bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Covalent Binding Reaction of Complement Component C3
Authors: Gadjeva Mihaela , Dodds Alister W. , Taniguchi-Sidle Aiko , Willis Antony C. , Isenman David E. , Law S. K. Alex 
Published: December 2022

AbstractThe covalent binding of C3 to target molecules on the surfaces of pathogens is crucial in most complement-mediated activities. When C3 is activated, the acyl group is transferred from the sulfhydryl of the internal thioester to the hydroxyl group of the acceptor molecule; consequently, C3 is bound to the acceptor surface by an ester bond. It has been determined that the binding reaction of the B isotype of human C4 uses a two-step mechanism. Upon activation, a His residue first attacks the internal thioester to form an acyl-imidazole bond. The freed thiolate anion of the Cys residue of the thioester then acts as a base to catalyze the transfer of the acyl group from the imidazole to the hydroxyl group of the acceptor molecule. In this article, we present results which indicate that this two-step reaction mechanism also occurs in C3.
IL-12 Modulates Expression of Hypersensitivity Pneumonitis
Authors: Gudmundsson Gunnar , Monick Martha M. , Hunninghake Gary W. 
Published: December 2022

AbstractHypersensitivity pneumonitis (HP) is a granulomatous, inflammatory lung disease caused by inhalation of organic Ags, most commonly thermophilic actinomycetes. Only a minority of individuals exposed to these Ags develops disease, suggesting that host factors are important for the expression of HP. We compared the expression of HP in a sensitive strain of mice, C57BL/6, and in a resistant strain of mice, DBA/2. They were exposed to the thermophilic bacteria Saccharopolyspora rectivirgula (SR) or to saline alone for 3 consecutive days/week for 3 wk. After exposure to Ag, C57BL/6 mice, but not DBA/2 mice, developed granulomatous inflammation with an increase in lung index (lung weight). Both strains had similar amounts of Ag delivered to the lungs after intranasal installation, as determined with 14C-labeled Ag. Both also had similar increases in total bronchoalveolar cells after Ag exposure, but the C57BL/6 mice had more lymphocytes. Compared with the resistant strain, the sensitive strain had a significantly greater Ag-induced increase in IL-12 and IFN-γ gene expression. DBA/2 mice resembled sensitive, C57BL/6 mice if they received IL-12 augmentation therapy at the time of Ag exposure. These findings were not limited to lung, since both unstimulated and SR-stimulated spleen cells from C57BL/6 mice released significantly more IL-12 than cells from DBA/2 mice. However, spleen cells from DBA/2 mice made more IFN-γ when exposed to IL-12, than cells from C57BL/6 mice. These results suggest that the IL-12 response to Ag may modulate in part the expression of HP.
T Cell Vaccination in Experimental Autoimmune Encephalomyelitis: A Mathematical Model
Authors: Borghans José A. M. , De Boer Rob J. , Sercarz Eli , Kumar Vipin 
Published: December 2022

AbstractT cell vaccination (TCV) is a method to induce resistance to autoimmune diseases by priming the immune system with autoreactive T cells. This priming evokes an anti-idiotypic regulatory T cell response to the receptors on the autoreactive T cells. Hence resistance is induced. To prevent the inoculated autoreactive cells from inducing autoimmunity, cells are given in a subpathogenic dose or in an attenuated form. We developed a mathematical model to study how the interactions between autoreactive T cells, self epitopes, and regulatory cells can explain TCV. The model is based on detailed data on experimental autoimmune encephalomyelitis, but can be generalized to other autoimmune diseases. We show that all of the phenomena collectively described as TCV occur quite naturally in systems where autoreactive T cells can be controlled by anti-idiotypic regulatory T cells. The essential assumption that we make is that TCV generally involves self epitopes for which T cell tolerance is incomplete. The model predicts a qualitative difference between the two vaccination methods: vaccination with normal autoreactive cells should give rise to a steady state of long lasting protection, whereas vaccination with attenuated cells should only confer transient resistance. Moreover, the model shows how autoimmune relapses can occur naturally without the involvement of T cells arising due to determinant spreading.
TNF Receptor-Associated Factor-3 Signaling Mediates Activation of p38 and Jun N-Terminal Kinase, Cytokine Secretion, and Ig Production Following Ligation of CD40 on Human B Cells
Authors: Grammer Amrie C. , Swantek Jennifer L. , McFarland Richard D. , Miura Yasushi , Geppert Thomas , Lipsky Peter E. 
Published: December 2022

