bluuebunny/crossref_metadata_2025 huggingface dataset:
Killer cell receptors: keeping pace with MHC class I evolution
Authors: Valiante Nicholas M. , Lienert Kristin , Shilling Heather G. , Smits Bouwien J. , Parham Peter
Published: April 2006

Summary: NK cells express receptors that bind to polymorphic determinants of MHC class 1 heavy chains. MHC ligands vary greatly between mammalian species, and the use of distinct molecular families of NK ceil receptors by humans and mice suggests that the receptors too can be evolving rapidly. The KIR (killer cell inhibitory receptor) family of receptors are found in primates and recognize c lass I epitopes that are of relatively recent origin in primate evolution. Therefore. KIR molecules have probably evolved class I receptor function more recently than C type lectins, which are represented in both humans and mice. Individual humans express NK cell receptors for which they have no class I ligand. demonstrating a loose ness ill the coupling of expression between the receptors and their ligands. However, study of a single donor suggests that every NK cell expresses at least one inhibitory receptor for a self‐HLA class I allotype, consistent with the missing self hypothesis. Thus the NK‐cell receptor‐class I interaction appears to control the NK‐cell repertoire during ontogeny of the individual and has the potential to be a selective factor influencing both MHC class I and NK cell receptor diversity in the evolution of populations and species.
Structure and function of the CD94 C‐type lectin receptor complex involved in recognition of HLA class I molecules
Authors: López‐Botet Miguel , Pérez‐Villar Juan J. , Carretero Marta , Rodríguez Antonio , Melero Ignacio , Bellón Teresa , Llano Manuel , Navarro Francisco
Published: April 2006

Summary: A multigene family of immunoglobulin superfamily (Ig‐SF) killer cell inhibitory receptors (KIRs) specifically recognize HLA class I molecules, while the interaction with H‐2 products is mediated by members of the murine Ly49 C‐type lectin family. A common structural feature of these receptors with inhibitory function is the presence of cytoplasmic immunoreceptor tyrosine‐based inhibitory motifs (ITIMs) that couple them to SHP phosphatases. Strong support for the involvement of the CD94 C‐type lectin receptor complex in NK cell‐mediated recognition of Bw6+ HLA‐B, HLA A and HLA‐C alleles has been obtained. The cloned CD94 molecule covalently assembles with at least two different glyco‐proteins (43 kDa and 39 kDa) to form functional receptors. NK cells inhibited upon HLA recognition express the CD94/p43 dimer, whose specificity for HLA molecules partially overlaps the Ig‐SF receptor system. By contrast. NK clones bearing the homologous CD94/p39 receptor are triggered upon its ligation by CD94‐specific mAbs. Remarkably, a set of Ig‐SF receptors (p50) homologous to p58 KIRs also display an activating function. CD94‐associated molecules belong to the NKG2 family of C‐type lectins; the NKG2‐A gene encodes for the p43 subunit. which contains cytoplasmic ITIMS. Expression of the different CD94 heterodimeric receptors will enable precise analysis of their putative interaction with HLA class I molecules.
Domain organization and sequence relationship of killer cell inhibitory receptors
Authors: Salter Russell D. , Chan Huei‐Wei , Tadikamalla Raghu , Lawlor David A.
Published: April 2006

Summary: Natural killer (NK) cells recognize class I HLA molecules via a family of related receptors composed of two Or three Ig‐like domains. Using neighbor‐joining analysis of available sequences, groups of these receptors were identified that are likely to share specificity in HLA binding, which in some cases had been previously determined for individual group members. Subgroups or clades were further identified which did tint appear to correlate with ligand binding, but instead reflect differences in the cytoplasmic region of the proteins. The Ig‐like domains, which form the extracellular segment responsible for specificity of HLA recognition, were individually shown to be characteristic of specific groups of receptors, and do not appear to have been assorted between groups. Thus it does not appear that recombination of domains played a major role in generating diversity within regions of these proteins important for HLA binding. Finally, the Ig‐like domains of KIR proteins are shown to be between 35‐45% identical to those of CD89, a receptor for IgA on myeloid cells. This level of homology, combined with their shared localization on chromosome 19q13.4, suggests a common evolutionary origin.
Polymorphism and domain variability of human killer cell inhibitory receptors
Authors: Selvakumar Annamalai , Steffens Uwe , Dupont Bo
Published: April 2006

Summary: Thirty‐two different full‐length cDNA clones for human killer cell inhibitory receptors (KIR) have been identified. They all belong to the immunoglobulin superfamily and encode mature proteins with one, two or three extracellular Ig domains. The inhibitory receptors have nearly identical transmembrane domains and cytoplasmic domains ranging in length from 76 to 95 amino‐acid residues. The activating receptors have a characteristic transmembrane domain with a charged lysine residue and a short cytoplasmic tail without the protein tyrosine phosphatase binding motif I/VXYXXL present in the inhibitory receptors. Sequence analysis demonstrates that three clusters correspond to the inhibitory receptors of 58 kDa, while two clusters encode activating receptors of 50 kDa. TWD other clusters correspond to the inhibitory receptors of 70 kDa and one cluster encodes genes with sequence homology to one of the two p70 clusters but contains the transmembrane and cytoplasmic domains characteristic of activating receptors. The data are consistent with a genomic organization of the KIR genetic region containing at least three KIR genes encoding receptors for each of the gene products of the HLA class I loci. Alternative mRNA splicing could be responsible for generation of activating or inhibitory receptors with the same extracellular domains. Separate genes encoding receptors with opposite function is, however, an equally likely possibility.
Follicular dendritic cells and presentation of antigen and costimulatory signals to B cells
Authors: Tew John G. , Wu Jiuhua , Qin Dahui , Helm Shirley , Burton Gregory F. , Szakal Andrus K.
Published: April 2006

