bluuebunny/crossref_metadata_2025 huggingface dataset:
Epstein-Barr Virus–induced Molecule 1 Ligand Chemokine Is Expressed by Dendritic Cells in Lymphoid Tissues and Strongly Attracts Naive T Cells and Activated B Cells
Authors: Ngo Vu N. , Lucy Tang H. , Cyster Jason G.
Published: July 2002

Movement of T and B lymphocytes through secondary lymphoid tissues is likely to involve multiple cues that help the cells navigate to appropriate compartments. Epstein-Barr virus– induced molecule 1 (EBI-1) ligand chemokine (ELC/MIP3β) is expressed constitutively within lymphoid tissues and may act as such a guidance cue. Here, we have isolated mouse ELC and characterized its expression pattern and chemotactic properties. ELC is expressed constitutively in dendritic cells within the T cell zone of secondary lymphoid tissues. Recombinant ELC was strongly chemotactic for naive (L-selectinhi) CD4 T cells and for CD8 T cells and weakly attractive for resting B cells and memory (L-selectinlo) CD4 T cells. After activation through the B cell receptor, the chemotactic response of B cells was enhanced. Like its human counterpart, murine ELC stimulated cells transfected with EBI-1/CC chemokine receptor 7 (CCR7). Our findings suggest a central role for ELC in promoting encounters between recirculating T cells and dendritic cells and in the migration of activated B cells into the T zone of secondary lymphoid tissues.
TRANCE Is Necessary and Sufficient for Osteoblast-mediated Activation of Bone Resorption in Osteoclasts
Authors: Fuller Karen , Wong Brian , Fox Simon , Choi Yongwon , Chambers Tim J.
Published: July 2002

TRANCE (tumor necrosis factor–related activation-induced cytokine) is a recently described member of the tumor necrosis factor superfamily that stimulates dendritic cell survival and has also been found to induce osteoclastic differentiation from hemopoietic precursors. However, its effects on mature osteoclasts have not been defined. It has long been recognized that stimulation of osteoclasts by agents such as parathyroid hormone (PTH) occurs through a hormonal interaction with osteoblastic cells, which are thereby induced to activate osteoclasts. To determine whether TRANCE accounts for this activity, we tested its effects on mature osteoclasts. TRANCE rapidly induced a dramatic change in osteoclast motility and spreading and inhibited apoptosis. In populations of osteoclasts that were unresponsive to PTH, TRANCE caused activation of bone resorption equivalent to that induced by PTH in the presence of osteoblastic cells. Moreover, osteoblast-mediated stimulation of bone resorption was abrogated by soluble TRANCE receptor and by the soluble decoy receptor osteoprotegerin (OPG), and stimulation of isolated osteoclasts by TRANCE was neutralized by OPG. Thus, TRANCE expression by osteoblasts appears to be both necessary and sufficient for hormone-mediated activation of mature osteoclasts, and TRANCE-R is likely to be a receptor for signal transduction for activation of the osteoclast and its survival.
Type I Interferons Keep Activated T Cells Alive
Authors: Marrack Philippa , Kappler John , Mitchell Tom
Published: July 2002

Antigen injection into animals causes antigen-specific T cells to become activated and, rapidly thereafter, die. This antigen-induced death is inhibited by inflammation. To find out how inflammation has this effect, various cytokines were tested for their ability to interfere with the rapid death of activated T cells. T cells were activated in vivo, isolated, and cultured with the test reagents. Two groups of cytokines were active, members of the interleukin 2 family and the interferons (IFNs) α and β. This activity of IFN-α/β has not been described previously. It was due to direct effects of the IFNs on the T cells and was not mediated by induction of a second cytokine such as interleukin 15. IFN-γ did not slow the death of activated T cells, and therefore the activity of IFN-α/β was not mediated only by activation of Stat 1, a protein that is affected by both classes of IFN. IFN-α/β did not raise the levels of Bcl-2 or Bcl-XL in T cells. Therefore, their activity was distinct from that of members of the interleukin 2 family or CD28 engagement. Since IFN-α/β are very efficiently generated in response to viral and bacterial infections, these molecules may be among the signals that the immune system uses to prevent activated T cell death during infections.
A Novel Cytoplasmic Protein with RNA-binding Motifs Is an Autoantigen in Human Hepatocellular Carcinoma
Authors: Zhang Jian-Ying , Chan Edward K.L. , Peng Xuan-Xian , Tan Eng M.
Published: July 2002

In hepatocellular carcinoma (HCC), autoantibodies to intracellular antigens are detected in 30–40% of patients. Patients with chronic hepatitis or liver cirrhosis develop HCC, and when this occurs, some patients exhibit autoantibodies of new specificities. It has been suggested that these novel autoantibody responses may be immune system reactions to proteins involved in transformation-associated cellular events. One HCC serum shown to contain antibodies to unidentified cellular antigens was used to immunoscreen a cDNA expression library, and a full length cDNA clone was isolated with an open reading frame encoding 556 amino acids with a predicted molecular mass of 62 kD. The 62-kD protein contained two types of RNA-binding motifs, the consensus sequence RNA–binding domain (CS-RBD) and four hnRNP K homology (KH) domains. This protein, provisionally called p62, has close identity (66–70%) to three other proteins at the amino acid sequence level, and all four proteins may belong to a family having CS-RBD in the NH2-terminal region and four KH domains in the mid-to-COOH– terminal region. The homologous proteins are: KH domain–containing protein overexpressed in cancer (Koc); zipcode binding protein, a protein which binds to a conserved nucleotide element in chicken β-actin mRNA (ZBP1); and a protein which binds to a promoter cis element in Xenopus laevis TFIIIA gene (B3). p62 protein is cytoplasmic in location, and autoantibodies were found in 21% of a cohort of HCC patients. Patients with chronic hepatitis and liver cirrhosis, conditions which are frequent precursors to HCC, were negative for these autoantibodies, suggesting that the immune response might be related to cellular events leading to transformation. However, the possible involvement of p62 autoantigen as a factor in the transformation process remains to be elucidated.
The P190, P210, and P230 Forms of the BCR/ABL Oncogene Induce a Similar Chronic Myeloid Leukemia–like Syndrome in Mice but Have Different Lymphoid Leukemogenic Activity
Authors: Li Shaoguang , Ilaria Robert L. , Million Ryan P. , Daley George Q. , Van Etten Richard A.
Published: July 2002

