bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Role forRAD51in the Generation of Immunoglobulin Gene Diversity in Rabbits
Authors: Barrington Robert A. , Fasullo Michael , Knight Katherine L. 
Published: December 2022

AbstractIg VDJ genes in rabbit somatically diversify by both hyperpointmutation and gene conversion. To elucidate the mechanism of gene conversion of IgH genes, we cloned a rabbit homologue of RAD51, a gene involved in gene conversion in Saccharomyces cerevisiae (yeast), and tested whether it could complement a yeast rad51 mutant deficient in recombination repair. We found that rabbit RAD51 partially complemented the defect in switching mating types by gene conversion as well as in DNA double-strand break repair after γ-irradiation. Further, by Western blot analysis, we found that levels of Rad51 were higher in appendix-derived B lymphocytes of 6-wk-old rabbits, a time at which IgH genes diversify by somatic gene conversion. We suggest that Rad51 is involved in somatic gene conversion of rabbit Ig genes.
Identification of Quantitative Trait Loci Governing Arthritis Severity and Humoral Responses in the Murine Model of Lyme Disease
Authors: Weis Janis J. , McCracken Barbara A. , Ma Ying , Fairbairn Daryl , Roper Randall J. , Morrison Tom B. , Weis John H. , Zachary James F. , Doerge R. W. , Teuscher Cory 
Published: December 2022

AbstractA spectrum of disease severity has been observed in patients with Lyme disease, with ∼60% of untreated individuals developing arthritis. The murine model of Lyme disease has provided strong evidence that the genetic composition of the host influences the severity of arthritis following infection with Borrelia burgdorferi: infected C3H mice develop severe arthritis while infected C57BL/6N mice develop mild arthritis. Regions of the mouse genome controlling arthritis severity and humoral responses during B. burgdorferi infection were identified in the F2 intercross generation of C3H/HeNCr and C57BL/6NCr mice. Rear ankle swelling measurements identified quantitative trait loci (QTL) on chromosomes 4 and 5, while histopathological scoring identified QTL on a unique region of chromosome 5 and on chromosome 11. The identification of QTL unique for ankle swelling or histopathological severity suggests that processes under distinct genetic control are responsible for these two manifestations of Lyme arthritis. Additional QTL that control the levels of circulating Igs induced by B. burgdorferi infection were identified on chromosomes 6, 9, 11, 12, and 17. Interestingly, the magnitude of the humoral response was not correlated with the severity of arthritis in infected F2 mice. This work defines several genetic loci that regulate either the severity of arthritis or the magnitude of humoral responses to B. burgdorferi infection in mice, with implications toward understanding the host-pathogen interactions involved in disease development.
Anti-TGF-β Treatment Promotes Rapid Healing ofLeishmania majorInfection in Mice by Enhancing In Vivo Nitric Oxide Production
Authors: Li Jian , Hunter Christopher A. , Farrell Jay P. 
Published: December 2022

AbstractCB6F1 mice display intermediate susceptibility to Leishmania major infection compared with the highly susceptible BALB/c and resistant C57BL/6 parental strains. During early weeks of infection, these mice develop dominant Th2 type responses to L. major, although they eventually exhibit a Th2 to Th1 switch and spontaneously resolve their infections. In this study, we have examined the effects of either IL-12 or anti-TGF-β therapy on the immune response and course of disease in chronically infected CB6F1 mice. Local treatment with IL-12 inoculated into the parasitized lesion at 4 wk of infection induced a marked increase in IFN-γ production but did not result in a significant reduction in numbers of parasite or promote more rapid healing. However, local treatment with an Ab to TGF-β led to both a decrease in parasite numbers and more rapid healing, despite the fact that such treatment did not significantly alter the pattern of IL-4 and IFN-γ production. Immunohistochemical studies showed that anti-TGF-β treatment resulted in increased nitric oxide production within parasitized lesions. Our results suggest that TGF-β may play an important regulatory role during chronic stages of a L. major infection by suppressing macrophage production of nitric oxide and that, in the absence of TGF-β, even the relatively low levels of IFN-γ observed in mice with dominant Th2-type responses are sufficient to activate macrophages to destroy amastigotes within parasitized lesions.
Cutting Edge: MHC Class I Triggering by a Novel Cell Surface Ligand Costimulates Proliferation of Activated Human T Cells
Authors: Agrawal Samir , Marquet Jeanine , Freeman Gordon J. , Tawab Abdul , Bouteiller Philippe Le , Roth Patricia , Bolton Wade , Ogg Graham , Boumsell Laurence , Bensussan Armand 
Published: December 2022

