anti-PLD4 mouse 7B4 antibody is SEQ ID NO: 100, and the amino acid sequence is SEQ ID NO: 101. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 7B4 antibody are SEQ ID NO: 17, SEQ ID NO: 18 and SEQ ID NO: 19, respectively. 
         [0147]    The nucleic acid sequence of the light chain variable region of the anti-PLD4 mouse 7B4 antibody (454 bp) [capital letters: mouse 7B4 VL variable region, small letters: mouse Ig κ light chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGAGTGTGCCCACTCAGGTCCTGGGGTTGCTGCTGCTGTGGCTTACAGA 
               
               
                   
               
               
                 TGCCAGATGTGACATCCAGATGACTCAGTCTCCAGCCTCCCTATCTGTAT 
               
               
                   
               
               
                 CTGTGGGAGAAACTGTCGCCATCACATGTCGAGCAAGTGAGAATATTTAC 
               
               
                   
               
               
                 AGTCATATAGCATGGTATCAGCAGAAAGAGGGAAAATCTCCTCAGCGCCT 
               
               
                   
               
               
                 GGTCTATGGTGCAACAAACTTAGCACATGGTGTGCCATCAAGGTTCAGTG 
               
               
                   
               
               
                 GCAGTGGATCAGGCACACAGTATTCCCTCAAGATCAACAGCCTTCAGTCT 
               
               
                   
               
               
                 GAAGATTTTGGGAGTTATTACTGTCAACATTTTTGGGGTACTCCGTGGAC 
               
               
                   
               
               
                 GTTCGGTGGAGGCACCAAGCTGGAAATCAAAcgggctgatgctgcaccaa 
               
               
                   
               
               
                 ctgtatccatcttcccaccatccagtgagcagttaacatctggaggtgcc 
               
               
                   
               
               
                 tcag 
               
             
          
         
       
     
         [0148]    The amino acid sequence of the light chain variable region of the mouse 7B4 antibody (151 a. a.) [capital letters: mouse 7B4 VL variable region, small letters: mouse Ig κ light chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MSVPTQVLGLLLLWLTDARC DIQMTQSPASLSVSVGETVAITC RASENIY                   SHIA WYQQKEGKSPQRLVY GATNLAH GVPSRFSGSGSGTQYSLKINSLQS               EDFGSYYC QHFWGTP WTFGGGTKLEIKradaaptvsifppsseqltsgga               s            
CDR1 in the light chain variable region of the 7B4 antibody RASENIYSHIA
 
CDR2 in the light chain variable region of the 7B4 antibody GATNLAH
 
CDR3 in the light chain variable region of the 7B4 antibody QHFWGTP
 
       5. Anti-PLD4 Mouse 8C11 Antibody 
       [0149]    The nucleic acid sequence of the heavy chain variable region of the obtained anti-PLD4 mouse 8C11 antibody is SEQ ID NO: 82, and the amino acid sequence is SEQ ID NO: 83. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 8C11 antibody are SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22, respectively. 
         [0150]    The nucleic acid sequence of the heavy chain variable region of the anti-PLD4 mouse 8C11 antibody (462 bp) [capital letters: mouse 8C11 VH variable region, small letters: mouse IgG2b heavy chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGGGATGGAGCTATATCATCCTCTTTTTGGTAGCAACAGCAACAGGGGT 
               
               
                   
               
               
                 CCACTCCCAGGTCCAACTGCAGCAGTCGGGGGCTGAACTGGTGAAGCCTG 
               
               
                   
               
               
                 GGGCTTCAGTGAAGTTGTCCTGCAAGGCTTCTGGCTACACCTTCACCAGC 
               
               
                   
               
               
                 TACTATTTGTACTGGGTGAGGCAGAGGCCTGGACAAGGCCTTGAGTGGAT 
               
               
                   
               
               
                 TGGACTGATTAATCCTACCAATAGTGATACTATCTTCAATGAGAAGTTCA 
               
               
                   
               
               
                 AGAGCAAGGCCACACTGACTGTAGACAAATCCTCCAGCACAGCATACATG 
               
               
                   
               
               
                 CAACTCAGCAGCCTGACATCTGAGGACTCTGCGGTCTATTACTGTACACG 
               
               
                   
               
               
                 AGAGGGGGGATATGGTTACGGCCCGTTTGCTTACTGGGGCCAAGGGACTC 
               
               
                   
               
               
                 TGGTCACTGTCTCTGCAgccaaaacaacacccccatcagtctatccactg 
               
               
                   
               
               
                 gcccctaagggc 
               
             
          
         
       
     
         [0151]    The amino acid sequence of the heavy chain variable region of the mouse 8C11 antibody (154 a. a.) [capital letters: mouse 8C11 VH variable region, small letters: mouse IgG2b heavy chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MGWSYIILFLVATATGVHS QVQLQQSGAELVKPGASVKLSCKASGYTFT S                   YYLY WVRQRPGQGLEWIG LINPTNSDTIFNEKFKS KATLTVDKSSSTAYM               QLSSLTSEDSAVYYCTR EGGYGYGPFAY WGQGTLVTVSAakttppsvypl               apkg            
CDR1 in the heavy chain variable region of the 8C11 antibody SYYLY
 
CDR2 in the heavy chain variable region of the 8C11 antibody LINPTNSDTIFNEKFKS
 
CDR3 in the heavy chain variable region of the 8C11 antibody EGGYGYGPFAY
 
         [0152]    The nucleic acid sequence of the light chain variable region of the obtained anti-PLD4 mouse 8C11 antibody is SEQ ID NO: 102, and the amino acid sequence is SEQ ID NO: 103. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 8C11 antibody are SEQ ID NO: 23, SEQ ID NO: 24 and SEQ ID NO: 25, respectively. 
         [0153]    The nucleic acid sequence of the light chain variable region of the anti-PLD4 mouse 8C11 antibody (457 bp) [capital letters: mouse 8C11 VL variable region, small letters: mouse Ig κ light chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGAAGTTGCCTGTTAGGCTGTTGGTGCTGATGTTCTGGATTCCTGCTTC 
               
               
                   
               
               
                 CAGCAGTGATGTTGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTC 
               
               
                   
               
               
                 TTGGAGATCAAGCCTCCATCTCTTGCACATCTAGTCAGACCCTTGTACAC 
               
               
                   
               
               
                 AGTAATGGAAACACCTATTTACATTGGTACCTGCAGAAGCCAGGCCAGTC 
               
               
                   
               
               
                 TCCAAAGCTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAG 
               
               
                   
               
               
                 ACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGC 
               
               
                   
               
               
                 AGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCACAGTACACA 
               
               
                   
               
               
                 TGTTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAAcgggctg 
               
               
                   
               
               
                 atgctgcaccaactgtatccatcttcccaccatccagtgagcagttaaca 
               
               
                   
               
               
                 tctggag 
               
             
          
         
       
     
         [0154]    The amino acid sequence of the light chain variable region of the mouse 8C11 antibody (152 a. a.) [capital letters: mouse 8C11 VL variable region, small letters: mouse Ig κ light chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MKLPVRLLVLMFWIPASSS DVVMTQTPLSLPVSLGDQASISC TSSQTLVH                   SNGNTYLH WYLQKPGQSPKLLIY KVSNRFS GVPDRFSGSGSGTDFTLKIS               RVEAEDLGVYFCS HSTHVP FTFGSGTKLEIKradaaptvsifppsseqlt               sg            
CDR1 in the light chain variable region of the 8C11 antibody TSSQTLVHSNGNTYLH
 
CDR2 in the light chain variable region of the 8C11 antibody KVSNRFS
 
CDR3 in the light chain variable region of the 8C11 antibody HSTHVP
 
       6. Anti-PLD4 Mouse 10C3 Antibody 
       [0155]    The nucleic acid sequence of the heavy chain variable region of the obtained anti-PLD4 mouse 10C3 antibody is SEQ ID NO: 84, and the amino acid sequence is SEQ ID NO: 85. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 10C3 antibody are SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, respectively. 
         [0156]    The nucleic acid sequence of the heavy chain variable region of the anti-PLD4 mouse 10C3 antibody (450 bp) [capital letters: mouse 10C3 VH variable region, small letters: mouse IgG2a heavy chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGAACTTCGGGCTCAGCTTGATTTTCCTTGCCCTCATTTTAAAAGGTGT 
               
               
                   
               
               
                 CCAGTGTGAGGTGCAGCTGGTGGAGTCTGGGGGAGACTTAGTGAGGCCTG 
               
               
                   
               
               
                 GAGGGTCCCTGAAACTCTCCTGTGCAGCCTCTGGATTCAGTTTCAGTAGC 
               
               
                   
               
               
                 TATGGCATGTCTTGGTTTCGCCAGACTCCAGACAAGAGGCTGGAGTGGGT 
               
               
                   
               
               
                 CGCAACCATTAGTAGTGGTGGTAGTTACATCTACTATCCAGAAAGTGTGA 
               
               
                   
               
               
                 AGGGGCGATTCACCATCTCCAGAGACAATGCCAGGAACATCCTGTACCTG 
               
               
                   
               
               
                 CAAATGAGCAGTCTGAAGTCTGAGGACACAGCCATGTATTATTGTGTAAG 
               
               
                   
               
               
                 ACTCTACGGTGGTAGGAGAGGCTATGGTTTGGACTACTGGGGTCAAGGAA 
               
               
                   
               
               
                 CCTCAGTCACCGTCTCCTCAgccaaaacaacagccccatcggtctatcca 
               
             
          
         
       
     
         [0157]    The amino acid sequence of the heavy chain variable region of the mouse 10C3 antibody (150 a. a.) [capital letters: mouse 10C3 VH variable region, small letters: mouse IgG2a heavy chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MNFGLSLIFLALILKGVQC EVQLVESGGDLVRPGGSLKLSCAASGFSFS S                   YGMS WFRQTPDKRLEWVA TISSGGSYIYYPESVKG RFTISRDNARNILYL               QMSSLKSEDTAMYYCVR LYGGRRGYGLDY WGQGTSVTVSSakttapsvyp            
CDR1 in the heavy chain variable region of the 10C3 antibody SYGMS
 
CDR2 in the heavy chain variable region of the 10C3 antibody TISSGGSYIYYPESVKG
 
CDR3 in the heavy chain variable region of the 10C3 antibody LYGGRRGYGLDY
 
         [0158]    The nucleic acid sequence of the light chain variable region of the obtained anti-PLD4 mouse 10C3 antibody is SEQ ID NO: 104, and the amino acid sequence is SEQ ID NO: 105. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 10C3 antibody are SEQ ID NO: 29, SEQ ID NO: 30 and SEQ ID NO: 31, respectively. 
         [0159]    The nucleic acid sequence of the light chain variable region of the anti-PLD4 mouse 10C3 antibody (423 bp) [capital letters: mouse 10C3 VL variable region, small letters: mouse Ig κ light chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGAGGTTCTCTGCTCAGCTTCTGGGGCTGCTTGTGCTCTGGATCCCTGG 
               
               
                   
               
               
                 ATCCACTGCGGAAATTGTGATGACGCAGGCTGCATTCTCCAATCCAGTCA 
               
               
                   
               
               
                 CTCTTGGAACATCAGCTTCCATCTCCTGCAGGTCTAGTAAGAGTCTCCTA 
               
               
                   
               
               
                 CATAGTGATGGCATCACTTATTTGTATTGGTATCTGCAGAAGCCAGGCCA 
               
               
                   
               
               
                 GTCTCCTCAGCTCCTGATTTATCAGATGTCCAACCTTGCCTCAGGAGTCC 
               
               
                   
               
               
                 CAGACAGGTTCAGTAGCAGTGGGTCAGGAACTGATTTCACACTGAGAATC 
               
               
                   
               
               
                 AGCAGAGTGGAGGCTGAGGATGTGGGTGTTTATTACTGTGCTCAAAATCT 
               
               
                   