The product of the Philadelphia chromosome (Ph) translocation, the BCR/ABL oncogene, exists in three principal forms (P190, P210, and P230 BCR/ABL) that are found in distinct forms of Ph-positive leukemia, suggesting the three proteins have different leukemogenic activity. We have directly compared the tyrosine kinase activity, in vitro transformation properties, and in vivo leukemogenic activity of the P190, P210, and P230 forms of BCR/ABL. P230 exhibited lower intrinsic tyrosine kinase activity than P210 and P190. Although all three oncogenes transformed both myeloid (32D cl3) and lymphoid (Ba/F3) interleukin (IL)-3–dependent cell lines to become independent of IL-3 for survival and growth, their ability to stimulate proliferation of Ba/F3 lymphoid cells differed and correlated directly with tyrosine kinase activity. In a murine bone marrow transduction/transplantation model, the three forms of BCR/ABL were equally potent in the induction of a chronic myeloid leukemia (CML)–like myeloproliferative syndrome in recipient mice when 5-fluorouracil (5-FU)–treated donors were used. Analysis of proviral integration showed the CML-like disease to be polyclonal and to involve multiple myeloid and B lymphoid lineages, implicating a primitive multipotential target cell. Secondary transplantation revealed that only certain minor clones gave rise to day 12 spleen colonies and induced disease in secondary recipients, suggesting heterogeneity among the target cell population. In contrast, when marrow from non– 5-FU–treated donors was used, a mixture of CML-like disease, B lymphoid acute leukemia, and macrophage tumors was observed in recipients. P190 BCR/ABL induced lymphoid leukemia with shorter latency than P210 or P230. The lymphoid leukemias and macrophage tumors had provirus integration patterns that were oligo- or monoclonal and limited to the tumor cells, suggesting a lineage-restricted target cell with a requirement for additional events in addition to BCR/ABL transduction for full malignant transformation. These results do not support the hypothesis that P230 BCR/ABL induces a distinct and less aggressive form of CML in humans, and suggest that the rarity of P190 BCR/ABL in human CML may reflect infrequent BCR intron 1 breakpoints during the genesis of the Ph chromosome in stem cells, rather than intrinsic differences in myeloid leukemogenicity between P190 and P210.
Allelic Exclusion of the T Cell Receptor β Locus Requires the Sh2 Domain–Containing Leukocyte Protein (Slp)-76 Adaptor Protein
Authors: Aifantis Iannis , Pivniouk Vadim I. , Gärtner Frank , Feinberg Jacqueline , Swat Wojciech , Alt Frederick W. , von Boehmer Harald , Geha Raif S.
Published: July 2002

Signaling via the pre-T cell receptor (TCR) is required for the proliferative expansion and maturation of CD4−CD8− double-negative (DN) thymocytes into CD4+CD8+ double-positive (DP) cells and for TCR-β allelic exclusion. The adaptor protein SH2 domain–containing leukocyte protein (SLP)-76 has been shown to play a crucial role in thymic development, because thymocytes of SLP-76−/− mice are arrested at the CD25+CD44− DN stage. Here we show that SLP-76−/− DN thymocytes express the pre-TCR on their surfaces and that introduction of a TCR-α/β transgene into the SLP-76−/− background fails to cause expansion of DN thymocytes or developmental progression to the DP stage. Moreover, analysis of TCR-β rearrangement in SLP-76−/− TCR-transgenic mice or in single CD25+CD44− DN cells from SLP-76−/− mice indicates an essential role of SLP-76 in TCR-β allelic exclusion.
Baff Binds to the Tumor Necrosis Factor Receptor–Like Molecule B Cell Maturation Antigen and Is Important for Maintaining the Peripheral B Cell Population
Authors: Thompson Jeffrey S. , Schneider Pascal , Kalled Susan L. , Wang LiChun , Lefevre Eric A. , Cachero Teresa G. , MacKay Fabienne , Bixler Sarah A. , Zafari Mohammad , Liu Zhong-Ying , Woodcock Stephen A. , Qian Fang , Batten Marcel , Madry Christine , Richard Yolande , Benjamin Christopher D. , Browning Jeffrey L. , Tsapis Andreas , Tschopp Jurg , Ambrose Christine
Published: July 2002

The tumor necrosis factor (TNF) family member B cell activating factor (BAFF) binds B cells and enhances B cell receptor–triggered proliferation. We find that B cell maturation antigen (BCMA), a predicted member of the TNF receptor family expressed primarily in mature B cells, is a receptor for BAFF. Although BCMA was previously localized to the Golgi apparatus, BCMA was found to be expressed on the surface of transfected cells and tonsillar B cells. A soluble form of BCMA, which inhibited the binding of BAFF to a B cell line, induced a dramatic decrease in the number of peripheral B cells when administered in vivo. Moreover, culturing splenic cells in the presence of BAFF increased survival of a percentage of the B cells. These results are consistent with a role for BAFF in maintaining homeostasis of the B cell population.
Taci Is a Traf-Interacting Receptor for Tall-1, a Tumor Necrosis Factor Family Member Involved in B Cell Regulation
Authors: Xia Xing-Zhong , Treanor James , Senaldi Giorgio , Khare Sanjay D. , Boone Tom , Kelley Michael , Theill Lars E. , Colombero Anne , Solovyev Irina , Lee Frances , McCabe Susan , Elliott Robin , Miner Kent , Hawkins Nessa , Guo Jane , Stolina Marina , Yu Gang , Wang Judy , Delaney John , Meng Shi-Yuan , Boyle William J. , Hsu Hailing
Published: July 2002