AbstractBY55 is a human cell surface molecule whose expression is restricted to NK cells, a subset of circulating CD8+ T lymphocytes, and all intestinal intraepithelial T lymphocytes. Here, we report that BY55 is a novel NK receptor showing broad specificity for both classical and nonclassical MHC class I molecules, and that optimal binding requires a prior aggregation of MHC class I complexes. Using BY55 transfectants, we have identified functional consequences of MHC class I/ligand interactions for the class I-bearing cell. The triggering of MHC class I molecules on human T cell clones by BY55 delivered a potent proliferative signal in the presence of soluble CD3 mAb. The costimulatory signal provided by MHC class I ligation was only seen in activated, and not resting, peripheral blood T cells. This observation represents an additional and/or alternative pathway to CD28 costimulation and may be of particular relevance in memory T cells lacking CD28, such as intestinal intraepithelial T lymphocytes, which are CD28− but BY55+.
Antigen-Induced Coreceptor Down-Regulation on Thymocytes Is Not a Result of Apoptosis
Authors: McGargill Maureen A. , Hogquist Kristin A. 
Published: December 2022

AbstractThe various stages of T cell development are typically characterized by the expression level of the two coreceptors, CD4 and CD8. During the CD4+CD8+ (double-positive, DP) stage of development, thymocytes that perceive a low avidity signal through the TCR go on to differentiate (positive selection), and ultimately down-regulate one coreceptor to express either CD4 or CD8. Alternatively, thymocytes that perceive a high avidity signal down-regulate both coreceptors and are induced to die via apoptosis (negative selection). However, it has recently been suggested that positively selected thymocytes may also partially down-regulate both coreceptors before up-regulating the one coreceptor that is ultimately expressed. This would imply that coreceptor down-regulation (dulling) is not a consequence of commitment to the death pathway. To explore this possibility, we have utilized an in vitro assay to demonstrate that dulling occurred in response to both positive and negative selecting ligands in vitro, was not a result of nonspecific membrane perturbation, was not dependent on the type of APC, and occurred before death in vitro. Furthermore, when thymocyte apoptosis was blocked, CD4 and CD8 were down-regulated in response to TCR stimulation. These data suggest that dulling in response to TCR ligation is distinct from death, and support a model in which DP dulling occurs during both positive and negative selection. The biological implications of this phenomenon are discussed.
IL-17 Is Produced by Some Proinflammatory Th1/Th0 Cells But Not by Th2 Cells
Authors: Aarvak Tanja , Chabaud Martine , Miossec Pierre , Natvig Jacob B. 
Published: December 2022

AbstractIL-17 is defined as a proinflammatory cytokine and produced by activated CD4+ T cells. In rheumatoid arthritis synovial tissue, high levels of IL-17 contribute to IL-6 production by synoviocytes. The present study was performed to see whether Th cells that produce IL-17 are associated with the Th1, Th2, or Th0 subset. Thirty-three CD4+, αβ+ T cell clones were developed from synovial membranes and synovial fluid of rheumatoid arthritis patients. Thirteen clones were defined as Th1 since they produced IFN-γ but not IL-4, and four clones were defined as Th0 type that produced both IL-4 and IFN-γ. Sixteen clones were defined as Th2 since they produced high levels of IL-4 and/or IL-10 but not IFN-γ. IL-17 was measured in a bioassay, where IL-6 production from synoviocytes was a measurement for IL-17 activity in the presence and absence of blocking anti-IL-17 mAb. Three Th1 clones and two Th0 clones produced IL-17. In contrast, none of the sixteen Th2 clones analyzed produced IL-17. In addition, six Th2 clones were further cultured in conditions that induced a switch to Th1 type. Induction of this Th1 phenotype also led to production of IL-17 in two of these clones. The results demonstrate that some cells of the Th1/Th0 phenotype produce IL-17 but not cells of the Th2 phenotype. Thus, IL-17 may define a new subset of T cells, and IL-17 production appears to be a mechanism for Th1/Th0 cells, the most frequent Th subtype present in the rheumatoid synovium, to contribute to the local inflammatory reactions.
Selective Expression of a Novel Surface Molecule by Human Th2 Cells In Vivo
Authors: Nagata Kinya , Tanaka Kazuya , Ogawa Kazuyuki , Kemmotsu Kazumi , Imai Toshio , Yoshie Osamu , Abe Hiroyuki , Tada Kohtaro , Nakamura Masataka , Sugamura Kazuo , Takano Shoichi 
Published: December 2022