               
               
                 AGAACTTTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAAcgggctg 
               
               
                   
               
               
                 atgctgcaccaactgtatccatc 
               
             
          
         
       
     
         [0160]    The amino acid sequence of the light chain variable region of the mouse 10C3 antibody (141 a. a.) [capital letters: mouse 10C3 VL variable region, small letters: mouse Ig κ light chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MRFSAQLLGLLVLWIPGSTA EIVMTQAAFSNPVTLGTSASISC RSSKSLL                   HSDGITYLY WYLQKPGQSPQLLIY QMSNLAS GVPDRFSSSGSGTDFTLRI               SRVEAEDVGVYYC AQNLEL YTFGGGTKLEIKradaaptvsi            
CDR1 in the light chain variable region of the 10C3 antibody RSSKSLLHSDGITYLY
 
CDR2 in the light chain variable region of the 10C3 antibody QMSNLAS
 
CDR3 in the light chain variable region of the 10C3 antibody AQNLEL
 
       7. Anti-PLD4 Mouse 11D10 Antibody 
       [0161]    The nucleic acid sequence of the heavy chain variable region of the obtained anti-PLD4 mouse 11D10 antibody is SEQ ID NO: 86, and the amino acid sequence is SEQ ID NO: 87. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 11D10 antibody are SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, respectively. 
         [0162]    The nucleic acid sequence of the heavy chain variable region of the anti-PLD4 mouse 11D10 antibody (450 bp) [capital letters: mouse 11D10 VH variable region, small letters: mouse 0.59 IgG2b heavy chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGAACTTCGGGCTCAGCTTGATTTTCCTTGCCCTCATTTTAAAAGGTGT 
               
               
                   
               
               
                 CCAGTGTGAGGTGCAGCTGGTGGAGTCTGGGGGAGACTTAGTGAGGCCTG 
               
               
                   
               
               
                 GAGGGTCCCTGAAACTCTCCTGTGCAGCCTCTGGATTCAGTTTCAGTAGC 
               
               
                   
               
               
                 TATGGCATGTCTTGGTTTCGCCAGACTCCAGACAAGAGGCTGGAGTGGGT 
               
               
                   
               
               
                 CGCAACCATTAGTAGTGGTGGTAGTTACATCTACTATCCAGAAAGTGTGA 
               
               
                   
               
               
                 AGGGGCGATTCACCATCTCCAGAGACAATGCCAGGAACATCCTGTACCTG 
               
               
                   
               
               
                 CAAATGAGCAGTCTGAAGTCTGAGGACACAGCCATGTATTATTGTGTAAG 
               
               
                   
               
               
                 ACTCTACGGTGGTAGGAGAGGCTATGGTTTGGACTACTGGGGTCAAGGAA 
               
               
                   
               
               
                 CCTCAGTCACCGTCTCCTCAgccaaaacaacacccccatcagtctatcca 
               
             
          
         
       
     
         [0163]    The amino acid sequence of the heavy chain variable region of the mouse 11D10 antibody (150 a. a.) [capital letters: mouse 11D10 VH variable region, small letters: mouse IgG2b heavy chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                    MNFGLSLIFLALILKGVQCEVQLVESGGDLVRPGGSLKLSCAASGFSFS S                   YGMS WFRQTPDKRLEWVA TISSGGSYTYYPESVKG RFTISRDNARNILYL               QMSSLKSEDTAMYYCVR LYGGRRGYGLDY WGQGTSVTVSS               akttppsvyp            
CDR1 in the heavy chain variable region of the 11D10 antibody SYGMS
 
CDR2 in the heavy chain variable region of the 11D10 antibody TISSGGSYIYYPESVKG
 
CDR3 in the heavy chain variable region of the 11D10 antibody LYGGRRGYGLDY
 
         [0164]    The nucleic acid sequence of the light chain variable region of the obtained anti-PLD4 mouse 11D10 antibody is SEQ ID NO: 106, and the amino acid sequence is SEQ ID NO: 107. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 11D10 antibody are SEQ ID NO: 29, SEQ ID NO: 30 and SEQ ID NO: 31, respectively. 
         [0165]    The nucleic acid sequence of the light chain variable region of the anti-PLD4 mouse 11D10 antibody (423 bp) [capital letters: mouse 11D10 VL variable region, small letters: mouse Ig κ light chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGAGGTTCTCTGCTCAGCTTCTGGGGCTGCTTGTGCTCTGGATCCCTGG 
               
               
                   
               
               
                 ATCCACTGCGGAAATTGTGATGACGCAGGCTGCATTCTCCAATCCAGTCA 
               
               
                   
               
               
                 CTCTTGGAACATCAGCTTCCATCTCCTGCAGGTCTAGTAAGAGTCTCCTA 
               
               
                   
               
               
                 CATAGTGATGGCATCACTTATTTGTATTGGTATCTGCAGAAGCCAGGCCA 
               
               
                   
               
               
                 GTCTCCTCAGCTCCTGATTTATCAGATGTCCAACCTTGCCTCAGGAGTCC 
               
               
                   
               
               
                 CAGACAGGTTCAGTAGCAGTGGGTCAGGAACTGATTTCACACTGAGAATC 
               
               
                   
               
               
                 AGCAGAGTGGAGGCTGAGGATGTGGGTGTTTATTACTGTGCTCAAAATCT 
               
               
                   
               
               
                 AGAACTTTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAAcgggctg 
               
               
                   
               
               
                 atgctgcaccaactgtatccatc 
               
             
          
         
       
     
         [0166]    The amino acid sequence of the light chain variable region of the mouse 11D10 antibody (141 a. a.) [capital letters: mouse 11D10 VL variable region, small letters: mouse Ig κ light chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MRFSAQLLGLLVLWIPGSTA EIVMTQAAFSNPVTLGTSASISC RSSKSLL                   IISDGITYLY WYLQKPGQSPQLLIY QMSNLAS GVPDRFSSSGSGTDFTLR               ISRVEAEDVGVYYC AQNLEL YTFGGGTKLEIKradaaptvsi            
CDR1 in the light chain variable region of the 11D10 antibody RSSKSLLHSDGITYLY
 
CDR2 in the light chain variable region of the 11D10 antibody QMSNLAS
 
CDR3 in the light chain variable region of the 11D10 antibody AQNLEL
 
       8. Anti-PLD4 Mouse 13D4 Antibody 
       [0167]    The nucleic acid sequence of the heavy chain variable region of the obtained anti-PLD4 mouse 13D4 antibody is SEQ ID NO: 88, and the amino acid sequence is SEQ ID NO: 89. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 13D4 antibody are SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34, respectively. 
         [0168]    The nucleic acid sequence of the heavy chain variable region of the anti-PLD4 mouse 13D4 antibody (472 bp) [capital letters: mouse 13D4 VH variable region, small letters: mouse IgG2b heavy chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGAAAGTGTTGAGTCTGTTGTACCTGTTGACAGCCATTCCTGGTATCCT 
               
               
                   
               
               
                 GTCTGATGTACAGCTTCAGGAGTCAGGACCTGGCCTCGTGAAACCTTCTC 
               
               
                   
               
               
                 AATCTCTGTCTCTCACCTGCTCTGTCACTGGCTACTCCATCACCAGTCAT 
               
               
                   
               
               
                 TATTACTGGACCTGGATCCGGCAGTTTCCAGGAAACAAACTGGAATGGAT 
               
               
                   
               
               
                 GGGCTACATAAGCTACGACGGTAGCAATAACTACAACCCATCTCTCAAAA 
               
               
                   
               
               
                 ATCGAATCTCCATCACTCGTGACACATCTAAGAACCAGTTTTTCCTGAAG 
               
               
                   
               
               
                 TTGAATTCTGTGACTACTGAGGACACAGCTACATATAACTGTGCAAGAGA 
               
               
                   
               
               
                 GGGCCCGCTCTACTATGGTAACCCCTACTGGTATTTCGATGTCTGGGGCG 
               
               
                   
               
               
                 CAGGGACCACGGTCACCGTCTCCTCAgccaaaacaacacccccatcagtc 
               
               
                   
               
               
                 tatccactggcccctaagggcg 
               
             
          
         
       
     
         [0169]    The amino acid sequence of the heavy chain variable region of the mouse 13D4 antibody (157 a. a.) [capital letters: mouse 13D4 VH variable region, small letters: mouse IgG2b heavy chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MKVLSLLYLLTAIPGILS DVQLQESGPGLVKPSQSLSLTCSVTGYSIT SH                   YYWT WIRQFPGNKLEWMG YISYDGSNNYNPSLKN RISITRDTSKNQFFLK               LNSVTTEDTATYNCAR EGPLYYGNPYWYFDV WGAGTTVTVSSakttppsv               yplapkg            
CDR1 in the heavy chain variable region of the 13D4 antibody SHYYWT
 
CDR2 in the heavy chain variable region of the 13D4 antibody YISYDGSNNYNPSLKN
 
CDR3 in the heavy chain variable region of the 13D4 antibody EGPLYYGNPYWYFDV
 
         [0170]    The nucleic acid sequence of the light chain variable region of the obtained anti-PLD4 mouse 13D4 antibody is SEQ ID NO: 108, and the amino acid sequence is SEQ ID NO: 109. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 13D4 antibody are SEQ ID NO: 35, SEQ ID NO: 36 and SEQ ID NO: 37, respectively. 
         [0171]    The nucleic acid sequence of the light chain variable region of the anti-PLD4 mouse 13D4 antibody (404 bp) [capital letters: mouse 13D4 VL variable region, small letters: mouse Ig κ light chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGATGTCCTCTGCTCAGTTCCTTGGTCTCCTGTTGCTCTGTTTTCAAGG 
               
               
                   
               
               
                 TACCAGATGTGATATCCAGATGACACAGACTACATCCTCCCTGTCTGCCT 
               
               
                   
               
               
                 CTCTGGGGGACAGAGTCACCATCAGTTGCAGGGCAAGTCAGGACATTGAC 
               
               
                   
               
               
                 AATTATTTAAACTGGTATCAGCAGAAACCAGATGGAACTGTTAAACTCCT 
               
               
                   
               
               
                 GATCTACTACACATCAAGATTACACTCAGGAGTCCCATCAAGGTTCAGTG 
               
               
                   
               
               
                 GCAGTGGGTCTGGAACAGATTATTCTCTCACCATTAGCAACCTGGAGCAA 
               
               
                   
               
               
                 GAAGATGTTGCCACTTACTTTTGCCAGCAGTTTAATACGCTTCCTCGGAC 
               
               
                   
               
               
                 GTTCGGTGGAGGCACCAAACTGGAAATCAAAcgggctgatgctgcaccaa 
               
               
                   
               
               
                 ctgt 
               
             
          
         
       
     
         [0172]    The amino acid sequence of the light chain variable region of the mouse 13D4 antibody (134 a. a.) [capital letters: mouse 13D4 VL variable region, small letters: mouse Ig κ light chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MMSSAQFLGLLLLCFQGTRC DIQMTQTTSSLSASLGDRVTISC RASQDID                   NYLN WYQQKPDGTVKLLIY YTSRLHS GVPSRFSGSGSGTDYSLTISNLEQ               EDVATYFC QQFNTLP RTFGGGTKLE1Kradaapt            
CDR1 in the light chain variable region of the 13D4 antibody RASQDIDNYLN
 
CDR2 in the light chain variable region of the 13D4 antibody YTSRLHS
 
CDR3 in the light chain variable region of the 13D4 antibody QQFNTLP
 
       9. Anti-PLD4 Mouse 13H11 Antibody 
       [0173]    The nucleic acid sequence of the heavy chain variable region of the obtained anti-PLD4 mouse 13H11 antibody is SEQ ID NO: 90, and the amino acid sequence is SEQ ID NO: 91. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 13H11 antibody are SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, respectively. 
         [0174]    The nucleic acid sequence of the heavy chain variable region of the anti-PLD4 mouse 13H11 antibody (471 bp) [capital letters: mouse 13H11 VH variable region, small letters: mouse IqG2b heavy chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGAAAGTGTTGAGTCTGTTGTACCTGTTGACAGCCATTCCTGGTATCCT 
               