Summary: This review focuses on how immunogens trapped by FDC In the form of Ag‐Ab complexes productively signal B cells. In vitro, Ag‐Ab complexes are poorly immunogenic but m vivo immune complexes elk ii potent recall responses. FDC trap Ag‐Ab complexes and make immune complex mated bodies or “iccosomes”. B cells endocytose iccosomes, the Ag is processed, and T‐cell help is elicited. In vitro, addition of FDC bearing appropriate Ag‐Ab complex to memory T and B cells provoke potent recall responses (IgG and IgE). FDC also provide nonspecific costimulatory signals which augment B‐cell proliferation and Ab production. B cell‐FDC contact is important and interference with ICAM‐1‐LFA‐1 interactions reduces FDC‐mediated costimulation. Preliminary data suggest that a costimulatory signal may be delivered via CRZL on FDC binding CR2 on B cells. FDC can also stimulate B cells to become chemotactically active and can protect lymphocytes from apoptosis. FDC also appear to be rich in that groups and may replace reducing compounds such as 2 mercaptoethanol in cultures. In short, FDC‐Ag specifically signals B cells through BCR, and FDC provide B cells with iccosomal‐Ag necessary for processing to elicit T i ell help. In addition, FDC provide nonspecific signals that are important to promote B‐cell proliferation, maintain viability, and induce chemotactic responsiveness.
Signaling thresholds and interclonal competition in preimmune B‐cell selection
Authors: Cyster Jason G.
Published: April 2006

Summary: The need to eliminate autoreactive B cells must be checked against the need for a diverse B‐cell repertoire. Protein tyrosine phosphatases SHPI and CD45 act antagonistically within B cells to set the threshold level of antigen‐receptor engagement required for B‐cell elimination. The fate of B cells binding weak autoantigens is also regulated by interclonal competition. In the presence of a normal diverse repertoire of competitor B cells, the autoantigen‐binding cells are excluded from follicles in spleen and lymph nodes and undergo rapid cell death. IN the absence of interclonal competition, the autoreactive cells enter the follicular microenvironment and survive. A model m which B cells compete for access to limiting follicular niches in order to survive is discussed.
A vision of cell death: insights into immune privilege
Authors: Ferguson Thomas A. , Griffith Thomas S.
Published: April 2006

Summary: Immune privilege is a term applied to several organs that have a unique relationship with the immune response. These sites prohibit the spread of inflammation since even minor episodes can threaten organ integrity and function. The most prominent examples of these are the eye, brain and reproductive organs where immune responses either do not proceed, or proceed in a manner different from other areas. Once thought to be a passive process relying on physical barriers, immune privilege can now be viewed as an active process that utilizes multiple mechanisms to maintain organ function. Recently there has been a renewed interest in immune privilege when it was shown that two privileged sites (the eye and testes) constitutively express FasL, which functions by killing lymphoid cells that invade these areas. Here we will examine the role of FasL in immune privilege and discuss how this molecule interacts with other elements of the inflammatory response to maintain organ integrity in the face of potentially damaging immune reactions.
Immunobiology and immunotherapeutic implication of syneneic/autologous graft‐versus‐host disease
Authors: Hess Allan D. , Thoburn Christopher J.
Published: April 2006

Summary: Administration of the immunosuppressive drug cyclosporine (CsA) after syngeneic/autologous bone marrow transplantation (BMT) elicits an autoimmune syndrome with pathology virtually identical to graft‐vs‐host disease (GVHD). The induction of this syndrome, termed syngeneic/autologous GVHD, is a two‐tiered process requiring both the active inhibition of thymic‐dependent clonal deletion and the elimination of mature T cells that have an immunoregulatory effect. Eradication of the peripheral immunoregulatory compartment by the preparative regimen provides a permissive environment for the activation of the syngeneic/autologous GVHD effector T cells. Although the repertoire of autoreactive effector T lymphocytes is highly conserved, these T cells promiscuously recognize MHC class II determinants. This novel specificity of the autoreactive lymphocytes appears to he dependent on the peptide derived from the MHC class 11 invariant chain. Recent studies also suggest that these promiscuous autoreactive T cells can effectively target and eliminate MHC class Il‐expressing tumor cells. Administration of cytokines that upregulate the target antigen or expand the effector population can potentiate the antitumor activity of syngeneic/autologous GVHD, Although the induction of syngeneic/autologous GVHD is an untoward effect of CsA immunosuppression, mobilization of these autoimmune mechanisms provides a promising immunotherapeutic approach for certain neoplastic diseases.
Human minor histocompatibility antigens: new concepts for marrow transplantation and adoptive immunotherapy
Authors: Goulmy Els
Published: April 2006