AbstractThe search for reliable marker molecules discriminating between human Th1 and Th2 cells identified a gene encoding a novel member of the G protein-coupled leukocyte chemoattractant receptor family, which is selectively expressed in Th2 but not Th1 lineage cells, thereby named CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). Studies with anti-CRTH2 mAbs demonstrated that CRTH2 was expressed in a small population (0.4–6.5%) of CD4+ T cells in fresh PBMCs of healthy adults, but no remarkable expression was seen in B cells and NK cells. In some cases, CD8+ T cells (∼3.5%) expressed CRTH2. Phenotypes of CD4+ T cells expressing CRTH2 were CD45RA−, CD45RO+, and CD25+, similar to those of Ag-activated effector/memory T cells. Freshly isolated CRTH2+ CD4+ T cells produced Th2- but little or no Th1-type cytokines upon stimulation with PMA and ionomycin. In addition, an allergen-induced proliferative response in fresh PBMCs was significantly and selectively reduced by subtracting CRTH2+ cells. Together, these results indicate that CRTH2 is selectively expressed in vivo in an activated state of Th2 cells including allergen-responsive Th2 cells, suggesting its pivotal roles in ongoing Th2-type immune reactions.
Alterations in CD4-Binding Regions of the MHC Class II Molecule I-Ek Do Not Impede CD4+ T Cell Development
Authors: Yelon Deborah , Schaefer Katherine L. , Berg Leslie J. 
Published: December 2022

AbstractThe T cell coreceptors CD4 and CD8 enhance T cell responses to TCR signals by participating in complexes containing TCR, coreceptor, and MHC molecules. These ternary complexes are also hypothesized to play a seminal role during T cell development, although the precise timing, frequency, and consequences of TCR-coreceptor-MHC interactions during positive selection and lineage commitment remain unclear. To address these issues, we designed transgenic mice expressing mutant I-Ek molecules with reduced CD4-binding capability. These transgenic lines were crossed to three different lines of I-Ek-specific TCR transgenic mice, and the efficiency of production of CD4+ lineage cells in the doubly transgenic progeny was assessed. Surprisingly, replacing wild-type I-Ek molecules with these mutant molecules did not affect the production of CD4+CD8− thymocytes or CD4+ peripheral T cells expressing any of the three TCRs examined. These data, when considered together with other experiments addressing the role of coreceptor during development, suggest that not all MHC class II-specific thymocytes require optimal and simultaneous TCR-CD4-MHC interactions to mature. Alternatively, it is possible that these particular alterations of I-Ek do not disrupt the CD4-MHC interaction adequately, potentially indicating functional differences between I-A and I-E MHC class II molecules.
cAMP Up-Regulates Cell Surface Expression of Lymphocyte CXCR4: Implications for Chemotaxis and HIV-1 Infection
Authors: Cole Steve W. , Jamieson Beth D. , Zack Jerome A. 
Published: December 2022

AbstractThe chemokine receptor CXCR4 mediates lymphocyte chemotaxis in response to stromal cell-derived factor-1 (SDF-1) and functions as a coreceptor for T cell-tropic strains of HIV-1. We examined the role of the cAMP-protein kinase A (PKA) signaling pathway in regulating expression of CXCR4. In response to exogenous dibutyryl cAMP or cAMP-inducing ligands, cell surface expression of CXCR4 was increased by up to 10-fold on CD3/CD28-stimulated PBMC and by up to sixfold on unstimulated PBMC. cAMP did not alter receptor mRNA levels or affect the size of the total CXCR4 pool. However, cAMP did significantly reduce CXCR4 internalization rates and thereby increased the fraction of the total CXCR4 pool expressed on the cell surface. cAMP-induced increases in CXCR4 expression counteracted SDF-1-induced receptor internalization and enhanced both chemotactic response to SDF-1 and cellular vulnerability to HIV-1 infection. Thus, altered chemokine receptor expression may provide one mechanism by which cAMP-inducing ligands influence lymphocyte localization and HIV pathogenesis.
Profound Enhancement of T Cell Activation Mediated by the Interaction Between the TCR and the D3 Domain of CD4
Authors: Vignali Dario A. A. , Vignali Kate M. 
Published: December 2022