               
                   
               
               
                 GTCTGATGTACAGCTTCAGGAGTCAGGACCTGGCCTCGTGAAACCTTCTC 
               
               
                   
               
               
                 AGTCTCTGTCTCTCACCTGCTCTGTCACTGGCTACTCCATCTCCAGTCAT 
               
               
                   
               
               
                 TATTACTGGAGTTGGATCCGGCAGTTTCCAGGAAACAGACTGGAATGGAT 
               
               
                   
               
               
                 GGGCTACATAAGCTACGACGGTAGCAATAACTACAACCCATCTCTCAAAA 
               
               
                   
               
               
                 ATCGAATCTCCATCACTCGTGACACATCTAAGAACCAGTTTTTCCTGAAG 
               
               
                   
               
               
                 TTGAATTCTGTGACTACTGAGGACACAGCTACATATAACTGTGCAAGAGA 
               
               
                   
               
               
                 GGGCCCGCTCTACTATGGTAACCCCTACTGGTATTTCGATGTCTGGGGCG 
               
               
                   
               
               
                 CAGGGACCACGGTCACCGTCTCCTCAgccaaaacaacacccccatcagtc 
               
               
                   
               
               
                 tatccactggcccctaagggc 
               
             
          
         
       
     
         [0175]    The amino acid sequence of the heavy chain variable region of the mouse 13H11 antibody (157 a. a.) [capital letters: mouse 13H11 VH variable region, small letters: mouse IgG2b heavy chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MKVLSLLYLLTAIPGILS DVQLQESGPGLVKPSQSLSLTCSVTGYSIS SH                   YYWS WIRQFPGNRLEWMG YISYDGSNNYNPSLKN RISITRDTSKNQFFLK               LNSVTTEDTATYNCAR EGPLYYGNPYWYFDV WGAGTTVTVSSakttppsv               yplapkg            
CDR1 in the heavy chain variable region of the 13H11 antibody SHYYWS
 
CDR2 in the heavy chain variable region of the 13H11 antibody YISYDGSNNYNPSLKN
 
CDR3 in the heavy chain variable region of the 13H11 antibody EGPLYYGNPYWYFDV
 
         [0176]    The nucleic acid sequence of the light chain variable region of the obtained anti-PLD4 mouse 13H11 antibody is SEQ ID NO: 110, and the amino acid sequence is SEQ ID NO: 111. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 13H11 antibody are SEQ ID NO: 41, SEQ ID NO: 42 and SEQ ID NO: 43, respectively. 
         [0177]    The nucleic acid sequence of the light chain variable region of the anti-PLD4 mouse 13H11 antibody (414 bp) [capital letters: mouse 13H11 VL variable region, small letters: mouse Ig κ light chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGATGTCCTCTGCTCAGTTCCTTGGTCTCCTGTTGCTCTGTTTTCAAGG 
               
               
                   
               
               
                 TACCAGATGTGATATCCAGATGACACAGACTACATCCTCCCTGTCTGCCT 
               
               
                   
               
               
                 CTCTGGGGGGCAGCGTCACCATCAGTTGCAGGGCAAGTCAGGACATTGAC 
               
               
                   
               
               
                 AATTATTTAAACTGGTATCAGCAAAAACCAGATGGAACTGTTAAACTCCT 
               
               
                   
               
               
                 GATCTACTACACATCAAGATTACACTCAGGAGTCCCATCAAGGTTCAGTG 
               
               
                   
               
               
                 GCAGTGGGTCTGGAACAGATTATTCTCTCACCATTAGCAACCTGGAACAA 
               
               
                   
               
               
                 GAAGATATTGCCACTTACTTTTGCCAACAGTTTAATACGCTTCCTCGGAC 
               
               
                   
               
               
                 GTTCGGTGGAGGCACCAAGCTGGAAATCAAAcgggctgatgctgcaccaa 
               
               
                   
               
               
                 ctgtatccatcttc 
               
             
          
         
       
     
         [0178]    The amino acid sequence of the light chain variable region of the mouse 13H11 antibody (138 a. a.) [capital letters: mouse 13H11 VL variable region, small letters: mouse Ig κ light chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MMSSAQFLGLLLLCFQGTRC DIQMTQTTSSLSASLGGSVTISC RASQDID                   NYLN WYQQKPDGTVKLLIY YTSRLHS GVPSRFSGSGSGTDYSLTISNLEQ               EDIATYFC QQFNTLP RTFGGGTKLEIKradaaptvsif            
CDR1 in the light chain variable region of the 13H11 antibody RASQDIDNYLN
 
CDR2 in the light chain variable region of the 13H11 antibody YTSRLHS
 
CDR3 in the light chain variable region of the 13H11 antibody QQFNTLP
 
       10. Anti-PLD4 Mouse 14C1 Antibody 
       [0179]    The nucleic acid sequence of the heavy chain variable region of the obtained anti-PLD4 mouse 14C1 antibody is SEQ ID NO: 92, and the amino acid sequence is SEQ ID NO: 93. The amino acid sequences of CDR1, CDR2 and CDR3 within the heavy chain variable region of the mouse 14C1 antibody are SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, respectively. 
         [0180]    The nucleic acid sequence of the heavy chain variable region of the anti-PLD4 mouse 14C1 antibody (470 bp) [capital letters: mouse 14C1 VH variable region, small letters: mouse IG1 heavy chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGAAAGTGTTGAGTCTGTTGTACCTGTTGACAGCCATTCCTGGTATCCT 
               
               
                   
               
               
                 GTCTGATGTACAGCTTCAGGAGTCAGGACCTGGCCTCGTGAAACCTTCTC 
               
               
                   
               
               
                 AGTCTCTGTCTCTCACCTGCTCTGTCACTGGCTACTCCATCTCCAGTCAT 
               
               
                   
               
               
                 TATTACTGGAGTTGGATCCGGCAGTTTCCAGGAAACAGACTGGAATGGAT 
               
               
                   
               
               
                 GGGCTACATAAGCTACGACGGTAGCAATAACTACAACCCATCTCTCAAAA 
               
               
                   
               
               
                 ATCGAATCTCCATCACTCGTGACACATCTAAGAACCAGTTTTTCCTGAAG 
               
               
                   
               
               
                 TTGAATTCTGTGACTACTGAGGACACAGCTACATATAACTGTGCAAGAGA 
               
               
                   
               
               
                 GGGCCCGCTCTACTATGGTAACCCCTACTGGTATTTCGATGTCTGGGGCG 
               
               
                   
               
               
                 CAGGGACCACGGTCACCGTCTCCTCAgccaaaacgacacccccatctgtc 
               
               
                   
               
               
                 tatccactggcccctaaggg 
               
             
          
         
       
     
         [0181]    The amino acid sequence of the heavy chain variable region of the mouse 14C1 antibody (156 a. a.) [capital letters: mouse 14C1 VH variable region, small letters: mouse IgG1 heavy chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MKVLSLLYLLTAIPGILS DVQLQESGPGLVKPSQSLSLTCSVTGYSIS SH                   YYWS WIRQFPGNRLEWMG YISYDGSNNYNPSLKN RISITRDTSKNQFFLK               LNSVTTEDTATYNCAR EGPLYYGNPYWYFDV WGAGTTVTVSS               akttppsvyplapk            
CDR1 in the heavy chain variable region of the 14C1 antibody SHYYWS
 
CDR2 in the heavy chain variable region of the 14C1 antibody YISYDGSNNYNPSLKN
 
CDR3 in the heavy chain variable region of the 14C1 antibody EGPLYYGNPYWYFDV
 
         [0182]    The nucleic acid sequence of the light chain variable region of the obtained anti-PLD4 mouse 14C1 antibody is SEQ ID NO: 112, and the amino acid sequence is SEQ ID NO: 113. The amino acid sequences of CDR1, CDR2 and CDR3 within the light chain variable region of the mouse 14C1 antibody are SEQ ID NO: 41, SEQ ID NO: 42 and SEQ ID NO: 43, respectively. 
         [0183]    The nucleic acid sequence of the light chain variable region of the anti-PLD4 mouse 14C1 antibody (465 bp) [capital letters: mouse 14C1 VL variable region, small letters: mouse Ig κ light chain constant region] 
         [0000]    
       
         
               
             
           
               
                 ATGATGTCCTCTGCTCAGTTCCTTGGTCTCCTGTTGCTCTGTTTTCAAGG 
               
               
                   
               
               
                 TACCAGATGTGATATCCAGATGACACAGACTACATCCTCCCTGTCTGCCT 
               
               
                   
               
               
                 CTCTGGGGGGCAGCGTCACCATCAGTTGCAGGGCAAGTCAGGACATTGAC 
               
               
                   
               
               
                 AATTATTTAAACTGGTATCAGCAAAAACCAGATGGAACTGTTAAACTCCT 
               
               
                   
               
               
                 GATCTACTACACATCAAGATTACACTCAGGAGTCCCATCAAGGTTCAGTG 
               
               
                   
               
               
                 GCAGTGGGTCTGGAACAGATTATTCTCTCACCATTAGCAACCTGGAACAA 
               
               
                   
               
               
                 GAAGATATTGCCACTTACTTTTGCCAACAGTTTAATACGCTTCCTCGGAC 
               
               
                   
               
               
                 GTTCGGTGGAGGCACCAAGCTGGAAATCAAAcgggctgatgctgcaccaa 
               
               
                   
               
               
                 ctgtatccatcttcccaccatccagtgagcagttaacatctggaggtgcc 
               
               
                   
               
               
                 tcagtcgtgtgcttc 
               
             
          
         
       
     
         [0184]    The amino acid sequence of the light chain variable region of the mouse 14C1 antibody (155 a. a.) [capital letters: mouse 14C1 VL variable region, small letters: mouse Ig κ light chain constant region] The underlined sequence shows its signal sequence and the double underline shows its CDR regions (CDR1, CDR2 and CDR3). 
         [0000]                      MMSSAQFLGLLLLCFQGTRC DIQMTQTTSSLSASLGGSVTISC RASQDID                   NYLN WYQQKPDGTVKLLIY YTSRLHS GVPSRFSGSGSGTDYSLTISNLEQ               EDIATYFC QQFNTLP RTFGGGTKLEIKradaaptvsifppsseqltsgga               svvcf            
CDR1 in the light chain variable region of the 14C1 antibody RASQDIDNYLN
 
CDR2 in the light chain variable region of the 14C1 antibody YTSRLHS
 
CDR3 in the light chain variable region of the 14C1 antibody QQFNTLP
 
         [0185]    The base sequences and the amino acid sequences of the heavy chain and the light chain of the created chimeric 11G9.6 antibody are as the sequence numbers given below. 
       Heavy Chain 
       [0186]    SEQ ID NO: 120 (base sequence)
 
SEQ ID NO: 121 (amino acid sequence)
 
       Light Chain 
       [0187]    SEQ ID NO: 122 (base sequence)
 
SEQ ID NO: 123 (amino acid sequence)
 
         [0188]    11. The nucleic acid sequence of the heavy chain of the anti-PLD4 chimeric 11G9.6 antibody (1401 bp) [capital letters: chimeric 11G9 VH variable region, small letters: human IgG1 heavy chain constant region](SEQ ID NO: 120) 
         [0000]    
       
         
               
             
           
               
                 ATGAAAGTGTTGAGTCTGTTGTACCTGTTGACAGCCATTCCTGGTATCCT 
               
               
                   
               
               
                 GTCTcagGTCCAACTGCAGCAGCCTGGGGCTGAACTGGTGAAGCCTGGGA 
               
               
                   