We and others recently reported tumor necrosis factor (TNF) and apoptosis ligand–related leukocyte-expressed ligand 1 (TALL-1) as a novel member of the TNF ligand family that is functionally involved in B cell proliferation. Transgenic mice overexpressing TALL-1 have severe B cell hyperplasia and lupus-like autoimmune disease. Here, we describe expression cloning of a cell surface receptor for TALL-1 from a human Burkitt's lymphoma RAJI cell library. The cloned receptor is identical to the previously reported TNF receptor (TNFR) homologue transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI). Murine TACI was subsequently isolated from the mouse B lymphoma A20 cells. Human and murine TACI share 54% identity overall. Human TACI exhibits high binding affinities to both human and murine TALL-1. Soluble TACI extracellular domain protein specifically blocks TALL-1–mediated B cell proliferation without affecting CD40- or lipopolysaccharide-mediated B cell proliferation in vitro. In addition, when injected into mice, soluble TACI inhibits antibody production to both T cell–dependent and –independent antigens. By yeast two-hybrid screening of a B cell library with TACI intracellular domain, we identified that, like many other TNFR family members, TACI intracellular domain interacts with TNFR-associated factor (TRAF)2, 5, and 6. Correspondingly, TACI activation in a B cell line results in nuclear factor κB and c-Jun NH2-terminal kinase activation. The identification and characterization of the receptor for TALL-1 provides useful information for the development of a treatment for B cell–mediated autoimmune diseases such as systemic lupus erythematosus.
Virulence Factors of Helicobacter pylori Responsible for Gastric Diseases in Mongolian Gerbil
Authors: Ogura Keiji , Maeda Shin , Nakao Masafumi , Watanabe Takeshi , Tada Mayumi , Kyutoku Toshimasa , Yoshida Haruhiko , Shiratori Yasushi , Omata Masao
Published: July 2002

Helicobacter pylori infection induces various gastroduodenal diseases. We examined the role of two genes, vacA and cagE, in the gastric pathogenesis induced by H. pylori using a long-term (62 wk) animal model. Reportedly, both genes are associated with the virulence of H. pylori: vacA encodes vacuolating cytotoxin, and cagE, with other genes in the cag pathogenicity islands, encodes a type IV secretion system. Mongolian gerbils were challenged in this study by a wild-type TN2 strain and its isogenic mutants of cagE or vacA. The wild-type and vacA mutants induced severe gastritis, whereas cagE mutants induced far milder changes. Gastric ulcer was induced at the highest rate (22/23) by the wild-type TN2, followed by the vacA mutant (19/28). No ulcer was found in the gerbils infected with the cagE mutant (0/27) or in controls (0/27). Intestinal metaplasia was also found in the gerbils infected with the wild-type (14/23) or vacA mutant (15/28). Gastric cancer developed in one gerbil with wild-type infection and in one with vacA mutant infection. In conclusion, the knocking out of the cagE gene deprived wild-type H. pylori of the pathogenicity for gastritis and gastric ulcer, suggesting that the secretion system encoded by cag pathogenicity island genes plays an essential role.
Cd8+ but Not Cd8− Dendritic Cells Cross-Prime Cytotoxic T Cells in Vivo
Authors: den Haan Joke M.M. , Lehar Sophie M. , Bevan Michael J.
Published: July 2002

Bone marrow–derived antigen-presenting cells (APCs) take up cell-associated antigens and present them in the context of major histocompatibility complex (MHC) class I molecules to CD8+ T cells in a process referred to as cross-priming. Cross-priming is essential for the induction of CD8+ T cell responses directed towards antigens not expressed in professional APCs. Although in vitro experiments have shown that dendritic cells (DCs) and macrophages are capable of presenting exogenous antigens in association with MHC class I, the cross-presenting cell in vivo has not been identified. We have isolated splenic DCs after in vivo priming with ovalbumin-loaded β2-microglobulin–deficient splenocytes and show that they indeed present cell-associated antigens in the context of MHC class I molecules. This process is transporter associated with antigen presentation (TAP) dependent, suggesting an endosome to cytosol transport. To determine whether a specific subset of splenic DCs is involved in this cross-presentation, we negatively and positively selected for CD8− and CD8+ DCs. Only the CD8+, and not the CD8−, DC subset demonstrates cross-priming ability. FACS® studies after injection of splenocytes loaded with fluorescent beads showed that 1 and 0.6% of the CD8+ and the CD8− DC subsets, respectively, had one or more associated beads. These results indicate that CD8+ DCs play an important role in the generation of cytotoxic T lymphocyte responses specific for cell-associated antigens.
C-Reactive Protein Binds to Apoptotic Cells, Protects the Cells from Assembly of the Terminal Complement Components, and Sustains an Antiinflammatory Innate Immune Response
Authors: Gershov Debra , Kim SunJung , Brot Nathan , Elkon Keith B.
Published: July 2002