Abstract
CD4 plays an important role in the activation and development of CD4+ T cells. This is mediated via its bivalent interaction with MHC class II molecules and the TCR:CD3 complex through p56lck. Recent studies have implicated a third site of interaction between the membrane-proximal extracellular domains of CD4 and the TCR. Due to these multiple interactions, direct evidence for the functional importance of this extracellular association has remained elusive. Furthermore, the residues that mediate this interaction are unknown. In this study, we analyzed the function of 61 CD4 mutants. Alanine substitution of just 2 residues, either Q114/F182 or F182/F201, which are partially buried and located close to the D2/D3 interface, completely abrogated CD4 function. Direct evidence for the functional importance of TCR:CD4.D3 interaction was obtained using an anti-CD3fos:anti-CD4jun-bispecific Ab. Surprisingly, it induced strong T cell activation in hybridomas transfected with cytoplasmic-tailless CD4, despite the lack of association with either p56lck or MHC class II molecules. However, this effect was completely abrogated with the CD4 mutants Q114A/F182A or F182A/F201A. These data demonstrate that TCR:CD4.D3 interaction can have a profound effect on T cell activation and obviates the need for receptor oligomerization.
TNF Receptor p55 Plays a Pivotal Role in Murine Keratinocyte Apoptosis Induced by Ultraviolet B Irradiation
Authors: Zhuang Lihua , Wang Binghe , Shinder Gayle A. , Shivji Gulnar M. , Mak Tak W. , Sauder Daniel N. 
Published: December 2022

Abstract
Excess exposure of skin to ultraviolet B (UVB) results in the appearance of so-called sunburn cells. Although it has been demonstrated that sunburn cells represent apoptotic keratinocytes, the molecular mechanisms for UVB-induced apoptosis in keratinocytes have not been fully elucidated. The cytokine, TNF-α, has been shown to induce apoptosis in a variety of cell types. Since UVB induces keratinocytes to release TNF-α, we hypothesized that TNF-α is involved in UVB-induced apoptosis in keratinocytes. In order to confirm this hypothesis and to further delineate which type of TNF receptor signaling mediates the apoptosis pathway, we performed both in vivo and in vitro experiments using gene-targeted knockout mice lacking either the TNF p55 receptor or the TNF p75 receptor. In the in vivo study, wild-type and mutant mice were exposed to UVB, and apoptotic keratinocytes were detected by examining DNA fragmentation using in situ nick-end labeling. For the in vitro experiments, keratinocytes derived from the wild-type and mutant mice were irradiated with UVB, and the degree of apoptosis was determined by flow cytometry, nick-end labeling of DNA, and a DNA ladder assay. Both in vivo and in vitro studies demonstrated that the deletion of TNF receptor p55 could suppress UVB-induced apoptosis in keratinocytes. Our observations support the notion that TNF-α is involved in UVB-induced keratinocyte apoptosis, and demonstrate that p55 receptor signaling plays a pivotal role in this event.
Elevation of Mitochondrial Transmembrane Potential and Reactive Oxygen Intermediate Levels Are Early Events and Occur Independently from Activation of Caspases in Fas Signaling
Authors: Banki Katalin , Hutter Eliza , Gonchoroff Nick J. , Perl Andras 
Published: December 2022

Abstract
Stimulation of the CD95/Fas/Apo-1 receptor leads to apoptosis through activation of the caspase family of cysteine proteases and disruption of the mitochondrial transmembrane potential (Δψm). We show that, in Jurkat human T cells and peripheral blood lymphocytes, Fas-induced apoptosis is preceded by 1) an increase in reactive oxygen intermediates (ROI) and 2) an elevation of Δψm. These events are followed by externalization of phosphatidylserine (PS), disruption of Δψm, and cell death. The caspase inhibitor peptides, DEVD-CHO, Z-VAD.fmk, and Boc-Asp.fmk, blocked Fas-induced PS externalization, disruption of Δψm, and cell death, suggesting that these events are sequelae of caspase activation. By contrast, in the presence of caspase inhibitors, ROI levels and Δψm of Fas-stimulated cells remained elevated. Because ROI levels and Δψm are regulated by the supply of reducing equivalents from the pentose phosphate pathway (PPP), we studied the impact of transaldolase (TAL), a key enzyme of the PPP, on Fas signaling. Overexpression of TAL accelerated Fas-induced mitochondrial ROI production, Δψm elevation, activation of caspase-8 and caspase-3, proteolysis of poly(A)DP-ribose polymerase, and PS externalization. Additionally, suppression of TAL diminished these activities. Therefore, by controlling the balance between mitochondrial ROI production and metabolic supply of reducing equivalents through the PPP, TAL regulates susceptibility to Fas-induced apoptosis. Early increases in ROI levels and Δψm as well as the dominant effect of TAL expression on activation of caspase-8/Fas-associated death domain-like IL-1β-converting enzyme, the most upstream member of the caspase cascade, suggest a pivotal role for redox signaling at the initiation of Fas-mediated apoptosis.
Activation of the Signal Transducer Glycoprotein 130 by Both IL-6 and IL-11 Requires Two Distinct Binding Epitopes
Authors: Kurth Ingo , Horsten Ursula , Pflanz Stefan , Dahmen Heike , Küster Andrea , Grötzinger Joachim , Heinrich Peter C. , Müller-Newen Gerhard 
Published: December 2022