               
               
                 CTTCAGTGAAAATGTCCTGCAAGGCTTCTGGCTACACCTTCACCAGCTAC 
               
               
                   
               
               
                 TGGATGCACTGGGTGAAGCAGAGGCCGGGACAAGGCCTTGAGTGGATTGG 
               
               
                   
               
               
                 AGATATTTATCCTGGTAGTGATAGTACTAACTACAATGAGAAGTTCAAGA 
               
               
                   
               
               
                 GCAAGGCCACACTGACTGTAGACACATCCTCCAGCACAGCCTACATGCAA 
               
               
                   
               
               
                 CTCAGCAGCCTGACATCTGAGGACTCTGCGGTCTATTACTGTGCAAGAGG 
               
               
                   
               
               
                 AGGGTGGTTGGATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCG 
               
               
                   
               
               
                 TCTCCTCAgctagcaccaagggcccatcggtcttccccctggcaccctcc 
               
               
                   
               
               
                 tccaagagcacctctgggggcacagcggccctgggctgcctggtcaagga 
               
               
                   
               
               
                 ctacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgacca 
               
               
                   
               
               
                 gcggcgtgcacaccacccggctgtcctacagtcctcaggactctactccc 
               
               
                   
               
               
                 tcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctac 
               
               
                   
               
               
                 atctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagt 
               
               
                   
               
               
                 tgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcac 
               
               
                   
               
               
                 ctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaag 
               
               
                   
               
               
                 gacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtgga 
               
               
                   
               
               
                 cgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcg 
               
               
                   
               
               
                 tggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagc 
               
               
                   
               
               
                 acgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaa 
               
               
                   
               
               
                 tggcaaggagtacaagtgcaaggtctccaacaaagccctcccagccccca 
               
               
                   
               
               
                 tcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtg 
               
               
                   
               
               
                 tacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcct 
               
               
                   
               
               
                 gacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtggg 
               
               
                   
               
               
                 agagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctg 
               
               
                   
               
               
                 gactccgacggctccacttcctctacagcaagctcaccgtggacaagagc 
               
               
                   
               
               
                 aggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctct 
               
               
                   
               
               
                 gcacaaccactacacgcagaagagcctctccctgtctccgggtaaatga 
               
             
          
         
       
     
         [0189]    12. The amino acid sequence of the heavy chain of the anti-PLD4 chimeric 11G9.6 antibody (466 a. a.) [capital letters: chimeric 11G9 VHvariable region, small letters: human IqG1 heavy chain constant region](SEQ ID NO: 121) 
         [0000]    
       
         
               
             
           
               
                 MKVLSLLYLLTAIPGILSQVQLQQPGAELVKPGTSVKMSCKASGYTFTSY 
               
               
                   
               
               
                 WMHWVKQRPGQGLEWIGDIYPGSDSTNYNEKFKSKATLTVDTSSSTAYMQ 
               
               
                   
               
               
                 LSSLTSEDSAVYYCARGGWLDAMDYWGQGTSVTVSSastkgpsvfplaps 
               
               
                   
               
               
                 skstsggtaalgclykdyfpepvtvswnsgaltsgvhtfpavlqssglys 
               
               
                   
               
               
                 lssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkthtcppcpa 
               
               
                   
               
               
                 pellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdg 
               
               
                   
               
               
                 vevhnaktkpreeqynstyrvvsvltylhqdwlngkeykckvsnkalpap 
               
               
                   
               
               
                 iektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavew 
               
               
                   
               
               
                 esngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhea 
               
               
                   
               
               
                 lhnhytqkslslspgk 
               
             
          
         
       
     
         [0190]    13. The nucleic acid sequence of the light chain of the anti-PLD4 chimeric 11G9.6 antibody (705 bp) [capital letters: chimeric 11G9 VL variable region], small letters: human Ig κ 
         [0000]    
       
         
               
             
           
               
                 ATGATGTCCTCTGCTCAGTTCCTTGGTCTCCTGTTGCTCTGTTTTCAAGG 
               
               
                   
               
               
                 TACCAGATGTGATATCCAGATGACACAGACTACATCCTCCCTGTCTGCCT 
               
               
                   
               
               
                 CTCTGGGAGACAGAGTCACCATCAGTTGCAGGGCAAGTCAGGACATTAGC 
               
               
                   
               
               
                 AATTATTTAAACTGGTATCAGCAGAAACCAGATGGAACTGTTAAACTCCT 
               
               
                   
               
               
                 GATCTACTACACATCAAGATTACACTCAGGAGTCCCATCAAGGTTCAGTG 
               
               
                   
               
               
                 GCAGTGGGTCTGGAACAGATTATTCTCTCACCATTAGCAACCTGGAGCAA 
               
               
                   
               
               
                 GAAGATATTGCCACTTACTTTTGCCAACAGGGTAATACGCTTCCGTGGAC 
               
               
                   
               
               
                 GTTCGGTGGAGGCACCAAGCTGGAAATCAAAcgaactgtggctgcaccat 
               
               
                   
               
               
                 ctgtcacatcacccgccatctgatgagcagttgaaatctggaactgcctc 
               
               
                   
               
               
                 tgagtgtgcctgctgaataacttctatcccagagaggccaaagtacagtg 
               
               
                   
               
               
                 gaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacag 
               
               
                   
               
               
                 agcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctg 
               
               
                   
               
               
                 agcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcaccca 
               
               
                   
               
               
                 tcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgct 
               
               
                   
               
               
                 ag 
               
             
          
         
       
     
         [0191]    14. The amino acid sequence of the light chain of the anti-PLD4 chimeric 11G9.6 antibody (234 a. a.) [capital letters: chimeric 11G9 VL variable region, small letters: human Ig κ light chain constant region](SEQ ID NO: 123) 
         [0000]                            MMSSAQFLGLLLLCFQGTRCDIQMTQTTSSLSASLGDRVTISCRA                       SQDISNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTD                       YSLTISNLEQEDIATYFCQQGNTLPWTFGGGTKLEIKrtvaapsv                       fifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsq                       esvteqdskdstyslsstltlskadyekhkvyacevthqglsspv                       tksfnrgec            
&lt;cDNA and Protein Sequences of PLD4-Related Molecules&gt;
 
         [0192]    Human PLD4 cDNA (1521 bp) (SEQ ID NO: 44) 
         [0000]    
       
         
               
               
             
           
               
                   
                 ATGCTGAAGCCTCTTTGGAAAGCAGCAGTGGCCCCCACATGGCCA 
               
               
                   
                   
               
               
                   
                 TGCTCCATGCCGCCCCGCCGCCCGTGGGACAGAGAGGCTGGCACG 
               
               
                   
                   
               
               
                   
                 TTGCAGGTCCTGGGAGCGCTGGCTGTGCTGTGGCTGGGCTCCGTG 
               
               
                   
                   
               
               
                   
                 GCTCTTATCTGCCTCCTGTGGCAAGTGCCCCGTCCTCCCACCTGG 
               
               
                   
                   
               
               
                   
                 GGCCAGGTGCAGCCCAAGGACGTGCCCAGGTCCTGGGAGCATGGC 
               
               
                   
                   
               
               
                   
                 TCCAGCCCAGCTTGGGAGCCCCTGGAAGCAGAGGCCAGGCAGCAG 
               
               
                   
                   
               
               
                   
                 AGGGACTCCTGCCAGCTTGTCCTTGTGGAAAGCATCCCCCAGGAC 
               
               
                   
                   
               
               
                   
                 CTGCCATCTGCAGCCGGCAGCCCCTCTGCCCAGCCTCTGGGCCAG 
               
               
                   
                   
               
               
                   
                 GCCTGGCTGCAGCTGCTGGACACTGCCCAGGAGAGCGTCCACGTG 
               
               
                   
                   
               
               
                   
                 GCTTCATACTACTGGTCCCTCACAGGGCCTGACATCGGGGTCAAC 
               
               
                   
                   
               
               
                   
                 GACTCGTCTTCCCAGCTGGGAGAGGCTCTTCTGCAGAAGCTGCAG 
               
               
                   
                   
               
               
                   
                 CAGCTGCTGGGCAGGAACATTTCCCTGGCTGTGGCCACCAGCAGC 
               
               
                   
                   
               
               
                   
                 CCGACACTGGCCAGGACATCCACCGACCTGCAGGTTCTGGCTGCC 
               
               
                   
                   
               
               
                   
                 CGAGGTGCCCATGTACGACAGGTGCCCATGGGGCGGCTCACCAGG 
               
               
                   
                   
               
               
                   
                 GGTGTTTTGCACTCCAAATTCTGGGTTGTGGATGGACGGCACATA 
               
               
                   
                   
               
               
                   
                 TACATGGGCAGTGCCAACATGGACTGGCGGTCTCTGACGCAGGTG 
               
               
                   
                   
               
               
                   
                 AAGGAGCTTGGCGCTGTCATCTATAACTGCAGCCACCTGGCCCAA 
               
               
                   
                   
               
               
                   
                 GACCTGGAGAAGACCTTCCAGACCTACTGGGTACTGGGGGTGCCC 
               
               
                   
                   
               
               
                   
                 AAGGCTGTCCTCCCCAAAACCTGGCCTCAGAACTTCTCATCTCAC 
               
               
                   
                   
               
               
                   
                 TTCAACCGTTTCCAGCCCTTCCACGGCCTCTTTGATGGGGTGCCC 
               
               
                   
                   
               
               
                   
                 ACCACTGCCTACTTCTCAGCGTCGCCACCAGCACTCTGTCCCCAG 
               
               
                   
                   
               
               
                   
                 GGCCGCACCCGGGACCTGGAGGCGCTGCTGGCGGTGATGGGGAGC 
               
               
                   
                   
               
               
                   
                 GCCCAGGAGTTCATCTATGCCTCCGTGATGGAGTATTTCCCCACC 
               
               
                   
                   
               
               
                   
                 ACGCGCTTCAGCCACCCCCCGAGGTACTGGCCGGTGCTGGACAAC 
               
               
                   
                   
               
               
                   
                 GCGCTGCGGGCGGCAGCCTTCGGCAAGGGCGTGCGCGTGCGCCTG 
               
               
                   
                   
               
               
                   
                 CTGGTCGGCTGCGGACTCAACACGGACCCCACCATGTTCCCCTAC 
               
               
                   
                   
               
               
                   
                 CTGCGGTCCCTGCAGGCGCTCAGCAACCCCGCGGCCAACGTCTCT 
               
               
                   
                   
               
               
                   
                 GTGGACGTGAAAGTCTTCATCGTGCCGGTGGGGAACCATTCCAAC 
               
               
                   
                   
               
               
                   
                 ATCCCATTCAGCAGGGTGAACCACAGCAAGTTCATGGTCACGGAG 
               
               
                   
                   
               
               
                   
                 AAGGCAGCCTACATAGGCACCTCCAACTGGTCGGAGGATTACTTC 
               
               
                   
                   
               
               
                   
                 AGCAGCACGGCGGGGGTGGGCTTGGTGGTCACCCAGAGCCCTGGC 
               
               
                   
                   
               
               
                   
                 GCGCAGCCCGCGGGGGCCACGGTGCAGGAGCAGCTGCGGCAGCTC 
               
               
                   
                   
               
               
                   
                 TTTGAGCGGGACTGGAGTTCGCGCTACGCCGTCGGCCTGGACGGA 
               
               
                   
                   
               
               
                   
                 CAGGCTCCGGGCCAGGACTGCGTTTGGCAGGGCTGA 
               
             
          
         
       
     
         [0193]    Human PLD4 Protein (506 Amino Acids) (SEQ ID NO: 1) 
         [0000]    
       
         
               
               
             
           
               
                   
                 MLKPLWKAAVAPTWPCSMPPRRPWDREAGTLQVLGALAVLWLGSV 
               
               
                   
                   
               