C-reactive protein (CRP) is a serum protein that is massively induced as part of the innate immune response to infection and tissue injury. As CRP has been detected in damaged tissues and is known to activate complement, we assessed whether apoptotic lymphocytes bound CRP and determined the effect of binding on innate immunity. CRP bound to apoptotic cells in a Ca2+-dependent manner and augmented the classical pathway of complement activation but protected the cells from assembly of the terminal complement components. Furthermore, CRP enhanced opsonization and phagocytosis of apoptotic cells by macrophages associated with the expression of the antiinflammatory cytokine transforming growth factor β. The antiinflammatory effects of CRP required C1q and factor H and were not effective once cells had become necrotic. These observations demonstrate that CRP and the classical complement components act in concert to promote noninflammatory clearance of apoptotic cells and may help to explain how deficiencies of the classical pathway and certain pentraxins lead to impaired handling of apoptotic cells and increased necrosis with the likelihood of immune response to self.
Autocrine Secretion of Interferon γ Negatively Regulates Homing of Immature B Cells
Authors: Flaishon Liat , Hershkoviz Rami , Lantner Frida , Lider Ofer , Alon Ronen , Levo Yoram , Flavell Richard A. , Shachar Idit
Published: July 2002

The mechanism by which immature B cells are sequestered from encountering foreign antigens present in lymph nodes or sites of inflammation, before their final maturation in the spleen, has not been elucidated. We show here that immature B cells fail to home to the lymph nodes. These cells can actively exclude themselves from antigen-enriched sites by downregulating their integrin-mediated adhesion to the extracellular matrix protein, fibronectin. This inhibition is mediated by interferon γ secretion. Perturbation of interferon γ activity in vivo leads to the homing of immature B cells to the lymph nodes. This is the first example of autocrine regulation of immune cell migration to sites of foreign antigen presentation.
Long-Term Antithrombotic Protection by in Vivo Depletion of Platelet Glycoprotein VI in Mice
Authors: Nieswandt Bernhard , Schulte Valerie , Bergmeier Wolfgang , Mokhtari-Nejad Rabée , Rackebrandt Kirsten , Cazenave Jean-Pierre , Ohlmann Philippe , Gachet Christian , Zirngibl Hubert
Published: July 2002

Coronary artery thrombosis is often initiated by abrupt disruption of the atherosclerotic plaque and activation of platelets on the subendothelial layers in the disrupted plaque. The extracellular matrix protein collagen is the most thrombogenic constituent of the subendothelial layer; therefore, a selective inhibition of the collagen activation pathway in platelets may provide strong antithrombotic protection while preserving other platelet functions. Here we demonstrate that treatment of mice with a monoclonal antibody against the activating platelet collagen receptor glycoprotein VI (GPVI; JAQ1) results in specific depletion of the receptor from circulating platelets and abolished responses of these cells to collagen and collagen-related peptides (CRPs). JAQ1-treated mice were completely protected for at least 2 wk against lethal thromboembolism induced by infusion of a mixture of collagen (0.8 mg/kg) and epinephrine (60 μg/ml). The tail bleeding times in JAQ1-treated mice were only moderately increased compared with control mice probably because the treatment did not affect platelet activation by other agonists such as adenosine diphosphate or phorbol myristate acetate. These results suggest that GPVI might become a target for long-term prophylaxis of ischemic cardiovascular diseases and provide the first evidence that it is possible to specifically deplete an activating glycoprotein receptor from circulating platelets in vivo.
Colony-Stimulating Factor 1 Promotes Progression of Mammary Tumors to Malignancy
Authors: Lin Elaine Y. , Nguyen Andrew V. , Russell Robert G. , Pollard Jeffrey W.
Published: July 2002

In human breast carcinomas, overexpression of the macrophage colony–stimulating factor (CSF-1) and its receptor (CSF-1R) correlates with poor prognosis. To establish if there is a causal relationship between CSF-1 and breast cancer progression, we crossed a transgenic mouse susceptible to mammary cancer with mice containing a recessive null mutation in the CSF-1 gene (Csf1op) and followed tumor progression in wild-type and null mutant mice. The absence of CSF-1 affects neither the incidence nor the growth of the primary tumors but delayed their development to invasive, metastatic carcinomas. Transgenic expression of CSF-1 in the mammary epithelium of both Csf1op/Csf1op and wild-type tumor-prone mice led to an acceleration to the late stages of carcinoma and to a significant increase in pulmonary metastasis. This was associated with an enhanced infiltration of macrophages into the primary tumor. These studies demonstrate that the growth of mammary tumors and the development to malignancy are separate processes and that CSF-1 selectively promotes the latter process. CSF-1 may promote metastatic potential by regulating the infiltration and function of tumor-associated macrophages as, at the tumor site, CSF-1R expression was restricted to macrophages. Our data suggest that agents directed at CSF-1/CSF-1R activity could have important therapeutic effects.
Matrix Metalloproteinase 9 Protects Mice from Anti–Glomerular Basement Membrane Nephritis through Its Fibrinolytic Activity
Authors: Lelongt Brigitte , Bengatta Soraya , Delauche Madeleine , Lund Leif R. , Werb Zena , Ronco Pierre M.
Published: July 2002

