bluuebunny/crossref_metadata_2025_split huggingface dataset:
Excessive degradation of intracellular protein in macrophages prevents presentation in the context of major histocompatibility complex class II molecules
Authors: Brazil Melanie I. , Weiß Siegfried , Stockinger Brigitta 
Published: March 2007

AbstractThe endogenous major histocompatibility complex (MHC) class II presentation pathway allows biosynthesized, intracellular antigens access for presentation to MHC class II‐restricted T cells. This pathway has been well documented in B cells and fibroblasts, but may not be universally available in all antigen‐presenting cell types. This study compares the ability of different antigen‐presenting cells, expressing endogenous C5 protein (fifth component of mouse complement) as a result of transfection, to present their biosynthesized C5 to MHC class II‐restricted T cells. B cells and fibroblasts expressing C5 were able to present several epitopes of this protein with MHC class II molecules, whereas macrophages were unable to do so, but readily presented C5 from an extracellular source. However, macrophage presentation of endogenous C5 could be achieved when they were treated with low doses of the lysosomotropic agent ammonium chloride. In the presence of an inhibitor of autophagy, presentation of endogenous C5 was abrogated, indicating that biosynthesized C5 is shuttled into lysosomal compartments for degradation before making contact with MHC class II molecules. Taken together, this suggests that proteolytic activity in lysosomes of macrophages may be excessive, compared with fibroblasts and B cells, and destroys epitopes of the C5 protein before they can gain access to MHC class II molecules. Thus, there are inherent differences in presentation pathways between antigen‐presenting cell types; this could reflect their specialized functions within the immune system with macrophages focussing preferentially on internalization, degradation, and presentation of extracellular material.
Differential expression of insulin‐dependent diabetes mellitus‐associated HLA‐DQA1 alleles in vivo
Authors: Maffei Antonella , Harris Paul E. , Reed Elaine F. , Pozzo Giovanna Del , Ciullo Marina , Suciu‐Foca Nicole , Guardiola John 
Published: March 2007

AbstractThe strong association of HLA‐DQ genes with insulin‐dependent diabetes mellitus (IDDM) susceptibility is persuasive evidence of their central role in the etiology of this autoimmune disease. Among other possibilities, it has been proposed that an unbalanced expression of IDDM‐associated DQA, and/or DQB alleles may lead to alterations in the composition of αβ heterodimers and preferential expression of a particular heterodimer on the antigen‐presenting cell surface, leading to self‐recognition. In this report, we demonstrate the differential expression of DQA1 alleles in vivo, in particular of the two diabetogenic alleles DQA1*0301 and DQA1*0501. Family studies suggest that unequal HLA‐DQA1 allele expression in heterozygous individuals is not associated in cis with the HLA‐DQA1 gene, but may be affected by trans‐acting determinant(s). We also discuss the segregation of this phenotype in IDDM‐affected members. Furthermore, we examined historical samples of PBL from an IDDM‐affected individual and an HLA‐identical unaffected sibling acting in a kidney transplant program as donor and recipient, respectively. This analysis allowed us to establish that unbalanced expression of DQA1*0301 and DQA1*0501 can be induced by microenvironmental conditions. Inducible differential expression of HLA‐DQA1 alleles may account for the discordance in the outcome of autoimmune disease in monozygotic twins and HLA‐identical siblings.
Antigen specificity of anti‐nuclear antibodies complexed to nucleosomes determines glomerular basement membrane binding in vivo
Authors: Van Bruggen Mieke C. J. , Walgreen Birgitte , Rijke Truus P. M. , Tamboer Wim , Kramers Kees , Smeenk Ruud J. T. , Monestier Marc , Fournie Gilbert J. , Berden Jo H. M. 
Published: March 2007