Summary: Bone marrow transplantation (BMT) is the present treatment for hematological malignancies, Two major drawbacks of allogeneic BMT are graft‐versus‐host disease (GVHD) and leukemia relapse. The use of HLA‐matched siblings as marrow donors results in the best transplant outcome. Nonetheless, the results of clinical BMT reveal that the selection of MHC‐identical donors'bone marrow (BM) is no guarantee for avoiding GVHD or ensuring disease‐free survival even when donor and recipient are closely related. It is believed that non‐MHC‐encoded so‐called minor histocompatibility antigens (mHag) are involved in both graft‐versus‐host and graft‐versus‐leukemia activities. The recent new insights into the chemical nature of mHag not only reveal their physiological function but, more importantly, provide insights into their rule in BMT. Together with the information on the human mHag genetics and tissue distribution gathered in the past, we may now apply this knowledge to the benefit of human BMT. Directly relevant is the utility of mHag molecular typing for diagnostics in BM donor selection. Most promising is the use of mHag‐specific cytotoxic T cells for adoptive immunotherapy of leukemia.
Factors influencing the outcome of bone marrow transplants using unrelated donors
Authors: Madrigal J. Alejandro , Scott Iain , Arguello Rafael , Szydlo Richard , Little Ann‐Margaret , Goldman John M.
Published: April 2006

Summary: The use of unrelated donors for bone marrow transplantation (BMT) is associated with an increased morbidity and mortality when compared with HLA‐identica3 donors, primarily due to an increased rate of graft‐versus‐host disease, but also to increased susceptibility to infections and graft failure. HLA matching for donors and recipients is the single most important factor influencing the outcome of BMT. However, unrelated donor selection generally relies on matching only for HLA‐A,‐B and ‐DR antigens without considering potential incompatibility for other HLA loci, such as HLA‐C.‐DQ and ‐DP In addition, other factors that affect the outcome of BMT need to be taken into consideration in selecting the best unrelated donor. In this review, we will focus on the effects of HLA‐associated factors in determining the result of a transplant procedure. We will also mention other relevant factors, drawing on our experience of laboratory studies performed at The Anthony Nolan Research Institute and clinical studies at the Hammersmith Hospital in London.
The potential role of NK cells in the separation of graft‐versus‐tumor effects from graft‐versus‐host disease after allogeneic bone marrow transplantation
Authors: Murphy William J. , Longo Dan L.
Published: April 2006

Summary: Allogeneic bone marrow transplantation (BMT) is being increasingly used for the treatment of a variety of cancers ranging from leukemias to breast cancer. However, significant obstacles currently limit the efficacy of this treatment procedure. The predominant two are the occurrence of graft‐versus‐host disease (GVHD) and relapse from the cancer. While regimens exist that prevent the occurrence or severity of GVHD these same regimens also increase the rate of relapse. Conversely, most attempts to reduce the relapse rate also result in increased GVHD. The use of NK cells as an adoptive immunotherapy after BMT is attractive for several reasons. NK cells exhibit antitumor effects both in vitro and in animal models and may, therefore, promote graft‐versus‐tumor (GVT) effects to remove minimal residual disease after allogeneic BMT. NK cells have also been shown to promote hematopoietic engraftment and donor cell reconstitution after allogeneic BMT in mice. The effects of NK cells on hematopoietic are believed to be due to the hematopoietic growth factors they can produce after activation. Another advantage in using NK cells is that they can prevent the occurrence of GVHD after allogeneic BMT in mice. This effect is mediated at least in part by the immunosuppressive cytokine, transforming growth factor beta (TGF‐β). BMT studies in mice also indicate that the beneficial effects of NK cells are optimal if they are administered soon after the transplant. Thereafter NK cells and, more importantly. IL‐Z, which is used to activate them, are detrimental and can exacerbate the subsequent GVHD, Thus, the use of activated NK cells after allogeneic BMT may provide GVT effects without inducing GVHD.
Cellular immunotherapy and autologous transplantation for hematologic malignancy
Authors: Margolin Kim A , Negrin Roberts S. , Wong Kumehameha K. , Chatterjee Sawati , Wright Christine , Forman Stephen J.
Published: April 2006

Summary: The success of allogeneic transplantation is in part due to the immunotherapeutic effect mediated by the graft, Autologous transplantation is hampered by the absence of this effect, leading to a higher relapse rate. We have conducted a series of studies designed to augment the immunologic activity of the graft after autologous transplant with a view towards introducing an autologous graft‐versus‐tumor effect that could decrease the rate of relapse after autologous transplant. These studies have included IL‐2 activation of marrow followed by post‐transplant infusional IL‐2. the development of a novel protocol for the generation of highly efficient cytotoxic effector cells, termed cytokine‐induced killer (CiK) cells, with broad and potent antitumor activity. In order to determine the potential for generating peptide‐specific cytolytic T cells, studies have been conducted upon transducing antigen‐presenting cells (APC) with AAV vector‐mediated gene transfer, a vector capable of transducing non‐proliferating target cells. Transduction of human monocytes and macrophages resulted in high expression of the transduced gene. This latter study forms the basis for determining whether genetic modification of APC can potentiate specific immune responses to tumor‐specific gene products. Taken together, these strategies will hopefully increase the therapeutic efficacy of autologous transplantation.
Responses by murine macrophages infected with Listeria monocytogenes crucial for the development of immunity to this pathogen
Authors: Kuhn Michael , Goebel Werner
Published: April 2006