Matrix metalloproteinase (MMP)9/gelatinase B is increased in various nephropathies. To investigate its role, we used a genetic approach. Adult MMP9-deficient (MMP9−/−) mice showed normal renal histology and function at 3 mo. We investigated the susceptibility of 3-mo-old mice to the accelerated model of anti-glomerular basement membrane nephritis, in which fibrin is an important mediator of glomerular injury and renal impairment. Unexpectedly, nephritis was more severe in MMP9−/− than in control mice, as attested by levels of serum creatinine and albuminuria, and the extent of crescents and fibrin deposits. Circulating or deposited immunoglobulin G, interleukin (IL)-1β, or IL-10 were the same in MMP9−/− and MMP9+/+ mice. However, we found that fibrin is a critical substrate for MMP9, and in its absence fibrin accumulated in the glomeruli. These data indicate that MMP9 is required for a novel protective effect on the development of fibrin-induced glomerular lesions.
Major Histocompatibility Complex Class II Presentation of Cell-associated Antigen Is Mediated by CD8α+ Dendritic Cells In Vivo
Authors: Valdez Yanet , Mah Weiling , Winslow Monte M. , Xu Lixin , Ling Peter , Townsend Sarah E.
Published: July 2002

Antigen-specific B cells express major histocompatibility complex class II and can present antigen directly to T cells. Adoptive transfer experiments using transgenic B and T cells demonstrated that antigen-specific B cells can also efficiently transfer antigen to another cell for presentation to T cells in vivo. To identify the antigen-presenting cell that receives antigens from B cells, a strategy was developed to follow the traffic of B cell–derived proteins in vivo. B cells were labeled with the fluorescent dye CFSE and loaded with antigen, before adoptive transfer into recipient mice. Populations of splenocytes from the recipient mice were later assayed for the presence of fluorescent proteins and for the ability to activate T cells. A small number of CD8α+CD4−CD11blo dendritic cells (DCs) contain proteins transferred from B cells and these DCs effectively present antigens derived from the B cells to T cells. The results suggest that CD8α+ DCs sample the cells and membranes in their environment for presentation to T cells circulating through the T cell zone. This function of CD8α+ DCs may be relevant to the priming of an immune response or the induction of T cell tolerance.
Contact-dependent Stimulation and Inhibition of Dendritic Cells by Natural Killer Cells
Authors: Piccioli Diego , Sbrana Silverio , Melandri Emiliano , Valiante Nicholas M.
Published: July 2002

Natural killer (NK) cells and dendritic cells (DCs) are two distinct cell types of innate immunity. It is known that the in vitro interaction of human NK cells with autologous DCs results in DC lysis. Here we show that contact-dependent interactions between activated human NK cells and immature DCs (iDCs) provides a “control switch” for the immune system. At low NK/DC ratios, this interaction dramatically amplifies DC responses, whereas at high ratios it completely turns off their responses. Specifically, culture of activated human NK cells with iDCs, at low NK/DC ratios (1:5), led to exponential increases in DC cytokine production, which were completely dependent on cell-to-cell contact. DC maturation was also driven by cognate interactions with NK cells and maturation was dependent on endogenously produced TNF-α in the culture. At slightly higher NK/DC ratios (5:1), inhibition of DC functions was the dominant feature due to potent killing by the autologous NK cells. Resting NK cells also stimulated autologous DC maturation in a TNF-α/contact-dependent manner, however, increasing the NK/DC ratio only led to an enhancement of this effect.
Interleukin 4 Reduces Expression of Inhibitory Receptors on B Cells and Abolishes CD22 and FcγRII-mediated B Cell Suppression
Authors: Rudge Elizabeth U. , Cutler Antony J. , Pritchard Nicholas R. , Smith Kenneth G.C.
Published: July 2002

Inhibitory receptors CD22, FcγRII (CD32), CD72, and paired immunoglobulin-like receptor (PIR)-B are critically involved in negatively regulating the B cell immune response and in preventing autoimmunity. Here we show that interleukin 4 (IL-4) reduces expression of all four on activated B cells at the level of messenger RNA and protein. This reduced expression is dependent on continuous exposure to IL-4 and is mediated through Stat6. Coligation of FcγRII to the B cell receptor (BCR) via intact IgG increases the B cell activation threshold and suppresses antigen presentation. IL-4 completely abolishes these negative regulatory effects of FcγRII. CD22 coligation with the BCR also suppresses activation — this suppression too is abolished by IL-4. Thus, IL-4 is likely to enhance the B cell immune response by releasing B cells from inhibitory receptor suppression. By this coordinate reduction in expression of inhibitory receptors, and release from CD22 and FcγRII-mediated inhibition, IL-4 is likely to play a role in T cell help of B cells and the development of T helper cell type 2 responses. Conversely, B cell activation in the absence of IL-4 would be more difficult to achieve, contributing to the maintenance of B cell tolerance in the absence of T cell help.
CD8 T Cells Are Required for the Formation of Ectopic Germinal Centers in Rheumatoid Synovitis
Authors: Kang Young Mo , Zhang Xiaoyu , Wagner Ulf G. , Yang Hongyu , Beckenbaugh Robert D. , Kurtin Paul J. , Goronzy Jörg J. , Weyand Cornelia M.
Published: July 2002

The assembly of inflammatory lesions in rheumatoid arthritis is highly regulated and typically leads to the formation of lymphoid follicles with germinal center (GC) reactions. We used microdissection of such extranodal follicles to analyze the colonizing T cells. Although the repertoire of follicular T cells was diverse, a subset of T cell receptor (TCR) sequences was detected in multiple independent follicles and not in interfollicular zones, suggesting recognition of a common antigen. Unexpectedly, the majority of shared TCR sequences were from CD8 T cells that were highly enriched in the synovium and present in low numbers in the periphery. To examine their role in extranodal GC reactions, CD8 T cells were depleted in human synovium-SCID mouse chimeras. Depletion of synovial CD8 T cells caused disintegration of the GC-containing follicles. In the absence of CD8 T cells, follicular dendritic cells disappeared, production of lymphotoxin-α1β2 markedly decreased, and immunoglobulin (Ig) secretion ceased. Immunohistochemical studies demonstrated that these CD8 T cells accumulated at the edge of the mantle zone. Besides their unique localization, they were characterized by the production of interferon (IFN)-γ, lack of the pore-forming enzyme perforin, and expression of CD40 ligand. Perifollicular IFN-γ+ CD8 T cells were rare in secondary lymphoid tissues but accounted for the majority of IFN-γ+ cells in synovial infiltrates. We propose that CD8+ T cells regulate the structural integrity and functional activity of GCs in ectopic lymphoid follicles.
Polycomb Group Gene rae28 Is Required for Sustaining Activity of Hematopoietic Stem Cells
Authors: Ohta Hideaki , Sawada Akihisa , Kim Ji Yoo , Tokimasa Sadao , Nishiguchi Seiji , Humphries R. Keith , Hara Junichi , Takihara Yoshihiro
Published: July 2002