AbstractMonoclonal anti‐nuclear antibodies which are complexed to nucleosomes are able to bind to the glomerular basement membrane (GBM) in vivo, whereas purified antibodies do not bind. The positively charged histone moieties in the nucleosome are responsible for the binding to anionic determinants in the GBM. We tested the hypothesis that the specificity of the autoantibodies complexed to the nucleosome influences the glomerular binding of the antibody‐nucleosome complex. We induced the formation of these immune complexes in vivo, by intraperitoneal inoculation of hybridomas producing monoclonal anti‐nuclear antibodies (four anti‐histone, three anti‐double stranded (ds)DNA and three anti‐nucleosome antibodies) into nude BALB/c mice. In ascites and plasma from the mice inoculated with these hybridomas, nucleosome/autoantibody complexes were detected in comparable amounts. Immunofluorescence of kidney sections revealed that about 60% of the mice inoculated with anti‐nucleosome or anti‐dsDNA hybridomas had immunoglobulin deposits in the GBM, whereas only 15% of the mice with anti‐histone hybridomas showed these deposits (p ≦ 0.04). In the Matrigel®‐ELISA (used as a GBM surrogate) ascites from anti‐nucleosome or anti‐DNA hybridomas displayed significantly higher titers (p ≦ 0.002) than ascites from anti‐histone hybridomas. In conclusion, nucleosome/immunoglobulin complexes comprising anti‐nucleosome or anti‐dsDNA auto‐antibodies do bind more frequently to the GBM in vivo than nucleosome/immunoglobulin complexes containing anti‐histone antibodies. It therefore appears that the specificity of the antibody bound to the nucleosome is a critical determinant for the nephritogenic potential of the nucleosome‐autoantibody complex.
Major histocompatibility complex‐controlled protective influences on experimental autoimmune encephalomyelitis are peptide specific
Authors: Issazadeh Shohreh , Kjellén Peter , Olsson Tomas , Mustafa Maha , Holmdahl Rikard 
Published: March 2007

AbstractThe myelin basic protein (MBP) peptide 63–88‐induced experimental autoimmune encephalomyelitis (EAE) and its associated T cell cytokine profile are influenced by the rat major histocompatibility complex (MHC). There is an allele‐specific protective influence of the MHC class I region, whereas the MHC class II region display either disease‐protective or ‐promoting effects. To investigate if the MHC‐associated protection is dependent on certain combinations of MBP peptide and MHC molecules, we have now used another peptide (MBP 89–101). A broader and different set of rat MHC alleles were associated with EAE induced with MBP 89–101 as compared to MBP 63–88. All EAE‐susceptible strains mounted peptide‐specific strong T helper (Th) 1‐like immune responses in vitro. Immunization of rats with an extended peptide (MBP 87–110) induced EAE associated with the same MHC haplotypes as the 89–101 peptide, except in LEW.1N (RT1n) rats which were relatively resistant. Only this strain responded with additional Th2‐like and transforming growth factor‐β responses to the peptide in vitro. In vivo depletion of CD8+ cells aggravated the disease in this strain. We conclude that both MHC‐controlled promoting and protective influences on EAE are dependent on certain MHC/MBP peptide combinations, and that the 87–110 region of MBP contains a major MHC‐associated encephalitogenic epitope in the rat.
Deletion of alloantigen‐reactive thymocytes as a mechanism of adult tolerance induction following intrathymic antigen administration
Authors: Jones Nick D. , Fluck Nick C. , Roelen Dave L. , Mellor Andrew L. , Morris Peter J. , Wood Kathryn J. 
Published: March 2007

AbstractDirect injection of foreign antigen into the adult thymus is a potent route of antigen delivery for the induction of tolerance in vivo. In this report, we demonstrate that tolerance to C57BL/10 (H2b/BL10) alloantigens can be induced in CBA/Ca (H2k/CBA) mice by intrathymic (IT) administration of BL10 spleen leukocytes coincident with transient peripheral immunomodulation of CD4+ T cells using a depleting anti‐CD4 monoclonal antibody. T cell receptor (TCR) transgenic mice (BM3.6; H2k) expressing a CD8‐independent TCR specific for H2Kb were used as recipients to facilitate investigation of the mechanisms responsible for tolerance induction by allowing visualization of events in the thymus following IT injection. IT administration of 5 × 107 BL10 spleen leukocytes and concomitant transient peripheral T cell depletion in BM3.6 mice resulted in a substantial H2Kb‐specific deletion of transgenic‐TCR+ (tg‐TCR) thymocytes which was dependent on the level of tg‐TCR expression. IT deletion and the failure to export CD8+ T cells to the peripheral lymphoid organs correlated with the induction of tolerance to H2Kb; TCR transgenic mice that had received IT injection of BL10 splenocytes and peripheral T cell depletion accepted a H2Kb+ cardiac allograft indefinitely. Analysis of tolerant BM3.6 mice revealed that there were low numbers of CD8+ T cells in the periphery giving rise to a substantially reduced reactivity in vitro despite the fact that no donor cells or IT deletion were observed in the thymi of the majority of tolerant mice. These results demonstrate for the first time that IT injection of foreign alloantigen into an adult thymus results in the deletion of thymocytes expressing a TCR specific for the injected alloantigen and suggest that this is an important mechanism of tolerance induction following IT injection of alloantigen in vivo. Furthermore, analysis of tolerant TCR‐transgenic mice suggests that IT deletion is not required for the maintenance of tolerance, and that peripheral mechanisms enforce continued hyporesponsiveness to H2Kb following transplantation.
Ras activation leads to cell proliferation or apoptotic cell death upon interleukin‐2 stimulation or lymphokine deprivation, respectively
Authors: Gómez Javier , Martínez‐A. Carlos , Fernández Belén , García Alphonse , Rebollo Angelita 
Published: March 2007