Summary: Macrophages and other mammalian cells respond lo infection with Listeria monocytogenes (L. monocytogenes) by the transient or persistent activation of host cell signal transduction pathways. In addition, L. monocytogenes infection influences expression of various host cell genes, such as stress genes, genes from the MHC I and II complex, cytokine genes, and cytokine receptor genes. The possible influences of the different host cell responses on the outcome of an L. monocytogenes infection in vitro as well as for the development of immunity are discussed.
Cytokines in the induction and expression of T‐cell‐mediated granuloma formation and protection in the murine model of listeriosis
Authors: Mielke Martin E. A. , Peters Christian , Hahn Helmut
Published: April 2006

Summary: Lymphocyte‐mediated inflammation is a hallmark of autoimmune diseases, such as multiple sclerosis, Crohn's disease, rheumatoid arthritis and sarcoidosis. However, this type of inflammation probably developed under evolutionary pressure from pathogenic microorganisms, such as mycobacteria and other intracellular infective agents. One such pathogen, the gram‐positive bacterium Listeria monocytogenes (L. monocytogenes), induces a cascade of tissue alterations that ultimately results in the eradication of the bacteria associated with a granulomatous response. Consequently, murine listeriosis has been established as a model to analyze not only T‐cell‐dependent antibacterial protection but also T‐cell‐mediated mononuclear inflammation in parenchymal organs. Extensive studies of the molecular basis of the latter phenomenon led to the conclusion that the most decisive step from non‐specific microabscess formation to granulomatous inflammation is the activation of non‐specifically invading CD4+ T cells, which results in high local concentrations of TNF‐α and IFN‐γ in the presence of IL‐2. This in turn induces CD11b‐independent mechanisms of intraparenchymal monocyte accumulation. Because any attempt to neutralize the effects of TNF‐α and IFN‐γ to modulate T‐cell‐mediated inflammation will also dramatically decrease host resistance, other anti‐inflammatory strategies based on the modulation of TNF‐α and IFN‐γ‐induced mechanisms of monocyte accumulation must be developed. Recalling the classical work by Dienes & Schoenheit on the induction d bacterial allergies (1), the cytokine phenotype of granuloma formation also has implications as regards the most potent adjuvant environment for the development of a T‐cell response. The murine listeriosis model is the basis for all conclusions in this article on the role of cytokines in the induction and expression of T‐cell‐mediated inflammation and. as we will show, promises to yield still more insights into the rational design of vaccines.
The role of antibody in recovery from alphavirus encephalitis
Authors: Griffin Diane , Levine Beth , Tyor William , Ubol Sukathida , Desprès Philippe
Published: April 2006

Alphaviruses infect neurons in the brain and spinal cord and cause acute encephalomyelitis in a variety of mammals. The outcome of infection is determined by whether the neurons survive infection and this, in turn, is determined by the virulence of the virus and the age of the host at the time of infection. We have been studying Sindbis virus (SV) infection i of mice as a model system for alphavirus‐induced encephalomyelitis. Investigation of intracerebral infection of weanling mice with two different strains of SV bas allowed us to analyze the role of the immune response in protection from fatal disease virulent NSV strain) and in CLEARANCE of virus from the nervous system during non‐fatal disease (less virulent SV AR339 strain). Neutralizing and non‐neutralizing antibodies to the El and E2 surface glycoproteins can protect mice from fatal NSV infection when given before or after infection, while T cells are not protective, The mechanism of antibody‐mediated protection is not known, but it is likely that more than one mechanism Is involved and that different mechanisms are involved in pre‐infection and post‐infection treatment protection. Clearance of infectious virus from the nervous system of mice during recovery from non‐fatal disease is accomplished by antibodies to the E2 glycoprotein. The process does not involve damage to the infected neurons and is independent of complement and mononuclear cells. Bivalent antibody is required and binds to the surface of the infected cell. Initially, release of virus by budding from the cell surface is prevented and, subsequently, intracellular virus replication is inhibited possibly through antiviral mechanisms induced in co‐operation with interferon. This non lytic mechanism for control of virus infection results in the prolonged presence of viral RNA in tissue and the need for prolonged intrathecal synthesis of antiviral antibody by B cells within the central nervous system.
The essential self: a commentary on Silverstein and Rose “On the mystique of the immunological self”
Authors: Langman Rodney E. , Cohn Melvin
Published: April 2006

Historical precedent supports an argument that a variety of factors, including the physical and chemical nature of the antigen, dose, timing, mode of access to the immune system, etc., combine to make a self‐nonself discrimination. This argument requires that specificity be ignored and the myriad of parameters that affect the class and magnitude of the response be dealt with — what might be called the immunogenicity‐tolerogenicity discrimination. Just as there can be no immune response if there are no specific receptors available, so the presence of immune receptors does not guarantee that an immune response will occur, and factors that contribute to the regulation of the magnitude and class of the immune response cannot be used to determine if a receptor is anti‐self or anti‐nonself.
Altered peptide ligand design: altering immune responses to class I MHC/peptide complexes
Authors: Collins Edward J. , Frelinger Jeffrey A.
Published: April 2006