AbstractCD40 engagement induces a variety of functional outcomes following association with adaptor molecules of the TNF receptor-associated factor (TRAF) family. Whereas TRAF2, -5, and -6 initiate NF-κB activation, the outcomes of TRAF3-initiated signaling are less characterized. To delineate CD40-induced TRAF3-dependent events, Ramos B cells stably transfected with a dominant negative TRAF3 were stimulated with membranes expressing recombinant CD154/CD40 ligand. In the absence of TRAF3 signaling, activation of p38 and control of Ig production were abrogated, whereas Jun N-terminal kinase activation and secretion of IL-10, lymphotoxin-α, and TNF-α were partially blocked. By contrast, induction of apoptosis, activation of NF-κB, generation of granulocyte-macrophage CSF, and up-regulation of CD54, MHC class II, and CD95 were unaffected by the TRAF3 dominant negative. Together, these results indicate that TRAF3 initiates independent signaling pathways via p38 and JNK that are associated with specific functional outcomes.
L-Selectin-Specific Autoantibodies in Murine Lupus: Possible Involvement in Abnormal Homing and Polarization of CD4+ T Cell Subsets
Authors: Hattori Susumu , Nishimura Hiroyuki , Tsurui Hiromichi , Kato Masayuki , Endo Naoki , Abe Masaaki , Akakura Shin , Mitsui Kenichi , Ishikawa Sho , Hirose Sachiko , Shirai Toshikazu 
Published: December 2022

AbstractOne notable functional abnormality in murine and human systemic lupus erythematosus (SLE) is the defect in the production of IL-2 in association with the deficit in naive CD4+ T cells. The mechanism is unknown, but one idea is that naturally occurring autoantibodies with specificities to the naive CD4+ T cell subpopulation are related to this event. We selected hybridoma monoclonal autoantibodies from SLE-prone (New Zealand Black (NZB) × New Zealand White (NZW))F1 mice that reacted with restricted populations of CD4+ T cells. One of these, H32, was specific for L-selectin, as determined by 1) distribution of Ag H32 on lymphoid cells similar to Mel-14, an epitope of L-selectin; 2) shedding of 80-kDa molecules with epitope H32 from the surface of lymph node cells coincidentally with Mel-14, when stimulated with phorbol ester; 3) cross-inhibitory activities on Ag binding between H32 and Mel-14; and 4) reactivity of H32 with recombinant mouse L-selectin. Pretreatment of 51Cr-labeled lymphocytes from BALB/c mice with H32 significantly inhibited their homing to lymph nodes in vivo. The BALB/c splenic H32+ CD4+ T cell subset produced few cytokines except IL-2, thus corresponding to naive ThP-type cells. This subset was markedly selectively depleted in aged (NZB × NZW)F1 mice. There was an age-associated increase in frequencies and titers of anti-L-selectin autoantibodies in sera from (NZB × NZW)F1 mice. Thus, abnormalities of naive CD4+ T cell subset, including IL-2 production in subjects with SLE, are at least partly attributed to the generation of autoantibodies to L-selectin.
Indirect T Cell Allorecognition and Alloantibody-Mediated Rejection of MHC Class I-Disparate Heart Grafts
Authors: Pettigrew Gavin J. , Lovegrove Emma , Bradley J. Andrew , Maclean John , Bolton Eleanor M. 
Published: December 2022