The rae28 gene (rae28), also designated as mph1, is a mammalian ortholog of the Drosophila polyhomeotic gene, a member of Polycomb group genes (PcG). rae28 constitutes PcG complex 1 for maintaining transcriptional states which have been once initiated, presumably through modulation of the chromatin structure. Hematopoietic activity was impaired in the fetal liver of rae28-deficient animals (rae28−/−), as demonstrated by progressive reduction of hematopoietic progenitors of multilineages and poor expansion of colony forming units in spleen (CFU-S12) during embryonic development. An in vitro long-term culture-initiating cell assay suggested a reduction in hematopoietic stem cells (HSCs), which was confirmed in vivo by reconstitution experiments in lethally irradiated congenic recipient mice. The competitive repopulating units (CRUs) reflect HSCs supporting multilineage blood-cell production. CRUs were generated, whereas the number of CRUs was reduced by a factor of 20 in the rae28−/− fetal liver. We also performed serial transplantation experiments to semiquantitatively measure self-renewal activity of CRUs in vivo. Self-renewal activity of CRUs was 15-fold decreased in rae28−/−. Thus the compromised HSCs were presumed to reduce hematopoietic activity in the rae28−/− fetal liver. This is the first report to suggest that rae28 has a crucial role in sustaining the activity of HSCs to maintain hematopoiesis.
Potassium Uptake Supporting Plant Growth in the Absence of AKT1 Channel Activity
Authors: Spalding Edgar P. , Hirsch Rebecca E. , Lewis Daniel R. , Qi Zhi , Sussman Michael R. , Lewis Bryan D.
Published: July 2002

A transferred-DNA insertion mutant of Arabidopsis that lacks AKT1 inward-rectifying K+ channel activity in root cells was obtained previously by a reverse-genetic strategy, enabling a dissection of the K+-uptake apparatus of the root into AKT1 and non-AKT1 components. Membrane potential measurements in root cells demonstrated that the AKT1 component of the wild-type K+ permeability was between 55 and 63% when external [K+] was between 10 and 1,000 μM, and NH4+ was absent. NH4+ specifically inhibited the non-AKT1 component, apparently by competing for K+ binding sites on the transporter(s). This inhibition by NH4+ had significant consequences for akt1 plants: K+ permeability, 86Rb+ fluxes into roots, seed germination, and seedling growth rate of the mutant were each similarly inhibited by NH4+. Wild-type plants were much more resistant to NH4+. Thus, AKT1 channels conduct the K+ influx necessary for the growth of Arabidopsis embryos and seedlings in conditions that block the non-AKT1 mechanism. In contrast to the effects of NH4+, Na+ and H+ significantly stimulated the non-AKT1 portion of the K+ permeability. Stimulation of akt1 growth rate by Na+, a predicted consequence of the previous result, was observed when external [K+] was 10 μM. Collectively, these results indicate that the AKT1 channel is an important component of the K+ uptake apparatus supporting growth, even in the “high-affinity” range of K+ concentrations. In the absence of AKT1 channel activity, an NH4+-sensitive, Na+/H+-stimulated mechanism can suffice.
Residues of a Pfaff system relative to an invariant subscheme
Authors: Sancho de Salas F.
Published: July 2002

In this paper we give a purely algebraic construction of the theory of residues of a Pfaff system relative to an invariant subscheme. This construction is valid over an arbitrary base scheme of any characteristic.
Total variation diminishing Runge-Kutta schemes
Authors: Gottlieb Sigal , Shu Chi-Wang
Published: July 2002

In this paper we further explore a class of high order TVD (total variation diminishing) Runge-Kutta time discretization initialized in a paper by Shu and Osher, suitable for solving hyperbolic conservation laws with stable spatial discretizations. We illustrate with numerical examples that non-TVD but linearly stable Runge-Kutta time discretization can generate oscillations even for TVD (total variation diminishing) spatial discretization, verifying the claim that TVD Runge-Kutta methods are important for such applications. We then explore the issue of optimal TVD Runge-Kutta methods for second, third and fourth order, and for low storage Runge-Kutta methods.
Linear algebraic groups and countable Borel equivalence relations
Authors: Adams Scot , Kechris Alexander
Published: July 2002

If

R
i

R_i

is an equivalence relation on a standard Borel space

B
i

 
(
i
=
1
,
2
)

B_i\ (i=1,2)

, then we say that

R
1

R_1

is Borel reducible to

R
2

R_2

if there is a Borel function

f
:

B
1

→

B
2

f: B_1\to B_2

such that

(
x
,
y
)
∈

R
1

⇔
(
f
(
x
)
,
f
(
y
)
)
∈

R
2

(x,y)\in R_1 \Leftrightarrow (f(x),f(y))\in R_2

. An equivalence relation

R
R

on a standard Borel space

B
B

is Borel if its graph is a Borel subset of

B
×
B

B\times B

. It is countable if each of its equivalence classes is countable. We investigate the complexity of Borel reducibility of countable Borel equivalence relations on standard Borel spaces. We show that it is at least as complex as the relation of inclusion on the collection of Borel subsets of the real line. We also show that Borel reducibility is