Summary: Class I proteins are responsible for binding proteins from endogenously synthesized proteins and displaying them on the cell surface. Our understanding of this process has reached the point where we can manipulate the biochemical properties of peptide/class I binding and determine the effects of this alteration on subsequent immune responses. In this article, we will review the biochemistry of peptide/class I binding, and the effects of structure on this interaction between class I proteins and their peptide ligands. We will review the data which suggest that the major relevant biochemical parameter of dass I peptide binding is the off‐rate. We will show that the design of altered ligands with improved binding, thermostability and immunogenicity is possible.
Modulation by epitope‐specific antibodies of class II MHC‐restricted presentation of the tetanus toxin antigen
Authors: Watts Colin , Antoniou Antony , Manoury Bénédicte , Hewitt Eric W , Mckay Lynn M. , Grayson Lisa , Fairweather Neil R , Emsley Paul , Isaacs Neil , Simits Phaedra D.
Published: April 2006

Summary: Above a certain affinity the dissociation rate of monovalent antigen from antibody becomes slower than the time taken for antigen capture, endocytosis and processing by professional antigen presenting cells. Thus, when high affinity antibodies drive antigen uptake, either directly via B‐cell membrane immunoglobulin or indirectly via Fc receptors, the substrate for processing may frequently be an antigen/antibody complex. Here we review studies using the tetanus toxin antigen which show that bound antibodies can dramatically affect proteolytic processing, dependent on the epitope specificity and multiplicity of antibodies bound. Certain antibodies protect or ‘footprint’ specific domains of the antigen during processing in B‐cell clones resulting in modulation of loading of class II MHC‐restricted T‐cell epitopes, Processing and class II MHC loading of some T‐cell epitopes within the footprinted region was hindered, as might be expected, but. surprisingly, presentation of other T‐cell epitopes was boosted considerably These studies show that protein/protein complexes can be processed in an unpredictable fashion by antigen presenting cells and indicate a possible mechanism whereby cryptic T‐cell epitopes might be revealed in autoimmune disease.
Myelin protein expression in lymphoid tissues: implications for peripheral tolerance
Authors: Voskuhl Rhonda R.
Published: April 2006

Summary: During chronic relapsing experimental autoimmune encephalomyelitis (EAE), T lymphocytes specific for myelin protein epitopes are stimulated in vivo. When epitopes are unique from the disease‐initiating myelin protein epitope, this phenomenon has been termed “epitope spreading”. These T‐lymphocyte responses have been detected primarily in lymph node and spleen during the relapsing phase of disease. If myelin proteins are sequestered behind the blood brain barrier, a fundamental question arises; where does the in vivo stimulation of T lymphocytes occur during relapsing EAE? While it has been thought that epitope spreading may occur within the central nervous system (CNS), here we present data supporting a novel hypothesis. Epitope spreading during EAE may not occur within the CNS, but rather within lymphoid tissues. Both myelin basic protein (MBP) and proteolipid protein (PLP) are expressed at the RNA and protein level in lymph node, thymus and spleen of SJL mice with relapsing EAB. This myelin protein expression occurs within T lymphocytes, B lymphocytes and macrophages. Further, T‐lymphocyte lines from SJL mice specific for the immunodominant and subdominant epitopes of MBP and PLP can recognize endogenous protein within cells derived from lymphoid tissues. Thus, immunologically relevant myelin proteins are endogenously produced and presented within lymphoid tissues. The hypothesis that epitope spreading occurs within lymphoid tissues would explain how myelin protein‐specific T lymphocytes become activated outside the CNS to allow their passage through the blood brain barrier to form new CNS lesions during relapses.
Diversification of response to hsp65 during the course of autoimmune arthritis is regulatory rather than pathogenic
Authors: Moudgil Kamal D.
Published: April 2006

Summary: Determinant spreading has been implicated in the pathogenesis of certain autoimmune diseases in animal models. We have observed that during the course of adjuvant arthritis (AA) in the Lewis rat, there is ‘diversification’ of response to the bacterial 65‐kDa heat shock protein (Bhsp65) towards its carboxy‐terminal determinants (BCTD). Strikingly, pretreatment of naive Lewis rats with BCTD affords significant protection from AA. Our preliminary studies indicate that the diversification of response to BCTD in the Lewis rat is probably triggered in vivo by the induction and enhanced processing of self(rat) hsp65. Thus, the self hsp65‐directed T‐cell responses appear to be involved in mediating natural remission from acute inflammatory arthritis induced by a foreign antigen, Myco‐bacterium tuberculosis. This the first report describing that the new T‐cell specificities arising during the course of an autoimmune disease are regulatory/protective rather than pathogenic. Moreover, our results suggest that a final common mechanism involving BCTD might be recruited by other rac strains which either are resistant to AA (WKY rats) or whose susceptibility to AA is modulated significantly by microbial flora (Fisher rats). The results of this study would contribute significantly to understanding of the pathogenesis of human rheumatoid arthritis, and in devising new therapeutic strategies for this disease.
Role of interleukin‐7 in T‐cell development from hematopoietic stem cells
Authors: Akashi Koichi , Kondo Motonari , Weissman Irving L
Published: April 2006