               
                   
                 ALICLLWQVPRPPTWGQVQPKDVPRSWEHGSSPAWEPLEAEARQQ 
               
               
                   
                   
               
               
                   
                 RDSCQLVLVESIPQDLPSAAGSPSAQPLGQAWLQLLDTAQESVHV 
               
               
                   
                   
               
               
                   
                 ASYYWSLTGPDIGVNDSSSQLGEALLQKLQQLLGRNISLAVATSS 
               
               
                   
                   
               
               
                   
                 PTLARTSTDLQVLAARGAHVRQVPMGRLTRGVLHSKFWVVDGRHI 
               
               
                   
                   
               
               
                   
                 YMGSANMDWRSLTQVKELGAVIYNCSHLAQDLEKTFQTYWVLGVP 
               
               
                   
                   
               
               
                   
                 KAVLPKTWPQNFSSHFNRFQPFHGLFDGVPTTAYFSASPPALCPQ 
               
               
                   
                   
               
               
                   
                 GRTRDLEALLAVMGSAQEFIYASVMEYFPTTRFSHPPRYWPVLDN 
               
               
                   
                   
               
               
                   
                 ALRAAAFGKGVRVRLLVGCGLNTDPTMFPYLRSLQALSNPAANVS 
               
               
                   
                   
               
               
                   
                 VDVKVFIVPVGNHSNIPFSRVNHSKFMVTEKAAYIGTSNWSEDYF 
               
               
                   
                   
               
               
                   
                 SSTAGVGLVVTQSPGAQPAGATVQEQLRQLFERDWSSRYAVGLDG 
               
               
                   
                   
               
               
                   
                 QAPGQDCVWQG 
               
             
          
         
       
     
         [0194]    Cynomolgus Monkey PLD4 cDNA (1521 bp) (SEQ ID NO: 63) 
         [0000]    
       
         
               
               
             
           
               
                   
                 ATGCTGAAGCCTCTTCGGAGAGCgGCAGTGACCCCCATGTGGCCG 
               
               
                   
                   
               
               
                   
                 TGCTCCATGCTGCCCCGCCGCCTGTGGGACAGAGAGGCTGGCACG 
               
               
                   
                   
               
               
                   
                 TTGCAGGTCCTGGGAGTGCTGGCTATGCTGTGGCTGGGCTCCATG 
               
               
                   
                   
               
               
                   
                 GCTCTTACCTACCTCCTGTGGCAAGTGCGCCGTCCTCCCACCTGG 
               
               
                   
                   
               
               
                   
                 GGCCAGGTGCAGCCCAAGGACGTGCCCAGGTCCTGGGGGCATGGT 
               
               
                   
                   
               
               
                   
                 TCCAGCCCAGCTCTGGAGCCCCTGGAAGCGGAGGTCAGGAAGCAG 
               
               
                   
                   
               
               
                   
                 AGGGACTCCTGCCAGCTTGTCCTTGTGGAAAGCATCCCCCAGGAC 
               
               
                   
                   
               
               
                   
                 CTGCCATTTGCAGCCGGCAGCCTCTCCGCCCAGCCTCTGGGCCAG 
               
               
                   
                   
               
               
                   
                 GCCTGGCTGCAGCTGCTGGACACTGCCCAGGAGAGCGTCCACGTG 
               
               
                   
                   
               
               
                   
                 GCTTCATACTACTGGTCCCTCACAGGGCCCGACATTGGGGTCAAC 
               
               
                   
                   
               
               
                   
                 GACTCATCTTCCCAGCTGGGAGAGGCCCTTCTGCAGAAGCTGCAG 
               
               
                   
                   
               
               
                   
                 CAGCTGCTGGGCAGGAACATTTCCTTGGCTGTGGCCACCAGCAGT 
               
               
                   
                   
               
               
                   
                 CCAACACTGGCCAGGAAGTCCACCGACCTGCAGGTCCTGGCTGCC 
               
               
                   
                   
               
               
                   
                 CGAGGTGCCCAGGTACGACGGGTGCCCATGGGGCGGCTCACCAGG 
               
               
                   
                   
               
               
                   
                 GGCGTTTTGCACTCCAAATTCTGGGTTGTGGATGGACgGCACATA 
               
               
                   
                   
               
               
                   
                 TACATGGGCAGTGCcAACATGGACTGGCGGTCCCTGACGCAGGTG 
               
               
                   
                   
               
               
                   
                 AAGGAGCTTGGCGCTGTCATCTATAACTGCAGCCACCTGGCCCAA 
               
               
                   
                   
               
               
                   
                 GACCTGGAGAAGACCTTCCAGACCTACTGGGTGCTGGGGGTGCCC 
               
               
                   
                   
               
               
                   
                 AAGGCTGTCCTCCCCAAAACCTGGCCTCAGAACTTCTCATCTCAC 
               
               
                   
                   
               
               
                   
                 ATCAACCGTTTCCAGCCCTTCCAGGGCCTCTTTGATGGGGTGCCC 
               
               
                   
                   
               
               
                   
                 ACCACTGCCTACTTCTCAGCATCGCCACCcGCACTCTGTCCCCAG 
               
               
                   
                   
               
               
                   
                 GGCCGCACCCCTGACCTGGAGGCGCTGTTGGCGGTGATGGGGAGC 
               
               
                   
                   
               
               
                   
                 GCCCAGGAGTTCATCTATGCCTCCGTGATGGAGTATTTCCCTACC 
               
               
                   
                   
               
               
                   
                 ACgCGCTTCAGCCACCCCCGCAGGTACTGGCCGGTGCTGGACAAC 
               
               
                   
                   
               
               
                   
                 GCGCTGCGGGCGGCAGCCTTCAGCAAGGGTGTGCGCGTGCGCCTG 
               
               
                   
                   
               
               
                   
                 CTGGTCAGCTGCGGACTCAACACGGACCCCACCATGTTCCCCTAT 
               
               
                   
                   
               
               
                   
                 CTGCGGTCCCTGCAGGCGCTCAGCAACCCCGCGGCCAACGTCTCT 
               
               
                   
                   
               
               
                   
                 GTGGACGTGAAAGTCTTCATCGTGCCGGTGGGGAATCATTCCAAC 
               
               
                   
                   
               
               
                   
                 ATCCCGTTCAGCAGGGTGAACCACAGCAAGTTCATGGTCACGGAG 
               
               
                   
                   
               
               
                   
                 AAGGCAGCCTACATAGGCACCTCCAACTGGTCGGAGGATTACTTC 
               
               
                   
                   
               
               
                   
                 AGCAGCACGACGGGGGTGGGCCTGGTGGTCACCCAGAGCCCCGGC 
               
               
                   
                   
               
               
                   
                 GCGCAGCCCGCGGGGGCCACGGTACAGGAGCAGCTGCGGCAGCTC 
               
               
                   
                   
               
               
                   
                 TTTGAGCGGGACTGGAGTTCGCGCTACGCCGTCGGCCTGGACGGA 
               
               
                   
                   
               
               
                   
                 CAGGCTCCGGGCCAGGACTGCGTTTGGCAGGGCTGA 
               
             
          
         
       
     
         [0195]    Cynomolgus monkey PLD4 protein (506 amino acids) (SEQ ID NO: 129) 
         [0000]    
       
         
               
               
             
           
               
                   
                 MLKPLRRAAVTPMWPCSMLPRRLWDREAGTLQVLGVLAMLWLGSM 
               
               
                   
                   
               
               
                   
                 ALTYLLWQVRRPPTWGQVQPKDVPRSWGHGSSPALEPLEAEVRKQ 
               
               
                   
                   
               
               
                   
                 RDSCQLVLVESIPQDLPFAAGSLSAQPLGQAWLQLLDTAQESVHV 
               
               
                   
                   
               
               
                   
                 ASYYWSLTGPDIGVNDSSSQLGEALLQKLQQLLGRNISLAVATSS 
               
               
                   
                   
               
               
                   
                 PTLARKSTDLQVLAARGAQVRRVPMGRLTRGVLHSKFWVVDGRHI 
               
               
                   
                   
               
               
                   
                 YMGSANMDWRSLTQVKELGAVIYNCSHLAQDLEKTFQTYWVLGVP 
               
               
                   
                   
               
               
                   
                 KAVLPKTWPQNFSSHINRFQPFQGLFDGVPTTAYFSASPPALCPQ 
               
               
                   
                   
               
               
                   
                 GRTPDLEALLAVMGSAQEFIYASVMEYFPTTRFSHPRRYWPVLDN 
               
               
                   
                   
               
               
                   
                 ALRAAAFSKGVRVRLLVSCGLNTDPTMFPYLRSLQALSNPAANVS 
               
               
                   
                   
               
               
                   
                 VDVKVFIVPVGNHSNIPFSRVNHSKFMVTEKAAYIGTSNWSEDYF 
               
               
                   
                   
               
               
                   
                 SSTTGVGLVVTQSPGAQPAGATVQEQLRQLFERDWSSRYAVGLDG 
               
               
                   
                   
               
               
                   
                 QAPGQDCVWQG 
               
             
          
         
       
     
         [0196]    Rhesus Monkey PLD4 cDNA (1521 bp) (SEQ ID NO: 124) 
         [0000]    
       
         
               
               
             
           
               
                   
                 ATGCTGAAGCCTCTTCGGAGAGCGGCAGTGACCCCCATGTGGCCG 
               
               
                   
                   
               
               
                   
                 TGCTCCATGCTGCCCCGCCGCCTGTGGGACAGAGAGGCTGGCACG 
               
               
                   
                   
               
               
                   
                 TTGCAGGTCCTGGGAGTGCTGGCTATGCTGTGGCTGGGCTCCATG 
               
               
                   
                   
               
               
                   
                 GCTCTTACCTACCTCCTGTGGCAAGTGCGCTGTCCTCCCACCTGG 
               
               
                   
                   
               
               
                   
                 GGCCAGGTGCAGCCCAGGGACGTGCCCAGGTCCTGGGGGCATGGT 
               
               
                   
                   
               
               
                   
                 TCCAGCCTAGCTCTGGAGCCCCTGGAAGCGGAGGTCAGGAAGCAG 
               
               
                   
                   
               
               
                   
                 AGGGACTCCTGCCAGCTTGTCCTTGTGGAAAGCATCCCCCAGGAC 
               
               
                   
                   
               
               
                   
                 CTGCCATTTGCAGCCGGCAGCCTCTCCGCCCAGCCTCTGGGCCAG 
               
               
                   
                   
               
               
                   
                 GCCTGGCTGCAGCTGCTGGACACTGCCCAGGAGAGCGTCCACGTG 
               
               
                   
                   
               
               
                   
                 GCTTCATACTACTGGTCCCTCACAGGGCCCGACATTGGGGTCAAC 
               
               
                   
                   
               
               
                   
                 GACTCATCTTCCCAGCTGGGAGAGGCCCTTCTGCAGAAGCTGCAG 
               
               
                   
                   
               
               
                   
                 CAGCTGCTGGGCAGGAACATTTCCTTGGCTGTGGCCACCAGCAGT 
               
               
                   
                   
               
               
                   
                 CCAACACTGGCCAGGAAGTCCACCGACCTGCAGGTCCTGGCTGCC 
               
               
                   
                   
               
               
                   
                 CGAGGTGCCCAGGTACGACGGGTGCCCATGGGGCGGCTCACCAGG 
               
               
                   
                   
               
               
                   
                 GGCGTTTTGCACTCCAAATTCTGGGTTGTGGATGGACGGCACATA 
               
               
                   
                   
               
               
                   
                 TACATGGGCAGTGCCAACATGGACTGGCGGTCCCTGACGCAGGTG 
               
               
                   
                   
               
               
                   
                 AAGGAGCTTGGCGCTGTCATCTATAACTGCAGCCACCTGGCCCAA 
               
               
                   
                   
               
               
                   