AbstractRecent studies in the rat have identified a role for T cell-dependent alloantibody in rejection of MHC class I-disparate allografts. RT1Aa-disparate PVG.R8 heart grafts are rejected acutely in naive, and hyperacutely in sensitized, PVG.RT1u recipients by CD4 T cell-dependent alloantibody. Here, we examined the T cell Ag recognition pathways responsible and show that direct injection into skeletal muscle of plasmid DNA, encoding a water-soluble form of the RT1Aa MHC class I heavy chain (pcmu-tAa), stimulates IgG2b cytotoxic alloantibody and markedly accelerates rejection of PVG.R8 heart grafts (median survival time 2 days). pcmu-tAa injection did not induce CTL to Aa, arguing against direct allorecognition of soluble Aa. Treatment with mAbs confirmed that the alloimmune response to pcmu-tAa injection depended on CD4, not CD8, T cells. Priming T cells for indirect allorecognition by injection of 15-mer peptides spanning the α1 and α2 domains of Aa failed to stimulate anti-Aa Ab but caused an accelerated Ab response to a PVG.R8 heart and a modest acceleration in graft rejection (median survival time 4 days). These results suggest that both soluble MHC class I and allopeptides prime CD4 T cells by the indirect pathway, but that soluble class I is a more effective immunogen for humoral alloimmunity because its tertiary protein structure provides B cell epitopes. We propose that priming humoral alloimmunity, like CTL priming, requires recognition of intact MHC on donor cells, but essential T cell help can be provided by CD4 T cells recognizing allogeneic class I exclusively by the indirect pathway.
Th2-Specific Protein/DNA Interactions at the Proximal Nuclear Factor-AT Site Contribute to the Functional Activity of the Human IL-4 Promoter
Authors: Li-Weber Min , Salgame Padmini , Hu Chenggang , Davydov Ilia V. , Laur Oskar , Klevenz Sibylle , Krammer Peter H. 
Published: December 2022

AbstractIL-4 is a pleiotropic immunoregulatory cytokine secreted by activated Th2, but not Th1, cells. The proximal IL-4 promoter contains MARE, C/EBP, P0, octamer-like, P1, and activating protein-1 elements. The half c-Maf binding site (MARE), P0, and P1 sites were previously shown to be involved in Th2-specific transcriptional activity. Except the MARE and P1 site, the molecular basis for Th2 specificity of the P0 site has not been analyzed. Here, we provide the first detailed analysis of the P0 binding factors and show that in Th2, but not in Th1, cells, NF-AT and proteins of the activating protein-1 family are involved in cooperative binding to the P0 and the adjacent octamer-like site. In the mouse Th2 D10 cells, Oct-1/Oct-2 are also found to participate in formation of the P0-binding complexes. Mutation, deletion, and methylation interference analysis demonstrate that both the P0 and the octamer-like sequence are required for inducible binding. Furthermore, we provide the first report of the functional relevance of each site in the human IL-4 promoter by mutagenesis/transfection analysis and demonstrate that the octamer-like, P0 and P1 sites are important for the biologic function of the IL-4 promoter. The MARE site, although it was shown to be critical for the function of the murine IL-4 promoter, does not appear essential for human IL-4 promoter activity in Jurkat T cells. These findings suggest that besides c-Maf, another Th2-specific factor(s) may be involved in tissue-specific expression of the IL-4 gene.
Control of IL-12 and IFN-γ Production in Response to Live or Dead Bacteria by TNF and Other Factors
Authors: Zhan Yifan , Cheers Christina 
Published: December 2022