Abstract
The coordination and regulation of immune responses are primarily mediated by cytokines that bind to specific cell surface receptors. Glycoprotein 130 (gp130) belongs to the family of class I cytokine receptors and is the common signal-transducing receptor subunit shared by the so-called IL-6 type cytokines (IL-6, IL-11, ciliary neurotrophic factor, leukemia inhibitory factor, oncostatin M, and cardiotrophin-1). The inflammatory cytokines IL-6 and IL-11 induce gp130 homodimerization after binding to their specific α receptors, which leads to the activation of the Janus kinase/STAT signal transduction pathway. A molecular model of IL-6/IL-6R/gp130, which is based on the structure of the growth hormone/growth hormone receptor complex, allowed the selection of several amino acids located in the cytokine-binding module of gp130 for mutagenesis. The mutants were analyzed with regard to IL-6- or IL-11-induced STAT activation and ligand binding. It was found that Y190 and F191 are essential for the interaction of gp130 with IL-6 as well as IL-11, suggesting a common mode of recognition of helical cytokines by class I cytokine receptors. Furthermore, the requirement of the gp130 N-terminal Ig-like domain for ligand binding and signal transduction was demonstrated by the use of deletion mutants. Thus, besides the observed analogy to the growth hormone/growth hormone receptor complex, there is a substantial difference in the mechanism of receptor engagement by cytokines that signal via gp130.
AIDS Primary Central Nervous System Lymphoma: Molecular Analysis of the Expressed VH Genes and Possible Implications for Lymphomagenesis
Authors: Julien Sylvie , Radosavljevic Mirjana , Labouret Nathalie , Camilleri-Broet Sophie , Davi Frederic , Raphael Martine , Martin Thierry , Pasquali Jean-Louis 
Published: December 2022

AbstractAIDS-associated primary central nervous system lymphomas are late events that have an extremely poor prognosis. Despite different hypotheses, the brain localization of these B cell lymphomas remains an enigma. To better define the cell origin of the lymphomas and the possible role of the B cell receptor (BCR) in the brain localization and/or in the oncogenic transformation, we analyzed the V region genes of the Ig heavy chain expressed by lymphoma cells in five randomly selected patients. After amplifying the rearranged VHDJH DNA by PCR, cloning, and sequencing of the amplified products, we observed that: 1) of the five lymphomas analyzed, four were clearly monoclonal; 2) there was no preferential use of one peculiar VH family or one peculiar segment of gene; 3) the mutation analysis showed that an Ag-driven process occurred in at least two cases, probably before the oncogenic event; and 4) there was no intraclonal variability, suggesting that the hypermutation mechanism is no longer efficient in these lymphoma B cells. Taken together, our results suggest that distinct Ags could be recognized by the BCR of the lymphoma cells in different patients and that, if the Ags are responsible for the brain localization of these B cells bearing mutated BCR, other factors must be involved in B cell transformations in primary central nervous system lymphoma.
Atypical VH-D-JH Rearrangements in Newborn Autoimmune MRL Mice
Authors: Klonowski Kimberly D. , Primiano Laura L. , Monestier Marc 
Published: December 2022

AbstractAntinuclear Abs are the hallmark of the autoimmune disease systemic lupus erythematosus (SLE). The ability of self reactive autoantibodies to bind to DNA and nucleosomes is partly conferred by an increased number of arginine and asparagine residues in the heavy chain third complementarity determining region. This increased content of cationic residues is primarily the result of unusual VH-D-JH rearrangements, which include D-D fusions and D gene inversions. While self Ag-driven clonal expansion is a major contributor to the production of antinuclear Abs in lupus, we explore in this study the hypothesis that newly emerging B cells from autoimmune mice display more frequently these unusual VH-D-JH rearrangements. To this end, libraries of PCR-generated VH-D-JH junctions from MRL and C3H newborn livers were analyzed. When compared with the C3H controls, D and JH gene usage in MRL junctions suggests a greater frequency of secondary D-JH rearrangements in this strain. Furthermore, B cells from the autoimmune-prone MRL mice have significantly increased numbers of atypical VH-D-JH rearrangements (D-D fusions and D inversions). Therefore, B cells from MRL mice manifest intrinsic defects that could confer an increased propensity to produce unusual VH-D-JH rearrangements early in ontogeny.