Summary: All lymphocytes are derived from hematopoietic stem cells (HSC). The interleukin‐7 receptor (IL‐7R) transduces non‐redundant signals for both T and B‐cell development from HSC. The upregulation of the IL‐7R occurs at the stage of the clonogenic common lymphoid progenitor, a recently identified population that can give rise to all lymphoid lineages (T, B and natural killer cells) at a single cell level. The IL‐7R plays a critical role in the rearrangement of immunoglobulin heavy chain genes required for B‐cell development, IL‐7R expression is critically regulated in developing thymocytes; thytnocytes that fail the positive selection process down‐regulate the IL‐7R, but those undergoing positive selection upregulate or maintain IL‐7R expression. Recent data indicate that IL‐7 signaling enhances the survival of developing thymocytes and mature T ceils, presumably by its upregulating Bcl‐2. Detailed analysis of the signaling cascades activated by the IL‐7R may help to reveal the differential roles of IL‐7 signaling in T and B‐cell development.
T‐cell survival
Authors: Marrack Philippa , Mitchell Tom , Bender Jeremy , Hildeman David , Kedl Ross , Teague Kent , Kappler John
Published: April 2006

Summary: Like other cells, T cells are dependent on signals from their environment for their survival. Resting T cells are supported in vitro by cytokines such as interleukin (IL)‐4, IL‐6 and IL‐7. The latter two cytokines are made constitutively in animals and hence might affect the lifetimes of their resting T cells. Resting T cells are also kept alive by interaction with an as yet unidentified molecule on the surface of other cells. Activated T cells are also supported in vitro by members of two families of these proteins, the IL‐2 family and the interferon‐αβ family. Members of the latter family may have effects on activated cells in vivo. Thus although both resting and activated T cells require signals to keep themselves alive, the signals are different for the two types of cells. This perhaps allows the immune response to control the numbers of activated cells during infections without compromising its pool of precursor, resting T cells.
T‐cell receptors in ectothermic vertebrates
Authors: Charlemagne Jacques , Fellah Julien S. , Guerra Arnaud De , Kerfourn Fabienne , Partula Sylvie
Published: April 2006

Summary: The structure and expression of genes encoding molecules homologous to mammalian T‐cell receptors (TCR) have been recently studied in ectothermic vertebrate species representative of chondrychthians, teleosts, and amphibians. The overall TCR chain structure is well conserved in phylogeny: TCRβ‐ and TCRα‐like chains were detected in all the species analyzed; TCRγ‐ and TCRS‐like chains were also present in a chondrychthian species. The diversity potential of the variable (V) and joining (J) segments is rather large and, as in mammals, conserved diversity (D) segment are associated to the TCRβ and TCR5 chains. An important level of junctional diversity occurred at the V‐(D)‐J junctions, with the potential addition of N‐ and P‐nucleotides.

Thus, the conservation of the structure and of the potential of diversity of TCR molecules have been under a permanent selective pressure during vertebrate evolution. The structure of MHC class I and class II molecules was also well conserved in jawed vertebrates. TCR and MFJC molecules are strongly functionally linked and play a determinant role in the initiation and the regulation of the specific immune responses; thus, it is not surprising that their structures have been reciprocally frozen during evolution.
The immunoglobulin light chain in poikilothermic vertebrates
Authors: Pilström Lars , Lundqvist Mats L , Warminster Niklas E. , Pilström Lars , Lundqvist Muts L. , Wermenstam Niklas E.
Published: April 2006

Summary: The immunoglobulin light chains are classified as κ or δ in mammals and birds (homoeothermic vertebrates), but the traditional criteria for this classification are not applicable to the light chains found in poikilothermic vertebrates. Still it is possible to find some relationships between Ig light chain sequences in these animals and in those of the homoeothermic animals. It is generally accepted that the Ig light chains contribute to the antigen binding capacity of antibodies and the variability is approximately similar in all studied vertebrate species except the elasmobranchs. This might be explained by the organisation of the Ig light chain locus in these animals and the fact that the variable and joining DNA segments are joined in the genome. These conclusions are limited by the small number of species studied in this respect.
Varied redox forms of teleost IgM: an alternative to isotypic diversity?
Authors: Kaattari Stephen , Evans David , Klemer John , Kaattari Stephen , Evans David , Kieraer John
Published: April 2006

Summary: Teleosts (bony fish) are thought to primarily or exclusively possess a single, structural form of immunoglobulin (Ig), a tetrameric IgM. However, in species wherein intact Ig has been electrophoretically analyzed under denaturing, non‐reducing conditions, a significato degree of structural diversity has been revealed. This IgM molecule appears to be assembled with great latitude in the degree of disulfide crosslinking between monomeric or hallmark subunits composing the complete IgM molecule. This heterogeneity in the basic structure (herein referred to as redox forms) is not due to isotopic differences as each B cell produces this heterogeneity within its immunoglobulin product. Additionally, in the case of the catfish, a single fish/mouse chimeric Ig H gene is capable of producing IgM with a comparable amount of structural heterogeneity within the mouse cell. Thus, the piscine B lymphocyte routinely assembles a variety of redox forms from one IgM H chain. This has both profound biosynthetic implications for macromolecular assembly processes as well as intriguing possibilities for the generation of teleost Ig functional diversity.
The impact of ancestral tetraploidy on antibody heterogeneity in salmonid fishes
Authors: Hordvik Ivar
Published: April 2006