Σ

2

1

{\boldsymbol \Sigma }^{\boldsymbol 1}_{\boldsymbol 2}

-complete. The proofs make use of the ergodic theory of linear algebraic groups, and more particularly the superrigidity theory of R. Zimmer.
Cell Proliferation and DNA Breaks Are Involved in Ultraviolet Light-induced Apoptosis in Nucleotide Excision Repair-deficient Chinese Hamster Cells
Authors: Dunkern Torsten R. , Kaina Bernd
Published: July 2002

UV light targets both membrane receptors and nuclear DNA, thus evoking signals triggering apoptosis. Although receptor-mediated apoptosis has been extensively investigated, the role of DNA damage in apoptosis is less clear. To analyze the importance of DNA damage induced by UV-C light in apoptosis, we compared nucleotide excision repair (NER)-deficient Chinese hamster ovary cells (lines 27-1 and 43-3B mutated for the repair genes ERCC3 and ERCC1, respectively) with the corresponding DNA repair-proficient fibroblasts (CHO-9 and ERCC1 complemented 43-3B cells). NER-deficient cells were hypersensitive as to the induction of apoptosis, indicating that apoptosis induced by UV-C light is due to unrepaired DNA base damage. Unrepaired lesions, however, do not activate the apoptotic pathway directly because apoptosis upon UV-C irradiation requires DNA replication and cell proliferation. It is also shown that in NER-deficient cells unrepaired lesions are converted into DNA double-strand breaks (DSBs) and chromosomal aberrations by a replication-dependent process that precedes apoptosis. We therefore propose that DSBs arising from replication of DNA containing nonrepaired lesions act as an ultimate trigger of UV-C–induced apoptosis. Induction of apoptosis by UV-C light was related to decline in the expression level of Bcl-2 and activation of caspases. Decline of Bcl-2 and subsequent apoptosis might also be caused, at least in part, by UV-C–induced blockage of transcription, which was more pronounced in NER-deficient than in wild-type cells. This is in line with experiments with actinomycin D, which provoked Bcl-2 decline and apoptosis. UV-C–induced apoptosis due to nonrepaired DNA lesions, replication-dependent formation of DSBs, and activation of the mitochondrial damage pathway is independent of functional p53 for which the cells are mutated.
The PSIPRED protein structure prediction server
Authors: McGuffin Liam J. , Bryson Kevin , Jones David T.
Published: July 2002

Summary: The PSIPRED protein structure prediction server allows users to submit a protein sequence, perform a prediction of their choice and receive the results of the prediction both textually via e-mail and graphically via the web. The user may select one of three prediction methods to apply to their sequence: PSIPRED, a highly accurate secondary structure prediction method; MEMSAT 2, a new version of a widely used transmembrane topology prediction method; or GenTHREADER, a sequence profile based fold recognition method.

Availability: Freely available to non-commercial users at http://globin.bio.warwick.ac.uk/psipred/

Contact: david.jones@brunel.ac.uk
Plk1 promotes nuclear translocation of human Cdc25C during prophase
Authors: Toyoshima‐Morimoto Fumiko , Taniguchi Eri , Nishida Eisuke
Published: July 2002

The nuclear accumulation of active M‐phase promoting factor (MPF) during prophase is thought to be essential for coordinating M‐phase events in vertebrate cells. The protein phosphatase Cdc25C, an activator of MPF, enters the nucleus to keep MPF active in the nucleus during prophase. However, the molecular mechanisms that control nuclear translocation of Cdc25C during prophase are unknown. We show that phosphorylation of a serine residue (Ser198) in a nuclear export signal sequence of human Cdc25C occurs during prophase and promotes nuclear localization of Cdc25C. We also show that Polo‐like kinase 1 (Plk1) is responsible for this phosphorylation and that constitutively active Plk1 promotes nuclear localization of Cdc25C. Remarkably, a mutant Cdc25C in which Ser198 is replaced by alanine remains in the cytoplasm when wild‐type Cdc25C accumulates in the nucleus during prophase. These results suggest that Plk1 phosphorylates Cdc25C on Ser198 and regulates nuclear translocation of Cdc25C during prophase.
The role of the mechanical system in control: a hypothesis of self–stabilization in hexapedal runners
Authors: Kubow T. M. , Full R. J.
Published: July 2002

To explore the role of the mechanical system in control, we designed a two dimensional, feed–forward, dynamic model of a hexapedal runner (death–head cockroach,Blaberus discoidalis). We chose to model many–legged, sprawled posture animals because of their remarkable stability. Since sprawled posture animals operate more in the horizontal plane than animals with upright postures, we decoupled the vertical and horizontal plane and only modelled the horizontal plane. The model was feed–forward with no equivalent of neural feedback among any of the components. The model was stable and its forward, lateral and rotational velocities were similar to that measured in the animal at its preferred velocity. It also self–stabilized to velocity perturbations. The rate of recovery depended on the type of perturbation. Recovery from rotational velocity perturbations occurred within one step, whereas recovery from lateral perturbations took multiple strides. Recovery from fore–aft velocity perturbations was the slowest. Perturbations were dynamically coupled—alterations in one velocity component necessarily perturbed the others. Perturbations altered the translation and/or rotation of the body which consequently provided ‘mechanical feedback’ by altering leg moment arms. Self–stabilization by the mechanical system can assist in making the neural contribution of control
Scleromochlus taylori and the origin of dinosaurs and pterosaurs
Authors: Benton Michael J.
Published: July 2002