                 GACCTGGAGAAGACCTTCCAGACCTACTGGGTGCTGGGGGTGCCC 
               
               
                   
                   
               
               
                   
                 AAGGCTGTCCTCCCCAAAACCTGGCCTCAGAACTTCTCATCTCAC 
               
               
                   
                   
               
               
                   
                 ATCAACCGTTTCCAGCCCTTCCAGGGCCTCTTTGATGGGGTGCCC 
               
               
                   
                   
               
               
                   
                 ACCACTGCCTACTTCTCAGCATCGCCACCCGCACTCTGTCCCCAG 
               
               
                   
                   
               
               
                   
                 GGCCGCACCCCTGACCTGGAGGCGCTGTTGGCGGTGATGGGGAGC 
               
               
                   
                   
               
               
                   
                 GCCCAGGAGTTCATCTATGCCTCCGTGATGGAGTATTTCCCTACC 
               
               
                   
                   
               
               
                   
                 ACGCGCTTCAGCCACCCCCGCAGGTACTGGCCGGTGCTGGACAAC 
               
               
                   
                   
               
               
                   
                 GCGCTGCGGGCGGCAGCCTTCAGCAAGGGTGTGCGCGTGCGCCTG 
               
               
                   
                   
               
               
                   
                 CTGGTCAGCTGCGGACTCAACACGGACCCCACCATGTTCCCCTAT 
               
               
                   
                   
               
               
                   
                 CTGCGGTCCCTGCAGGCGCTCAGCAACCCCGCGGCCAACGTCTCT 
               
               
                   
                   
               
               
                   
                 GTGGACGTGAAAGTCTTCATCGTGCCGGTGGGGAATCATTCCAAC 
               
               
                   
                   
               
               
                   
                 ATCCCGTTCAGCAGGGTGAACCACAGCAAGTTCATGGTCACGGAG 
               
               
                   
                   
               
               
                   
                 AAGGCAGCCTACATAGGCACCTCCAACTGGTCGGAGGATTACTTC 
               
               
                   
                   
               
               
                   
                 AGCAGCACGACGGGGGTGGGCCTGGTGGTCACCCAGAGCCCCGGC 
               
               
                   
                   
               
               
                   
                 GCGCAGCCCGCGGGGGCCACGGTACAGGAGCAGCTGCGGCAGCTC 
               
               
                   
                   
               
               
                   
                 TTTGAGCGGGACTGGAGTTCGCGCTACGCCGTCGGCCTGGACGGA 
               
               
                   
                   
               
               
                   
                 CAGGCTCCGGGCCAGGACTGCGTTTGGCAGGGCTGA 
               
             
          
         
       
     
         [0197]    Rhesus Monkey PLD4 Protein (506 Amino Acids) (SEQ ID NO: 130) 
         [0000]    
       
         
               
               
             
           
               
                   
                 MLKPLRRAAVTPMWPCSMLPRRLWDREAGTLQVLGVLAMLWLGSM 
               
               
                   
                   
               
               
                   
                 ALTYLLWQVRCPPTWGQVQPRDVPRSWGHGSSLALEPLEAEVRKQ 
               
               
                   
                   
               
               
                   
                 RDSCQLVLVESIPQDLPFAAGSLSAQPLGQAWLQLLDTAQESVHV 
               
               
                   
                   
               
               
                   
                 ASYYWSLTGPDIGVNDSSSQLGEALLQKLQQLLGRNISLAVATSS 
               
               
                   
                   
               
               
                   
                 PTLARKSTDLQVLAARGAQVRRVPMGRLTRGVLHSKFWVVDGRHI 
               
               
                   
                   
               
               
                   
                 YMGSANMDWRSLTQVKELGAVIYNCSHLAQDLEKTFQTYWVLGVP 
               
               
                   
                   
               
               
                   
                 KAVLPKTWPQNFSSHINRFQPFQGLFDGVPTTAYFSASPPALCPQ 
               
               
                   
                   
               
               
                   
                 GRTPDLEALLAVMGSAQEFIYASVMEYFPTTRFSHPRRYWPVLDN 
               
               
                   
                   
               
               
                   
                 ALRAAAFSKGVRVRLLVSCGLNTDPTMFPYLRSLQALSNPAANVS 
               
               
                   
                   
               
               
                   
                 VDVKVFIVPVGNHSNIPFSRVNHSKFMVTEKAAYIGTSNWSEDYF 
               
               
                   
                   
               
               
                   
                 SSTTGVGLVVTQSPGAQPAGATVQEQLRQLFERDWSSRYAVGLDG 
               
               
                   
                   
               
               
                   
                 QAPGQDCVWQG 
               
             
          
         
       
     
         [0198]    Mouse PLD4 cDNA (1512 Base Pairs) (SEQ ID NO: 131) 
         [0000]    
       
         
               
               
             
           
               
                   
                 ATGGACAAGAAGAAAGAGCACCCAGAGATGCGGATACCACTCCAG 
               
               
                   
                   
               
               
                   
                 ACAGCAGTGGAGGTCTCTGATTGGCCCTGCTCCACATCTCATGAT 
               
               
                   
                   
               
               
                   
                 CCACATAGCGGACTTGGCATGGTACTGGGGATGCTAGCTGTACTG 
               
               
                   
                   
               
               
                   
                 GGACTCAGCTCTGTGACTCTCATCTTGTTCCTGTGGCAAGGGGCC 
               
               
                   
                   
               
               
                   
                 ACTTCTTTCACCAGTCATCGGATGTTCCCTGAGGAAGTGCCCTCC 
               
               
                   
                   
               
               
                   
                 TGGTCCTGGGAGACCCTGAAAGGAGACGCTGAGCAGCAGAATAAC 
               
               
                   
                   
               
               
                   
                 TCCTGTCAGCTCATCCTTGTGGAAAGCATCCCCGAGGACTTGCCA 
               
               
                   
                   
               
               
                   
                 TTTGCAGCTGGCAGCCCCACTGCCCAGCCCCTGGCCCAGGCTTGG 
               
               
                   
                   
               
               
                   
                 CTGCAGCTTCTTGACACTGCTCGGGAGAGCGTCCACATTGCCTCG 
               
               
                   
                   
               
               
                   
                 TACTACTGGTCCCTCACTGGACTGGACATTGGAGTCAATGACTCG 
               
               
                   
                   
               
               
                   
                 TCTTCTCGGCAGGGAGAGGCCCTTCTACAGAAGTTCCAACAGCTT 
               
               
                   
                   
               
               
                   
                 CTTCTCAGGAACATCTCTGTGGTGGTGGCCACCCACAGCCCAACA 
               
               
                   
                   
               
               
                   
                 TTGGCCAAGACATCCACTGACCTCCAGGTCTTGGCTGCCCATGGT 
               
               
                   
                   
               
               
                   
                 GCCCAGATACGACAAGTGCCCATGAAACAGCTTACTGGGGGTGTT 
               
               
                   
                   
               
               
                   
                 CTACACTCCAAATTCTGGGTTGTGGATGGGCGACACGTCTACGTG 
               
               
                   
                   
               
               
                   
                 GGCAGCGCCAACATGGACTGGCGGTCCCTGACTCAGGTGAAGGAA 
               
               
                   
                   
               
               
                   
                 CTTGGTGCAATCATCTACAACTGCAGCAACCTGGCTCAAGACCTT 
               
               
                   
                   
               
               
                   
                 GAGAAAACATTCCAGACCTACTGGGTGCTAGGGACTCCCCAAGCT 
               
               
                   
                   
               
               
                   
                 GTTCTCCCTAAAACCTGGCCTCGGAACTTCTCATCCCACATCAAC 
               
               
                   
                   
               
               
                   
                 CGCTTCCATCCCTTGCGGGGTCCCTTTGATGGGGTTCCCACCACG 
               
               
                   
                   
               
               
                   
                 GCCTATTTCTCGGCCTCCCCTCCCTCCCTCTGCCCGCATGGCCGG 
               
               
                   
                   
               
               
                   
                 ACCCGGGATCTGGACGCAGTGTTGGGAGTGATGGAGGGTGCTCGC 
               
               
                   
                   
               
               
                   
                 CAGTTCATCTATGTCTCGGTGATGGAGTATTTCCCTACCACGCGC 
               
               
                   
                   
               
               
                   
                 TTCACCCACCATGCCAGGTACTGGCCCGTGCTGGACAATGCGCTA 
               
               
                   
                   
               
               
                   
                 CGGGCAGCGGCCCTCAATAAGGGTGTGCATGTGCGCTTACTGGTC 
               
               
                   
                   
               
               
                   
                 AGCTGCTGGTTCAACACAGACCCCACCATGTTCGCTTATCTGAGG 
               
               
                   
                   
               
               
                   
                 TCCCTGCAGGCTTTCAGTAACCCCTCGGCTGGCATCTCAGTGGAT 
               
               
                   
                   
               
               
                   
                 GTGAAAGTCTTCATCGTGCCTGTGGGAAATCATTCCAACATCCCG 
               
               
                   
                   
               
               
                   
                 TTCAGCCGCGTGAACCACAGCAAGTTCATGGTCACAGACAAGACA 
               
               
                   
                   
               
               
                   
                 GCCTATGTAGGCACCTCTAACTGGTCAGAAGACTACTTCAGCCAC 
               
               
                   
                   
               
               
                   
                 ACCGCTGGTGTGGGCCTGATTGTCAGCCAGAAGACCCCCAGAGCC 
               
               
                   
                   
               
               
                   
                 CAGCCAGGCGCAACCACCGTGCAGGAGCAGCTGAGGCAACTCTTT 
               
               
                   
                   
               
               
                   
                 GAACGAGACTGGAGTTCCCACTATGCTATGGACCTAGACAGACAA 
               
               
                   
                   
               
               
                   
                 GTCCCGAGCCAGGACTGTGTCTGGTAG 
               
             
          
         
       
     
         [0199]    Mouse PLD4 Protein (503 Amino Acids) (SEQ ID NO: 132) 
         [0000]    
       
         
               
               
             
           
               
                   
                 MDKKKEHPEMRIPLQTAVEVSDWPCSTSHDPHSGLGMVLGMLAVL 
               
               
                   
                   
               
               
                   
                 GLSSVTLILFLWQGATSFTSHRMFPEEVPSWSWETLKGDAEQQNN 
               
               
                   
                   
               
               
                   
                 SCQLILVESIPEDLPFAAGSPTAQPLAQAWLQLLDTARESVHIAS 
               
               
                   
                   
               
               
                   
                 YYWSLTGLDIGVNDSSSRQGEALLQKFQQLLLRNISVVVATHSPT 
               
               
                   
                   
               
               
                   
                 LAKTSTDLQVLAAHGAQIRQVPMKQLTGGVLHSKFWVVDGRHVYV 
               
               
                   
                   
               
               
                   
                 GSANMDWRSLTQVKELGAIIYNCSNLAQDLEKTFQTYWVLGTPQA 
               
               
                   
                   
               
               
                   
                 VLPKTWPRNFSSHINRFHPLRGPFDGVPTTAYFSASPPSLCPHGR 
               
               
                   
                   
               
               
                   
                 TRDLDAVLGVMEGARQFIYVSVMEYFPTTRFTHHARYWPVLDNAL 
               
               
                   
                   
               
               
                   
                 RAAALNKGVHVRLLVSCWFNTDPTMFAYLRSLQAFSNPSAGISVD 
               
               
                   
                   
               
               
                   
                 VKVFIVPVGNHSNIPFSRVNHSKFMVTDKTAYVGTSNWSEDYFSH 
               
               
                   
                   
               
               
                   
                 TAGVGLIVSQKTPRAQPGATTVQEQLRQLFERDWSSHYAMDLDRQ 
               
               
                   
                   
               
               
                   
                 VPSQDCVW 
               
             
          
         
       
     
         [0200]    Human PLD3 cDNA Sequence (SEQ ID NO: 55) 
         [0000]    
       