Summary: The immunoglobulin heavy chain locus in teleost fish is structurally similar to that in mammals, comprising a series of variable gene segments upstream of two constant region genes coding for IgM and IgD. Atlantic salmon have been shown to possess two distinct heavy chain loci, related to the tetraploid ancestry of this fish family. The nature (and results) of the evolutionary processes following the tetraploidization event are the focus of this review. Salmonid fish did not return quickly to a diploid state, but are still in the process of re‐establishing disomic inheritance. Thus, a specific locus in one species may still be endowed with four alleles, while it may have been converted to a pair of isoloci in another species. Analyses of immunoglobulin heavy chain genes in Atlantic salmon (Salmo salar) have strongly indicated that the ancestral heavy chain locus was subjected to tetrasomy throughout the radiation of the genera Oncorhynchus and Salmo, and that disomic inheritance was established in the Salmo lineage in the comparatively recent past. The introduction of disomic inheritance at these loci has resulted in two subsets of IgM and IgD heavy chains in Atlantic salmon.
What brought the adaptive immune system to vertebrates? ‐ The jaw hypothesis and the seahorse
Authors: Matsunaga Takeshi , Rahman Arman
Published: April 2006

Summary: A hypothesis is discussed that the adaptive immune system of vertebrates evolved in the gastrointestinal regions of primitive jawed fish (placoderms) due to increased localized injuries and infections which were inadvertently brought about by the novel jaw structures and the predatory life style. The question whether the modern jawless fish, cyclostomes, have adaptive immunity or not is briefly but critically reviewed. The discovery that the gut‐associated immune tissues in mammals constitute the primary immune tissues for the local T cells and that some epithelial γσ T cells have a unique propensity is summarized and discussed in relation to the jaw hypothesis. Initial study of the seahorse (Hippocampus) indicates that the gut‐associated immune tissues may be absent in this teleost species, suggesting an evolutionary link between the adaptive immune system and the jaw structure or eating habit.
Structure of MHC class I and class II cDNAs and possible immunodeficiency linked to class II expression in the Mexican axolotl
Authors: Tournefier A. , Laurens V. , Chapusot C. , Ducoroy P. , Padros M. R. , Salvudori F. , Sammut B.
Published: April 2006

Summary: Despite the fact that the axolotl (Ambystoma spp. a urodele amphibian) displays a large T‐cell repertoire and a reasonable B‐cell repertoire, its humoral immune response is slow (60 days), non‐anamnestic, with a unique IgM class. The cytotoxic immune response is slow as well (21 days) with poor mixed lymphocyte reaction stimulation. Therefore, this amphibian can be considered as immunodeficient. The reason for this subdued immune response could be an altered antigenic presentation by major histocompatibility complex (MHC) molecules. This article summarizes our work on axolotl MHC genes. Class I genes have been characterized and the cDNA sequences show a good conservation of non‐polymorphic peptide binding positions of the a chain as well as a high diversity of the variable amino acids positions, suggesting that axolotl class I molecules can present numerous antigenic epitopes. Moreover, class I genes are ubiquitously transcribed at the lime of hatching. These class 1 genes also present an important polylocism and belong to the same linkage group as the class II B gene, they can be reasonably considered as classical class 1a genes. However, only one class II B gene has been characterized so far by Southern blot analysis. As in higher vertebrates, this gene is transcribed in lymphoid organs when they start to be functional. The sequence analysis shows that the peptide binding region of this class II β chain is relatively well conserved, but most of all does not present any variability in the β domain in inbred as well as in wild axolotls presuming a limited antigenic presentation of few antigenic epitopes. The immunodeficiency of the axolotl could then be explained by an altered class 11 presentation of antigenic peptides, putting into question the existence of cellular co‐operation in this lowervertebrate. It will be interesting to analyze the situation in other urodele species and to determine whether our observations in axolotl represent a normal feature in urodele amphibians. But already two different models in amphibians, Xenopus and axolotl, must be considered in our search for understanding immune system and MHC evolution.
Evolution of somatic hypermutation and gene conversion in adaptive immunity
Authors: Diaz Marilyn , Flcjnik Martin E.
Published: April 2006

Summary: Examples of somatic hypermutation of antigen receptor genes can be seen in most lineages of vertebrates, including the cartilaginous fish. Analysis of the phylogenetic data reveals that two distinctive features of the mechanism are shared by most species studied: the mutation hot spot sequence AGY, and a preponderance of point mutations. These data suggest that some of the components of the machinery are shared between ectotherms and mammals. However, unique characters in particular species may have occurred by independent recruitment of novel factors onto the mechanisni. A spotty phylogenetic distribution of gene conversion has also been revealed and can be explained if the two mechanisms share some characteristics. Both mutation and conversion require transcription‐related sequences and/or factors. We theorized that targeting to V genes can be attained by a paused replication fork that has collided with a transcription complex stalled by a defective Ig transcription activator; the paused replication fork results in recruitment of an error‐prone translesion synthesis DNA polymerase (somatic hypermutation) or of DNA repair mechanisms with homologous recombination (gene conversion). In addition, the pathway recruited in different species may be directed by the degree of homology among V genes.
Recombination‐based mechanisms for somatic hypermutation
Authors: Kong Qingzhong , Harris Reuben S. , Maizels Nancy
Published: April 2006