AbstractWhen mice were infected i.v. with either Listeria monocytogenes or Brucella abortus, bioactive IL-12 was briefly detected in serum and supernatants of spleen homogenates immediately ex vivo. Although the time scale was more prolonged for the more slowly growing B. abortus, in both instances IL-12 production ceased while bacteria still persisted in high numbers. Production of IL-12, detected in serum and spleen, was neither increased nor prolonged by injecting Abs to IL-10 or IL-4. In contrast with live organisms, heat-killed bacteria did not induce detectable IL-12 in vivo and were less efficient when added in vitro to resident peritoneal cells or spleen cells. Mice lacking the receptors for TNF (TNFR−/− mice) were severely deficient in IL-12 production, suggesting a controlling role for TNF, which we have previously shown to be triggered by live, rather than dead, bacteria. Infection in the TNFR−/− mice was exacerbated, although in the Brucella-infected mice splenomegaly, the main indicator of immunopathology, was reduced. Production of NO by macrophages was deficient, but the TNFR−/− mice were not deficient in IFN-γ production. In addition to being poor inducers of IL-12, killed bacteria actively suppressed IL-12 production in response to live bacteria, by mechanism(s) unknown. The implications of these findings are discussed in light of the fact that only live bacteria satisfactorily induce cell-mediated immunity to infection.
IL-10 Regulates Thrombus-Induced Vein Wall Inflammation and Thrombosis
Authors: Downing L. Joseph , Strieter Robert M. , Kadell Amy M. , Wilke Carol A. , Austin John C. , Hare Bradley D. , Burdick Marie D. , Greenfield Lazar J. , Wakefield Thomas W. 
Published: December 2022

AbstractVein wall inflammation associated with venous thrombosis is mediated by an imbalance in proinflammatory as compared with antiinflammatory molecules. We hypothesize that IL-10 is an important antiinflammatory cytokine that influences vein wall inflammation and thrombus propagation during venous thrombosis. To test this hypothesis a model of inferior vena caval thrombosis was used. Studies were performed at sacrifice 2 days after thrombus induction and included leukocyte morphometrics, myeloperoxidase activity, vein wall permeability, thrombus weight, and IL-10 ELISA analysis from the vein wall. IL-10 was elevated in the vein wall during venous thrombosis. Neutralization of IL-10 increased inflammation, while supplementation with rIL-10 demonstrated a dose- and time-dependent decrease in inflammation. Interestingly, a low 2.5-μg rIL-10 dose given at time of initiation of thrombosis most significantly decreased inflammation. Thrombus weight was importantly diminished by reconstitution of IL-10. These studies support an important role for IL-10 in the regulation of thrombus-associated inflammation and thrombosis and suggest that IL-10 could be used as a therapeutic agent in the treatment of venous thrombosis.
Inhibition of Collagen-Induced Arthritis in Mice by Viral IL-10 Gene Transfer
Authors: Ma Yuhe , Thornton Sherry , Duwel Laura E. , Boivin Gregory P. , Giannini Edward H. , Leiden Jeffrey M. , Bluestone Jeffrey A. , Hirsch Raphael 
Published: December 2022

AbstractAutoimmune arthritides are characterized by an imbalance between pro- and anti-inflammatory cytokines. Viral IL-10 (vIL-10) shares many of the anti-inflammatory properties of mouse and human IL-10, but lacks their immunostimulatory properties and may therefore offer superior immunosuppression. Viral IL-10 has a short half-life; however, genetic modification of cells in vivo offers a potential means of achieving prolonged therapeutic titers. To determine the effects on collagen-induced arthritis of vIL-10 gene transfer, DBA/1 mice were administered i.v. or intra-articular injections of Av(vIL-10), a replication-deficient adenovirus encoding vIL-10. The i.v. injection of Av(vIL-10) before disease onset delayed the onset and reduced the severity of collagen-induced arthritis, but treatment of established disease was ineffective. The preventative effects were not due to decreased anti-type II collagen Ab production. Rather, T cells from mice treated with Av(vIL-10) demonstrated a decreased in vitro proliferative response to type II collagen, and a delay was observed in up-regulation of synovial mRNA for the proinflammatory cytokines IL-2 and IL-1β. Intra-articular injection of Av(vIL-10) into knee joints did not reduce arthritis in the knees, but inhibited the development of arthritis in the paws. Humoral and cellular immune responses against Av(vIL-10) were observed. These results demonstrate that vIL-10 can significantly alter the course of autoimmune arthritis and emphasize the complexities of using gene transfer as a method of drug delivery for arthritis.
Reduced Susceptibility to Collagen-Induced Arthritis in Mice Deficient in IFN-γ Receptor
Authors: Kageyama Yasunori , Koide1 Yukio , Yoshida Atsushi , Uchijima Masato , Arai Tomio , Miyamoto Shigehito , Ozeki Takao , Hiyoshi Mitsuru , Kushida Kazuhiro , Inoue Tetsuo 
Published: December 2022