AbstractLymphokine‐dependent cells undergo apoptosis upon lymphokine withdrawal. We describe that lymphokine deprivation of the interleukin (IL)‐2‐ or IL‐4‐dependent mouse T cell line TS1αβ induces Ras activation which plays a role in programed cell death, since blocking Ras activity reduces the induction of apoptosis. Induction of apoptosis by lymphokine deprivation can be prevented by expression of the Bcl‐2 protein. Rescue from cell death by IL‐2 also promotes Ras activation, but, in contrast to lymphokine withdrawal, stimulates Bcl‐2 expression. IL‐4‐induced cell survival is Ras‐ and Bcl‐2 independent. These results are compatible with a model in which cell proliferation requires the simultaneous induction of at least two pathways which act in combination to prevent cell death.
Normal B cells fail to secrete interleukin‐12
Authors: Guéry Jean‐Charles , Ria Francesco , Galbiati Francesca , Adorini Luciano 
Published: March 2007

AbstractInterleukin‐12 is a key regulatory cytokine produced by antigen‐presenting cells (APC) which drives the development of interferon‐γ (IFN‐γ)‐producing cells and promotes cell‐mediated immunity. Following subcutaneous immunization with protein antigen in adjuvant, dendritic cells (DC) but not small nor large B cells in immune lymph nodes express antigenic complexes and secrete substantial amounts of bioactive IL‐12 p75 upon antigen‐specific interaction with T cells. We have analyzed secretion of IL‐12 p40 and p75 by cell populations enriched in DC, macrophages or B cells in response to nonspecific stimulation or to interaction with antigen‐specific CD4+ cells. These APC populations do not produce IL‐12 constitutively but, upon stimulation with heat‐fixed Staphylococcus aureus and IFN‐γ, IL‐12 p40 and p75 are secreted by DC and macrophages, whereas B cells fail to produce IL‐12. B cells also fail to secrete IL‐12 in response to stimulation with LPS and IFN‐γ. Co‐culture with CD4+ T hybridoma cells and antigen induces IL‐12 secretion by DC. Up‐regulation of IL‐12 secretion by interaction with antigen‐specific CD4+ T cells is abrogated by anti‐class II monoclonal antibodies (mAb), by soluble CD40 molecules and by anti‐CD40 ligand mAb, demonstrating a positive feedback between T cells and DC mediated by TCR‐peptide/class II and by CD40‐CD40 ligand interactions. Expression of class II and CD40 molecules is comparable in B cells and DC, and both APC types activate CD4+ T cells. Yet, even upon interaction with antigen‐specific T cells, B cells fail to secrete IL‐12. The capacity of B cells to present antigen but not to secrete IL‐12 may explain their propensity to selectively drive T helper type 2 cell development.
Lack of correlation between rejection of tumor cells co‐expressing interleukin‐2 and B7.1 and vaccine efficiency
Authors: Cayeux Sophie , Richter Günther , Becker Christian , Beck Christian , Aicher Alexandra , Pezzutto Antonio , Dörken Bernd , Blankenstein Thomas 
Published: March 2007