         
               
               
             
           
               
                   
                 ATGAAGCCTAAACTGATGTACCAGGAGCTGAAGGTGCCTGCAGAG 
               
               
                   
                   
               
               
                   
                 GAGCCCGCCAATGAGCTGCCCATGAATGAGATTGAGGCGTGGAAG 
               
               
                   
                   
               
               
                   
                 GCTGCGGAAAAGAAAGCCCGCTGGGTCCTGCTGGTCCTCATTCTG 
               
               
                   
                   
               
               
                   
                 GCGGTTGTGGGCTTCGGAGCCCTGATGACTCAGCTGTTTCTATGG 
               
               
                   
                   
               
               
                   
                 GAATACGGCGACTTGCATCTCTTTGGGCCCAACCAGCGCCCAGCC 
               
               
                   
                   
               
               
                   
                 CCCTGCTATGACCCTTGCGAAGCAGTGCTGGTGGAAAGCATTCCT 
               
               
                   
                   
               
               
                   
                 GAGGGCCTGGACTTCCCCAATGCCTCCACGGGGAACCCTTCCACC 
               
               
                   
                   
               
               
                   
                 AGCCAGGCCTGGCTGGGCCTGCTCGCCGGTGCGCACAGCAGCCTG 
               
               
                   
                   
               
               
                   
                 GACATCGCCTCCTTCTACTGGACCCTCACCAACAATGACACCCAC 
               
               
                   
                   
               
               
                   
                 ACGCAGGAGCCCTCTGCCCAGCAGGGTGAGGAGGTCCTCCGGCAG 
               
               
                   
                   
               
               
                   
                 CTGCAGACCCTGGCACCAAAGGGCGTGAACGTCCGCATCGCTGTG 
               
               
                   
                   
               
               
                   
                 AGCAAGCCCAGCGGGCCCCAGCCACAGGCGGACCTGCAGGCTCTG 
               
               
                   
                   
               
               
                   
                 CTGCAGAGCGGTGCCCAGGTCCGCATGGTGGACATGCAGAAGCTG 
               
               
                   
                   
               
               
                   
                 ACCCATGGCGTCCTGCATACCAAGTTCTGGGTGGTGGACCAGACC 
               
               
                   
                   
               
               
                   
                 CACTTCTACCTGGGCAGTGCCAACATGGACTGGCGTTCACTGACC 
               
               
                   
                   
               
               
                   
                 CAGGTCAAGGAGCTGGGCGTGGTCATGTACAACTGCAGCTGCCTG 
               
               
                   
                   
               
               
                   
                 GCTCGAGACCTGACCAAGATCTTTGAGGCCTACTGGTTCCTGGGC 
               
               
                   
                   
               
               
                   
                 CAGGCAGGCAGCTCCATCCCATCAACTTGGCCCCGGTTCTATGAC 
               
               
                   
                   
               
               
                   
                 ACCCGCTACAACCAAGAGACACCAATGGAGATCTGCCTCAATGGA 
               
               
                   
                   
               
               
                   
                 ACCCCTGCTCTGGCCTACCTGGCGAGTGCGCCCCCACCCCTGTGT 
               
               
                   
                   
               
               
                   
                 CCAAGTGGCCGCACTCCAGACCTGAAGGCTCTACTCAACGTGGTG 
               
               
                   
                   
               
               
                   
                 GACAATGCCCGGAGTTTCATCTACGTCGCTGTCATGAACTACCTG 
               
               
                   
                   
               
               
                   
                 CCCACTCTGGAGTTCTCCCACCCTCACAGGTTCTGGCCTGCCATT 
               
               
                   
                   
               
               
                   
                 GACGATGGGCTGCGGCGGGCCACCTACGAGCGTGGCGTCAAGGTG 
               
               
                   
                   
               
               
                   
                 CGCCTGCTCATCAGCTGCTGGGGACACTCGGAGCCATCCATGCGG 
               
               
                   
                   
               
               
                   
                 GCCTTCCTGCTCTCTCTGGCTGCCCTGCGTGACAACCATACCCAC 
               
               
                   
                   
               
               
                   
                 TCTGACATCCAGGTGAAACTCTTTGTGGTCCCCGCGGATGAGGCC 
               
               
                   
                   
               
               
                   
                 CAGGCTCGAATCCCATATGCCCGTGTCAACCACAACAAGTACATG 
               
               
                   
                   
               
               
                   
                 GTGACTGAACGCGCCACCTACATCGGAACCTCCAACTGGTCTGGC 
               
               
                   
                   
               
               
                   
                 AACTACTTCACGGAGACGGCGGGCACCTCGCTGCTGGTGACGCAG 
               
               
                   
                   
               
               
                   
                 AATGGGAGGGGCGGCCTGCGGAGCCAGCTGGAGGCCATTTTCCTG 
               
               
                   
                   
               
               
                   
                 AGGGACTGGGACTCCCCTTACAGCCATGACCTTGACACCTCAGCT 
               
               
                   
                   
               
               
                   
                 GACAGCGTGGGCAACGCCTGCCGCCTGCTCTGA 
               
             
          
         
       
     
         [0201]    Human PLD3 Protein (490 Amino Acids) (SEQ ID NO: 127) 
         [0000]    
       
         
               
               
             
           
               
                   
                 MKPKLMYQELKVPAEEPANELPMNEIEAWKAAEKKARWVLLVLIL 
               
               
                   
                   
               
               
                   
                 AVVGFGALMTQLFLWEYGDLHLFGPNQRPAPCYDPCEAVLVESIP 
               
               
                   
                   
               
               
                   
                 EGLDFPNASTGNPSTSQAWLGLLAGAHSSLDIASFYWTLTNNDTH 
               
               
                   
                   
               
               
                   
                 TQEPSAQQGEEVLRQLQTLAPKGVNVRIAVSKPSGPQPQADLQAL 
               
               
                   
                   
               
               
                   
                 LQSGAQVRMVDMQKLTHGVLHTKFWVVDQTHFYLGSANMDWRSLT 
               
               
                   
                   
               
               
                   
                 QVKELGVVMYNCSCLARDLTKIFEAYWFLGQAGSSIPSTWPRFYD 
               
               
                   
                   
               
               
                   
                 TRYNQETPMEICLNGTPALAYLASAPPPLCPSGRTPDLKALLNVV 
               
               
                   
                   
               
               
                   
                 DNARSFIYVAVMNYLPTLEFSUPHRFWPAIDDGLRRATYERGVKV 
               
               
                   
                   
               
               
                   
                 RLLISCWGHSEPSMRAFLLSLAALRDNHTHSDIQVKLFVVPADEA 
               
               
                   
                   
               
               
                   
                 QARIPYARVNHNKYMVTERATYIGTSNWSGNYFTETAGTSLLVTQ 
               
               
                   
                   
               
               
                   
                 NGRGGLRSQLEAIFLRDWDSPYSHDLDTSADSVGNACRLL 
               
             
          
         
       
     
         [0202]    Human PLD5 cDNA (1338 Base Pairs) (SEQ ID NO: 6) 
         [0000]    
       
         
               
               
             
           
               
                   
                 ATGGGAGAGGATGAGGATGGACTCTCAGAAAAAAATTGCCAAAAT 
               
               
                   
                   
               
               
                   
                 AAATGTCGAATTGCCCTGGTGGAAAATATTCCTGAAGGCCTTAAC 
               
               
                   
                   
               
               
                   
                 TATTCAGAAAATGCACCATTTCACTTATCACTTTTCCAAGGCTGG 
               
               
                   
                   
               
               
                   
                 ATGAATTTACTCAACATGGCCAAAAAGTCTGTTGACATAGTGTCT 
               
               
                   
                   
               
               
                   
                 TCCCATTGGGATCTCAACCACACTCATCCATCAGCATGTCAGGGT 
               
               
                   
                   
               
               
                   
                 CAACGTCTTTTTGAAAAGTTGCTCCAGCTGACTTCGCAAAATATT 
               
               
                   
                   
               
               
                   
                 GAAATCAAGCTAGTGAGTGATGTAACAGCTGATTCAAAGGTATTA 
               
               
                   
                   
               
               
                   
                 GAAGCCTTGAAATTAAAGGGAGCCGAGGTGACGTACATGAACATG 
               
               
                   
                   
               
               
                   
                 ACCGCTTACAACAAGGGCCGGCTGCAGTCCTCCTTCTGGATCGTG 
               
               
                   
                   
               
               
                   
                 GACAAACAGCACGTGTATATCGGCAGTGCCGGTTTGGACTGGCAA 
               
               
                   
                   
               
               
                   
                 TCCCTGGGACAGATGAAAGAACTCGGTGTCATCTTCTACAACTGC 
               
               
                   
                   
               
               
                   
                 AGCTGCCTGGTCCTAGATTTACAAAGGATATTTGCTCTATATAGT 
               
               
                   
                   
               
               
                   
                 TCATTAAAATTCAAAAGCAGAGTGCCTCAAACCTGGTCCAAAAGA 
               
               
                   
                   
               
               
                   
                 CTCTATGGAGTCTATGACAATGAAAAGAAATTGCAACTTCAGTTG 
               
               
                   
                   
               
               
                   
                 AATGAAACCAAATCTCAAGCATTTGTATCGAATTCTCCAAAACTC 
               
               
                   
                   
               
               
                   
                 TTTTGCCCTAAAAACAGAAGTTTTGACATAGATGCCATCTACAGT 
               
               
                   
                   
               
               
                   
                 GTGATAGATGATGCCAAGCAGTATGTGTACATCGCTGTCATGGAC 
               
               
                   
                   
               
               
                   
                 TACCTGCCTATCTCCAGCACAAGCACCAAAAGGACTTACTGGCCA 
               
               
                   
                   
               
               
                   
                 GACTTGGATGCAAAAATAAGAGAAGCATTAGTTTTACGAAGCGTT 
               
               
                   
                   
               
               
                   
                 AGAGTTCGACTCCTTTTAAGCTTCTGGAAGGAAACTGATCCCCTT 
               
               
                   
                   
               
               
                   
                 ACGTTTAACTTTATTTCATCTCTTAAAGCGATTTGCACTGAAATA 
               
               
                   
                   
               
               
                   
                 GCCAACTGCAGTTTGAAAGTTAAATTTTTTGATCTGGAAAGAGAG 
               
               
                   
                   
               
               
                   
                 AATGCTTGTGCTACAAAAGAACAAAAGAATCACACCTTTCCTAGG 
               
               
                   
                   
               
               
                   
                 TTAAATCGCAACAAGTACATGGTGACAGATGGAGCAGCTTATATT 
               
               
                   
                   
               
               
                   
                 GGAAATTTTGATTGGGTAGGGAATGATTTCACTCAGAATGCTGGC 
               
               
                   
                   
               
               
                   
                 ACGGGCCTTGTTATCAACCAGGCAGATGTGAGGAACAACAGAAGC 
               
               
                   
                   
               
               
                   
                 ATCATTAAGCAACTTAAAGATGTGTTTGAAAGGGACTGGTATTCA 
               
               
                   
                   
               
               
                   
                 CCGTATGCCAAAACCTTACAGCCAACCAAACAGCCGAACTGCTCA 
               
               
                   
                   
               
               
                   
                 AGCCTGTTCAAACTCAAACCCCTCTCCAACAAAACTGCCACAGAC 
               
               
                   
                   
               
               
                   
                 GACACAGGCGGAAAGGATCCCCGGAACGTATGA 
               
             
          
         
       
     
         [0203]    Human PLDS Protein (445 Amino Acids) (SEQ ID NO: 128) 
         [0000]    
       
         
               
               
             
           
               
                   
                 MGEDEDGLSEKNCQNKCRIALVENIPEGLNYSENAPFHLSLFQGW 
               
               
                   
                   
               
               
                   