The phylogenetic position of
Scleromochlus taylori
has been disputed recently, in terms of whether it is a basal sister group of Pterosauria or of Dinosauromorpha. The seven specimens, all from the Lossiemouth Sandstone Formation (late Carnian, Late Triassic) of Lossiemouth, near Elgin, north–east Scotland, suggest that
Scleromochlus
shares no unique features with either Pterosauria or Dinosauromorpha, together the Ornithodira, but is a close outgroup.
Scleromochlus
retains a primitive ankle structure, and it has a slender humerus, femur and fibula.
Scleromochlus
shows the classic bird–like characters of a tibia that is longer than the femur, and a closely appressed group of four elongate metatarsals. A new group name, Avemetatarsalia (‘bird feet’), is established here for the clade consisting of
Scleromochlus
and Ornithodira, and their descendants. A reanalysis of crown–group archosaur relationships confirms the split into Crurotarsi (crocodile relatives) and Ornithodira (bird relatives), as well as the clear division of Ornithodira into Pterosauria and Dinosauromorpha. Relationships within Crurotarsi are, however, much less clear: Ornithosuchidae probably reside within that clade, and there might be a clade ‘Rauisuchia’ consisting of Prestosuchidae and
Postosuchus
, but support for these relationships is weak.
Scleromochlus
was probably a bipedal cursor that could adopt a digitigrade stance. However, it is possible that
Scleromochlus
was also a saltator, capable of leaping long distances.
Risk factors for human disease emergence
Authors: Taylor Louise H. , Latham Sophia M. , woolhouse Mark E.J.
Published: July 2002

A comprehensive literature review identifies 1415 species of infectious organism known to be pathogenic to humans, including 217 viruses and prions, 538 bacteria and rickettsia, 307 fungi, 66 protozoa and 287 helminths. Out of these, 868 (61%) are zoonotic, that is, they can be transmitted between humans and animals, and 175 pathogenic species are associated with diseases considered to be ‘emerging’. We test the hypothesis that zoonotic pathogens are more likely to be associated with emerging diseases than non–emerging ones. Out of the emerging pathogens, 132 (75%) are zoonotic, and overall, zoonotic pathogens are twice as likely to be associated with emerging diseases than non–zoonotic pathogens. However, the result varies among taxa, with protozoa and viruses particularly likely to emerge, and helminths particularly unlikely to do so, irrespective of their zoonotic status. No association between transmission route and emergence was found. This study represents the first quantitative analysis identifying risk factors for human disease emergence.
Elements of episodic–like memory in animals
Authors: Clayton N. S. , Griffiths D. P. , Emery N. J. , Dickinson A.
Published: July 2002

A number of psychologists have suggested that episodic memory is a uniquely human phenomenon and, until recently, there was little evidence that animals could recall a unique past experience and respond appropriately. Experiments on food–caching memory in scrub jays question this assumption. On the basis of a single caching episode, scrub jays can remember when and where they cached a variety of foods that differ in the rate at which they degrade, in a way that is inexplicable by relative familiarity. They can update their memory of the contents of a cache depending on whether or not they have emptied the cache site, and can also remember where another bird has hidden caches, suggesting that they encode rich representations of the caching event. They make temporal generalizations about when perishable items should degrade and also remember the relative time since caching when the same food is cached in distinct sites at different times. These results show that jays form integrated memories for the location, content and time of caching. This memory capability fulfils Tulving's behavioural criteria for episodic memory and is thus termed ‘episodic–like’. We suggest that several features of episodic memory may not be unique to humans.
C/EBPα induces adipogenesis through PPARγ: a unified pathway
Authors: Rosen Evan D. , Hsu Chung-Hsin , Wang Xinzhong , Sakai Shuichi , Freeman Mason W. , Gonzalez Frank J. , Spiegelman Bruce M.
Published: July 2002

PPARγ and C/EBPα are critical transcription factors in adipogenesis, but the precise role of these proteins has been difficult to ascertain because they positively regulate each other's expression. Questions remain about whether these factors operate independently in separate, parallel pathways of differentiation, or whether a single pathway exists. PPARγ can promote adipogenesis in C/EBPα-deficient cells, but the converse has not been tested. We have created an immortalized line of fibroblasts lacking PPARγ, which we use to show that C/EBPα has no ability to promote adipogenesis in the absence of PPARγ. These results indicate that C/EBPα and PPARγ participate in a single pathway of fat cell development with PPARγ being the proximal effector of adipogenesis.
fzr-1 and lin-35/Rb function redundantly to control cell proliferation in C. elegans as revealed by a nonbiased synthetic screen
Authors: Fay David S. , Keenan Sean , Han Min
Published: July 2002

We report here a synthetic-lethal screen in Caenorhabditis elegans that overcomes a number of obstacles associated with the analysis of functionally redundant genes. Using this approach, we have identified mutations that synthetically interact withlin-35/Rb, a SynMuv gene and the sole member of the Rb/pocket protein family in C. elegans. Unlike the original SynMuv screens, our approach is completely nonbiased and can theoretically be applied to any situation in which a mutation fails to produce a detectable phenotype. From this screen we have identifiedfzr-1, a gene that synthetically interacts with lin-35to produce global defects in cell proliferation control.fzr-1 encodes the C. elegans homolog of Cdh1/Hct1/FZR, a gene product shown in other systems to regulate the APC cyclosome. We have also uncovered genetic interactions between fzr-1 and a subset of class B SynMuv genes, and between lin-35 and the putative SCF regulator lin-23. We propose that lin-35,fzr-1, and lin-23 function redundantly to control cell cycle progression through the regulation of cyclin levels.