AbstractGenetically modifying tumor cells to express a variety of cytokines such as interleukin‐2 (IL‐2) or the co‐stimulatory molecule B7.1 leads to increased immunogenicity and reduced tumorigenicity of tumors in several models with T cells involved in the process. We have previously reported decreased tumorigenicity of the murine plasmacytoma J558L [major histocompatibility complex (MHC) class I+ and class II−] expressing IL‐2 or B7.1. When systemic immunity was analyzed, immunization with either J558‐IL2 or J558‐B7.1 cells generated moderate protection against unmodified J558L tumor cells, comparable to immunization with a tumor cells/adjuvant Corynebacterium parvum mixture. In this study, we asked whether the co‐expression of IL‐2 and B7.1 in tumor cells would augment vaccine potency, cytotoxic T lymphocyte (CTL) activity and protective immunity. Rejection of single IL‐2 or B7.1 or co‐transfected IL‐2/B7.1 cells occurred in most syngeneic animals but not in T cell‐deficient nude mice, thus confirming that T cells were required for tumor rejection. We knew from previous experiments that CD8+ T cells were responsible for rejection. Surprisingly, immunization with J558‐IL2/B7.1 cells followed by challenge with parental J558L caused a reduction in systemic protection as compared to J558‐B7.1 or J558‐IL2 alone. We examined the mechanism underlying this unexpected result: 6 days after injection of J558‐IL2/B7.1 cells, tumor were nearly completely destroyed and were almost devoid of CD8+ cells, while CD8+ cells were increased in both IL‐2‐ and B7.1‐transfected tumors. In addition, immunization with J558‐IL2/B7.1 tumors had an adverse effect on the generation of CTL. Mice immunized with J558‐B7.1 and to a lesser extent J558‐IL2 cells mounted a CTL response against J558L cells while, in contrast, no CTL activity could be detected in mice immunized with J558‐IL2/B7.1, thus showing a correlation between the absence of CTL activity and the lack of in vivo protection. We demonstrate that “hyperstimulation” of the immune response by genetically modified cancer vaccines can have adverse effects on tumor immunity, even though the mechanism is not yet completely understood.
A role for Th2 cytokines in the suppression of CD8+ T cell‐mediated graft rejection
Authors: Scully Ralph , Cobbold Stephen P. , Mellor Andrew L. , Wissing Martin , Arnold Bernd , Waldmann Herman 
Published: March 2007

AbstractA major histocompatibility complex (MHC) class I‐specific T cell receptor (TCR)‐transgenic mouse was used to study classical‐type transplantation tolerance in the adult. Engraftment of MHC class I‐incompatible bone marrow and tolerance to donor‐type skin grafts were obtained using dimethylmyeleran (DMM) as a myeloablative agent and a non‐depleting anti‐CD8 monoclonal antibody (mAb) as the sole immunosuppressant. Surprisingly, bone marrow engraftment was facilitated by host CD4+ T cells, a subset normally considered unable to reject class I MHC‐incompatible grafts. A combination of mAb to interleukins (IL)−4 and −10 antagonized the “permissive” effects of host CD4+ T cells, indicating a possible role for Th2‐type immunoregulation that can act on CD8+ T cells in this form of transplantation tolerance. The fate of graft‐reactive T cells was monitored using anti‐clonotypic antibodies. It was observed that bone marrow engraftment then led to peripheral deletion of mAb‐blockaded, clonotype+ CD8+ T cells.
Complex CD44 splicing combinations in synovial fibroblasts from arthritic joints
Authors: Croft Daniel R. , Dull Peter , Davies Derek , Jackson David G. , McIntyre Peter , Kramer Ijsbrand M. 
Published: March 2007

AbstractCD44 is a broadly expressed cell surface glycoprotein which is the major cell surface receptor for the glycosaminoglycan, hyaluronan. In humans, alternative splicing of up to 9 variant exons (v2–v10) into CD44 mRNA, together with post‐translational modification via glycosylation and chondroitin sulfate attachment has the potential of generating a large number of CD44 isoforms. Insertion of these various exons has the potential to change the functional capacities of the molecule and has implications in disease. We have analyzed CD44 splice variant expression in cultured VCAM‐1‐positive synovial fibroblasts isolated from patients with osteo‐ or rheumatoid arthritis and from normal synovium. Rheumatoid and osteoarthritic tissue express CD44 splice variants at the cell surface level. At the mRNA level exons v3, v6, v7, v8, v9 and v10 were detected in different splicing combinations. Rheumatoid tissue showed high expression, osteoarthritic tissues showed great variation. In contrast, non‐inflamed tissue showed no splicing events. Our results indicate that the nature of CD44 splice variant expression may be linked to the inflammatory state of the synovial joint.
Mouse macrophage development in the absence of the common γ chain: defining receptor complexes responsible for IL‐4 and IL‐13 signaling
Authors: Andersson Åsa , Grunewald Susanne M. , Duschl Albert , Fischer Alain , Disanto James P. 
Published: March 2007