Summary: We review some experiments designed to test recombination‐based mechanisms for somatic hypermutation in twice, particularly mechanisms involving templated mutation or gene conversion. As recombination and repair functions are highly conserved among prokaryotes and eukaryotes, pathways of mutation in microorganisms may prove relevant to the mechanism of somatic hypermutation. Estherichia coli initates a recombination‐based pathway of mutation in response to environmental stimuli, and this “adaptive” pathway of mutation has striking similarities with somatic hypermutation, as does a process of mutagenic repair that occurs at double‐strand breaks in Saccharomyces cerevisiae. We present model for recombination‐based hypermutation of the immunoglobulin loci which could result in cither templated cir non‐templated mutation.
Somatic hypermutation in mouse λ chains
Authors: Azuma Takachika
Published: April 2006

Summary: The frequency and distribution of somatic hypermutation in immunoglobulin genes and the effect of amino acid substitution on the structure/function of antibodies were studied using hybridomas that secrete anti‐(4‐hydroxy‐3‐nitrophenyl)acetyl (NP) monoclonal antibodies bearing Xl chains. A high frequency of mutation was observed in V‐J exons and J‐C introns of rearranged and active λ1 chains but not in the 5′‐non‐coding regions of these chains. Since a similar distribution was observed in inactive λ2 chain genes, 5′‐non‐coding regions containing a promoter were considered to be protected from mutation in view of their apparent importance. Using transgenic mice carrying chloramphenicol acetyl transferase transgenes driven by the VH promoter and heavy‐chain intron enhancer, it was also revealed that these cis‐acting elements are important in the induction of somatic hypermutation and are capable of inducing mutation even in non‐immunoglobulin genes.
Antibody feedback and somatic mutation in B cells: regulation of mutation by immune complexes with IgG antibody
Authors: Song Haifeng , Nie Xiaobo , Basu Subhendu , Cerny Jan
Published: April 2006

Summary: In response to an appropriate antigenic stimulus, and with help from T lymphocytes, naive B cells differentiate into plasmacytes which produce the primary (germline‐encoded) IgM and IgG antibody with low affinity for the antigen. The isotype switch from IgM to IgG coincides with the burst of germinal center reaction and the onset of “somatic hypermutation. Here we propose that formation of immune complexes between the residual antigen and the primary IgG antibody, which activate complement and localize specifically in the network of follicular dendritic cells, provides an important signal for triggering the mutation mechanism in germinal center B cells. This hypothesis has been supported by studies on immunogenicity of immune complexes in vivo. The experiments have included an immunization with pre‐formed antigen/IgG antibody complex and/or an administration of IgG and body shortly after the antigen injection. Either of these strategies, which are known to augment the germinal center formation, resulted in earlier onset of somatic mutation and increased mutation frequency in VDJ rearrangements in antigen‐reactive B cells, provided that help from T cells was also present. It is presumed that the antigen/antibody/complement complex is able to deliver this important signal by cross‐linking of antigen receptor with the CD21/CD19/CD81 molecules on B cells. As a corollary, the signaling by immune complexes may lower the threshold of cell activation determined by receptor affinity for antigen and stimulate diverse V‐gene repertoire of B‐cell clones in germinal centers.
Insight into the origin and clonal history of B‐cell tumors as revealed by analysis of immunoglobulin variable region genes
Authors: Stevenson Freda , Sahota Surinder , Zhu Delin , Ottensmeier Christion , Chapman Caroline , Oscier David , Hamblin Terry
Published: April 2006

Summary: Recombination of VH DH and JH genes is a unique first step in normal B‐cell development. Subsequent differentiation to a mature plasma cell is accompanied by further events in the Ig genes, including VI‐Jt joining, somatic hypermutation and isotype switching. Chromosomal changes leading to B‐cell tumors can occur at many points in this sequence, and may be partly a consequence of the genetic mobility and mutability permitted in order to generate a diverse antibody repertoire, V genes of neo‐plastic B cells may reflect the point of maturation reached by the B cell of origin, prior to transformation, Analysis of tumors therefore provides useful information on V‐gene patterns in normal B cells, and may add another dimension to classification of B‐cell tumors. Transformation ma)’ also preserve cell populations normally destined to die by apoptosis. Tumor cells arrested in the sire where somatic hypermutation and isotype switch are occurring can still be subject to these processes, and could be influenced by persisting antigen. However, mutation is silenced at the point of exit lo the periphery, leading lo fixed mutational patterns in tumors of mature B cells, V‐gene analysis provides an invaluable tool for understanding the genesis of neoplastic change. It also has a clear clinical relevance in tracking tumor cells, measuring residual disease, and finally in offering the opportunity of developing vaccines for treatment.