AbstractCollagen-induced arthritis (CIA) is an arthritic model that was developed after immunization with type II collagen (CII). Apparently, contradictory results have been reported regarding the role of IFN-γ in the development of CIA. Therefore, we employed IFN-γR-deficient mice to study the role of IFN-γ. To introduce the CIA susceptibility gene (H-2q), IFN-γR-deficient (H-2b/b/IFN-γR−/−) mice were mated with DBA/1 (H-2q/q/IFN-γR+/+) mice; next, the F1 mice were interbred to yield F2 offspring bearing different combinations of H-2 (H-2q/q, H-2q/b, and H-2b/b) and IFN-γR (IFN-γR+/+, IFN-γR+/−, and IFN-γR−/−) genes. Although the H-2q allele appeared to confer susceptibility to CIA, mice that were homozygous for the IFN-γR mutation showed a substantially decreased incidence and severity of CIA. The CII-specific IgG levels of serum samples, which are known to be involved in the development of CIA, were remarkably reduced in IFN-γR−/− mice. Furthermore, the anti-CII IgG2a levels controlled by IFN-γR were significantly reduced in IFN-γR−/− F2 mice compared with those seen in IFN-γR+/+ and IFN-γR+/− mice, although the levels of all IgG subclass Abs examined were lower in IFN-γR−/− mice than in IFN-γR+/+ mice. No clear evidence of the imbalance of Th1/Th2 cytokines was observed in CII-immunized, IFN-γR-deficient mice. Taken together, these results suggest that IFN-γ exacerbates CIA by affecting, at least, levels of CII-specific IgG Ab rather than the imbalance of Th1/Th2 cells.
Antagonistic Action of IFN-β and IFN-γ on High Affinity Fcγ Receptor Expression in Healthy Controls and Multiple Sclerosis Patients
Authors: Van Weyenbergh Johan , Lipinski Pawel , Abadie Annie , Chabas Dorothée , Blank Ulrich , Liblau Roland , Wietzerbin Juana 
Published: December 2022

Abstract
Monocyte-macrophage activation by IFN-γ is characterized by a pronounced increase of high affinity Fc receptors for IgG (FcγRI), capable of triggering respiratory burst, phagocytosis, Ab-dependent cytotoxicity, and release of proinflammatory cytokines. In view of the antagonism of IFN-β on IFN-γ action, of interest in the chronic inflammatory disorder multiple sclerosis, we examined the possible effect of IFN-β on IFN-γ induction of FcγRI gene expression. We found that IFN-β significantly down-regulated IFN-γ-induced FcγRI surface expression in peripheral blood monocytes from healthy donors, in a dose- and time-dependent manner. This down-regulation of FcγRI surface levels did not correspond to a decrease in FcγRI mRNA, suggesting a posttranscriptional effect of IFN-β. Down-regulation of FcγRI surface expression correlated with diminished cellular signaling through FcγRI, since the IFN-γ-induced increase in Fcγ receptor-triggered respiratory burst was nearly completely abrogated by simultaneous addition of IFN-β. Finally, the same antagonism between both IFNs on FcγRI surface expression was observed in peripheral blood monocytes derived from multiple sclerosis patients; inhibition by IFN-β was even increased (82 ± 11%), as compared with healthy controls (67 ± 4%). These results may partially help explain the beneficial effect of IFN-β in multiple sclerosis.
Cutting Edge: Class II Transactivator-Independent Endothelial Cell MHC Class II Gene Activation Induced by Lymphocyte Adhesion
Authors: Collinge Mark , Pardi Ruggero , Bender Jeffrey R. 
Published: December 2022