AbstractThe common γ chain (γc) forms a critical component of the receptors for interleukins (IL)‐2, IL‐4, IL‐7, IL‐9, and IL‐15. We analyzed γc‐deficient mice to define a role for γc signaling in the development and function of the macrophage lineage. No major differences in absolute cell numbers, cell surface phenotype, or in vitro function of γ−c compared to γ+c macrophages were observed. We therefore conclude that signaling through the γc chain is not essential for the differentiation of mouse macrophages. Although B and T cells require γc for IL‐4 responses, IL‐4 up‐regulated major histocompatibility class II molecules and inhibited nitric oxide production from γ−c macrophages following stimulation with lipopolysaccharide and interferon‐γ. γ−c macrophages could also respond to IL‐13, consistent with the model of a type II IL‐4 receptor α/IL‐13R which can function in the absence of γc. Both IL‐4 and IL‐13 responses could be completely inhibited with the mouse IL‐4 antagonist QY, suggesting that all of the observed IL‐13 responses pass through the type II receptor, making it the primary signaling receptor complex for IL‐13 in mouse macrophages.
Th1 and Th2 subsets equally undergo Fas‐dependent and ‐independent activation‐induced cell death
Authors: Watanabe Norihiko , Arase Hisashi , Kurasawa Kazuhiro , Iwamoto Itsuo , Kayagaki Nobuhiko , Yagita Hideo , Okumura Ko , Miyatake Shoichiro , Saito Takashi 
Published: March 2007

AbstractStimulation of previously activated T cells results in apoptosis, termed activation‐induced cell death (AICD). Recent analysis revealed that the Fas/Fas ligand (FasL) interaction is predominantly involved in AICD of T cells. Furthermore, based on the analysis of various T cell clones and lines, it has been reported that FasL is expressed mainly in Th1 but not in Th2 cells. However, the exact expression pattern of FasL and its function in normal activated T cells has not been determined. In the present study, by utilizing completely differentiated Th1 and Th2 cell populations obtained from ovalbumin‐specific T cell receptor (TCR)‐transgenic mice, the FasL expression on Th1 and Th2 was determined. Furthermore, involvement of Fas‐FasL interaction in AICD of Th1 and Th2 cells was analyzed by two approaches: one was the inhibition of AICD by anti‐FasL monoclonal antibodies, and the other AICD of Th1/Th2 subsets from TCR‐transgenic mice backcrossed to lpr mice. We demonstrated that Th2 cells express FasL on the cell surface at a level similar to that expressed by Th1 cells, and that both subsets were equally susceptible to the Fas‐mediated AICD. These observations suggest not only that the expression of FasL is not always correlated with Th subsets as defined by the cytokine‐producing profile, but also that the responses of both Th1 and Th2 subsets are regulated by Fas‐mediated AICD. Finally, analysis of the kinetics of AICD revealed a novel Fas/FasL‐independent pathway in its initial stage. These findings revealed the precise function of Fas/FasL‐mediated as well as Fas/FasL‐independent AICD in the regulation of helper T cell responses.
Normal thymic selection, normal viability and decreased lymphoproliferation in T cell receptor‐transgenic CTLA‐4‐deficient mice
Authors: Waterhouse Paul , Bachmann Martin F. , Penninger Josef M. , Ohashi Pamela S. , Mak Tak W. 
Published: March 2007

AbstractCTLA‐4 is a T cell surface receptor essential for the negative regulation of T cell activation. In the CTLA‐4‐deficient mouse, a dramatic accumulation of activated peripheral T cells effects extensive damage to host tissues, resulting in mortality within 5 weeks of age. To determine whether the accumulation of activated T cells in CTLA‐4−/− mice is due to a defect in thymic selection, we examined negative selection in CTLA‐4−/− mice using two transgenic T cell receptor (TCR) models of thymic selection. Neither the H‐Y‐specific TCR nor the lymphocytic choriomeningitis virus (LCMV)‐specific TCR transgenic models revealed a defect in positive or negative selection in CTLA‐4−/− mice in vivo or in vitro. In fact, the negatively selecting phenotype of male H‐YTCR‐transgenic mice greatly mitigated the accumulation of activated peripheral T cells. Further, peripheral CTLA‐4−/− T cells expressing a single LMCV‐specific transgenic TCR did not have an activated phenotype, indicating that CTLA‐4−/− T cells require specific antigen for proliferation. These results demonstrate that specific antigen is required for the lymphoproliferation observed in CTLA‐4−/− mice, and that CTLA‐4 deficiency does not lead to a gross defect in negative selection.