                 MNLLNMAKKSVDIVSSHWDLNHTHPSACQGQRLFEKLLQLTSQNI 
               
               
                   
                   
               
               
                   
                 EIKLVSDVTADSKVLEALKLKGAEVTYMNMTAYNKGRLQSSFWIV 
               
               
                   
                   
               
               
                   
                 DKQHVYIGSAGLDWQSLGQMKELGVIFYNCSCLVLDLQRIFALYS 
               
               
                   
                   
               
               
                   
                 SLKFKSRVPQTWSKRLYGVYDNEKKLQLQLNETKSQAFVSNSPKL 
               
               
                   
                   
               
               
                   
                 FCPKNRSFDIDAIYSVIDDAKQYVYIAVMDYLPISSTSTKRTYWP 
               
               
                   
                   
               
               
                   
                 DLDAKIREALVLRSVRVRLLLSFWKETDPLTFNFISSLKAICTEI 
               
               
                   
                   
               
               
                   
                 ANCSLKVKFFDLERENACATKEQKNHTFPRLNRNKYMVTDGAAYI 
               
               
                   
                   
               
               
                   
                 GNFDWVGNDFTQNAGTGLVINQADVRNNRSIIKQLKDVFERDWYS 
               
               
                   
                   
               
               
                   
                 PYAKTLQPTKQPNCSSLFKLKPLSNKTATDDTGGKDPRNV 
               
             
          
         
       
     
         [0204]    Human PLD4-Ig Fusion Protein cDNA (2142 bp) (SEQ ID NO: 125) 
         [0000]    
       
         
               
               
             
           
               
                   
                 ATGGAGTTTCAGACCCAGGTCTTTGTATTCGTGTTGCTCTGGTTG 
               
               
                   
                   
               
               
                   
                 TCTGGTGTTGATGGAgattacaaggatgacgacgataaaGGATCC 
               
               
                   
                   
               
               
                   
                 cccagagggcccacaatcaagccctgtcctccatgcaaatgccca 
               
               
                   
                   
               
               
                   
                 gcacctaacctcttgggtggaccatccgtcttcatcttccctcca 
               
               
                   
                   
               
               
                   
                 aagatcaaggatgtactcatgatctccctgagccccatagtcaca 
               
               
                   
                   
               
               
                   
                 tgtgtggtggtggatgtgagcgaggatgacccagatgtccagatc 
               
               
                   
                   
               
               
                   
                 agctggtttgtgaacaacgtggaagtacacacagctcagacacaa 
               
               
                   
                   
               
               
                   
                 acccatagagaggattacaacagtactctccgggtggtcagtgcc 
               
               
                   
                   
               
               
                   
                 ctccccatccagcaccaggactggatgagtggcaaggagttcaaa 
               
               
                   
                   
               
               
                   
                 tgcaaggtcaacaacaaagacctcccagcgcccatcgagagaacc 
               
               
                   
                   
               
               
                   
                 atctcaaaacccaaagggtcagtaagagctccacaggtatatgtc 
               
               
                   
                   
               
               
                   
                 ttgcctccaccagaagaagagatgactaagaaacaggtcactctg 
               
               
                   
                   
               
               
                   
                 acctgcatggtcacagacttcatgcctgaagacatttacgtggag 
               
               
                   
                   
               
               
                   
                 tggaccaacaacgggaaaacagagctaaactacaagaacactgaa 
               
               
                   
                   
               
               
                   
                 ccagtcctggactctgatggacttacttcatgtacagcaagctga 
               
               
                   
                   
               
               
                   
                 gagtggaaaagaagaactgggtggaaagaaatagctactcctgtt 
               
               
                   
                   
               
               
                   
                 cagtggtccacgagggtctgcacaatcaccacacgactaagagct 
               
               
                   
                   
               
               
                   
                 tctcccggactccgggtaaaCGTCCTCCCACCTGGGGCCAGGTGC 
               
               
                   
                   
               
               
                   
                 AGCCCAAGGACGTGCCCAGGTCCTGGGAGCATGGCTCCAGCCCAG 
               
               
                   
                   
               
               
                   
                 CTTGGGAGCCCCTGGAAGCAGAGGCCAGGCAGCAGAGGGACTCCT 
               
               
                   
                   
               
               
                   
                 GCCAGCTTGTCCTTGTGGAAAGCATCCCCCAGGACCTGCCATCTG 
               
               
                   
                   
               
               
                   
                 CAGCCGGCAGCCCCTCTGCCCAGCCTCTGGGCCAGGCCTGGCTGC 
               
               
                   
                   
               
               
                   
                 AGCTGCTGGACACTGCCCAGGAGAGCGTCCACGTGGCTTCATACT 
               
               
                   
                   
               
               
                   
                 ACTGGTCCCTCACAGGGCCTGACATCGGGGTCAACGACTCGTCTT 
               
               
                   
                   
               
               
                   
                 CCCAGCTGGGAGAGGCTCTTCTGCAGAAGCTGCAGCAGCTGCTGG 
               
               
                   
                   
               
               
                   
                 GCAGGAACATTTCCCTGGCTGTGGCCACCAGCAGCCCGACACTGG 
               
               
                   
                   
               
               
                   
                 CCAGGACATCCACCGACCTGCAGGTTCTGGCTGCCCGAGGTGCCC 
               
               
                   
                   
               
               
                   
                 ATGTACGACAGGTGCCCATGGGGCGGCTCACCAGGGGTGTTTTGC 
               
               
                   
                   
               
               
                   
                 ACTCCAAATTCTGGGTTGTGGATGGACGGCACATATACATGGGCA 
               
               
                   
                   
               
               
                   
                 GTGCCAACATGGACTGGCGGTCTCTGACGCAGGTGAAGGAGCTTG 
               
               
                   
                   
               
               
                   
                 GCGCTGTCATCTATAACTGCAGCCACCTGGCCCAAGACCTGGAGA 
               
               
                   
                   
               
               
                   
                 AGACCTTCCAGACCTACTGGGTACTGGGGGTGCCCAAGGCTGTCC 
               
               
                   
                   
               
               
                   
                 TCCCCAAAACCTGGCCTCAGAACTTCTCATCTCACTTCAACCGTT 
               
               
                   
                   
               
               
                   
                 TCCAGCCCTTCCACGGCCTCTTTGATGGGGTGCCCACCACTGCCT 
               
               
                   
                   
               
               
                   
                 ACTTCTCAGCGTCGCCACCAGCACTCTGTCCCCAGGGCCGCACCC 
               
               
                   
                   
               
               
                   
                 GGGACCTGGAGGCGCTGCTGGCGGTGATGGGGAGCGCCCAGGAGT 
               
               
                   
                   
               
               
                   
                 TCATCTATGCCTCCGTGATGGAGTATTTCCCCACCACGCGCTTCA 
               
               
                   
                   
               
               
                   
                 GCCACCCCCCGAGGTACTGGCCGGTGCTGGACAACGCGCTGCGGG 
               
               
                   
                   
               
               
                   
                 CGGCAGCCTTCGGCAAGGGCGTGCGCGTGCGCCTGCTGGTCGGCT 
               
               
                   
                   
               
               
                   
                 GCGGACTCAACACGGACCCCACCATGTTCCCCTACCTGCGGTCCC 
               
               
                   
                   
               
               
                   
                 TGCAGGCGCTCAGCAACCCCGCGGCCAACGTCTCTGTGGACGTGA 
               
               
                   
                   
               
               
                   
                 AAGTCTTCATCGTGCCGGTGGGGAACCATTCCAACATCCCATTCA 
               
               
                   
                   
               
               
                   
                 GCAGGGTGAACCACAGCAAGTTCATGGTCACGGAGAAGGCAGCCT 
               
               
                   
                   
               
               
                   
                 ACATAGGCACCTCCAACTGGTCGGAGGATTACTTCAGCAGCACGG 
               
               
                   
                   
               
               
                   
                 CGGGGGTGGGCTTGGTGGTCACCCAGAGCCCTGGCGCGCAGCCCG 
               
               
                   
                   
               
               
                   
                 CGGGGGCCACGGTGCAGGAGCAGCTGCGGCAGCTCTTTGAGCGGG 
               
               
                   
                   
               
               
                   
                 ACTGGAGTTCGCGCTACGCCGTCGGCCTGGACGGACAGGCTCCGG 
               
               
                   
                   
               
               
                   
                 GCCAGGACTGCGTTTGGCAGGGCTGA 
               
             
          
         
       
     
         [0205]    Human PLD4-Ig Fusion Protein (713 Amino Acids) (SEQ ID NO: 126) 
         [0000]    
       
         
               
               
             
           
               
                   
                 MEFQTQVFVFVLLWLSGVDGDYKDDDDKGSPRGPTIKPCPPCKCP 
               
               
                   
                   
               
               
                   
                 APNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQI 
               
               
                   
                   
               
               
                   
                 SWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFK 
               
               
                   
                   
               
               
                   
                 CKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTL 
               
               
                   
                   
               
               
                   
                 TCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKL 
               
               
                   
                   
               
               
                   
                 RVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGKRPPTWGQV 
               
               
                   
                   
               
               
                   
                 QPKDVPRSWEHGSSPAWEPLEAEARQQRDSCQLVLVESIPQDLPS 
               
               
                   
                   
               
               
                   
                 AAGSPSAQPLGQAWLQLLDTAQESVHVASYYWSLTGPDIGVNDSS 
               
               
                   
                   
               
               
                   
                 SQLGEALLQKLQQLLGRNISLAVATSSPTLARTSTDLQVLAARGA 
               
               
                   
                   
               
               
                   
                 HVRQVPMGRLTRGVLHSKFWVVDGRHIYMGSANMDWRSLTQVKEL 
               
               
                   
                   
               
               
                   
                 GAVIYNCSHLAQDLEKTFQTYWVLGVPKAVLPKTWPQNFSSHFNR 
               
               
                   
                   
               
               
                   
                 FQPFHGLFDGVPTTAYFSASPPALCPQGRTRDLEALLAVMGSAQE 
               
               
                   
                   
               
               
                   
                 FIYASVMEYFPTTRFSHPPRYWPVLDNALRAAAFGKGVRVRLLVG 
               
               
                   
                   
               
               
                   
                 CGLNTDPTMFPYLRSLQALSNPAANVSVDVKVFIVPVGNHSNIPF 
               
               
                   
                   
               
               
                   
                 SRVNHSKFMVTEKAAYIGTSNWSEDYFSSTAGVGLVVTQSPGAQP 
               
               
                   
                   
               
               
                   
                 AGATVQEQLRQLFERDWSSRYAVGLDGQAPGQDCVWQG 
               
             
          
         
       
     
       Accession Numbers 
     NITE ABP-1211 
     NITE ABP-1212 
     NITE ABP-1213 
     NITE ABP-1214 
     SEQUENCE LISTING FREE TEXT 
       [0206]    SEQ ID NO: 45: Forward primer
 
SEQ ID NO: 46: Reverse primer
 
SEQ ID NO: 47: Forward primer
 
SEQ. ID NO: 48: Reverse primer
 
SEQ ID NO: 49: Forward primer
 
SEQ ID NO: 50: Reverse primer
 
SEQ ID NO: 51: Forward primer
 
SEQ ID NO: 52: Reverse primer
 
SEQ ID NO: 53: Forward primer
 
SEQ ID NO: 54: Reverse primer
 
SEQ ID NO: 70: Anchor primer
 
SEQ ID NO: 70: n is deoxyinosine
 
SEQ ID NO: 71: AUAP primer
 
       SEQ ID NO: 72: Primer 
     SEQ ID NO: 73: Primer 
     SEQ ID NO: 114: Primer 
     SEQ ID NO: 115: Primer 
     SEQ ID NO: 116: Primer 
     SEQ ID NO: 117: Primer 
     SEQ ID NO: 118: Primer 
     SEQ ID NO: 119: Primer 
     SEQUENCE LISTING 
       [0207]