Abstract
NK cells induce MHC class II molecules on the surface of allogeneic endothelial cells in an adhesion-dependent, IFN-γ-independent manner. Here, we demonstrate that NK cells induce HLA-DR on the surface of a mutant cell line that is defective in IFN-γ-induced MHC class II expression. RNA analysis in these cells and in a cell line that is defective in class II transactivator (CIITA) demonstrates that NK cell-induced HLA-DRα mRNA expression is also CIITA-independent. The Janus kinase-1-deficient cell line U4A expresses HLA-DRα mRNA in response to NK cell activation, and HLA-DRα promoter constructs transfected into these cells are induced by NK cells but not IFN-γ. These data indicate that the IFN-γ-independent component of the target cell HLA-DR expression induced by lymphocyte adhesion uses a signaling pathway that is distinct from the IFN-γ-dependent mechanism and also suggest that CIITA is not required.
Impaired Alloantigen-Mediated T Cell Apoptosis and Failure To Induce Long-Term Allograft Survival in IL-2-Deficient Mice
Authors: Dai Zhenhua , Konieczny Bogumila T. , Baddoura Fady K. , Lakkis Fadi G. 
Published: December 2022

AbstractWe examined whether IL-2 regulates alloimmune responses by studying allograft survival in wild-type (IL-2+/+) and IL-2 gene-knockout (IL-2−/−) mice. The acute rejection of vascularized, cardiac allografts and the generation of allospecific CTLs were not impaired in the absence of IL-2. In contrast, blocking the B7-CD28 T cell costimulation pathway with CTLA4Ig induced long-term allograft survival (&gt;100 days) in IL-2+/+ recipients but failed to do so in IL-2−/− mice or in wild-type mice that had been treated with IL-2-neutralizing Ab around the time of transplantation. Allografts rejected by IL-2−/− recipients exhibited extensive mononuclear cell infiltrates despite CTLA4Ig administration. In vivo allostimulation in the absence of IL-2 led to exaggerated T lymphocyte proliferation and impaired apoptosis of activated T cells in untreated and CTLA4Ig-treated mice. These findings indicate that endogenous IL-2 is required for the induction of long-term allograft survival, and that IL-2 regulates alloimmune responses by preparing activated T lymphocytes for alloantigen-induced apoptosis.
CD1 Expression Defines Subsets of Follicular and Marginal Zone B Cells in the Spleen: β2-Microglobulin-Dependent and Independent Forms
Authors: Amano Masahiko , Baumgarth Nicole , Dick Michael D. , Brossay Laurent , Kronenberg Mitchell , Herzenberg Lee A. , Strober Samuel 
Published: December 2022

AbstractWe have used multicolor FACS analysis, immunohistology, and functional assays to study the expression of CD1 on B cell subsets from normal and β2m−/− mice. Two B cell subpopulations were identified that express high levels of CD1 in normal mice: splenic marginal zone B cells (IgMhigh IgDlow CD21high CD24intermediate CD23− CD43−) and a newly identified subpopulation of follicular B cells. The latter cells are unusual, because they are IgDhigh CD23+, like follicular B cells, but express high levels of CD21 and IgM, an expression pattern that is associated with marginal zone B cells. Therefore, the high-level expression of CD1 and CD21 was found to be closely associated on splenic B cells. Immunohistology confirmed the expression of CD1 on marginal zone B cells and on clusters of B cells in splenic follicles. Both the high-level CD1 expression by these cells and the low-level CD1 expression by subpopulations of B cells in the spleen, lymph node, peritoneal cavity, and bone marrow were markedly reduced in β2m−/− mice. Despite this, a CD1-restricted T cell clone proliferated vigorously in response to LPS-activated spleen cells that had been obtained from both β2m−/− and wild-type mice. This response was inhibited by the 3C11 anti-CD1 mAb. These results show the heterogeneity of B cell subsets in their expression of the β2m-dependent form of CD1. They further suggest that a β2m-independent form of CD1 is expressed on B cells that can stimulate T cells; however, this form is not easily visualized with the anti-CD1 mAb used here.