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Class II Major Histocompatibility Complex (class + ii_major_histocompatibility_complex)
Selected AbstractsBinding interactions between peptides and proteins of the class II Major Histocompatibility ComplexMEDICINAL RESEARCH REVIEWS, Issue 2 2002Benjamin J. McFarland Abstract The activation of helper T cells by peptides bound to proteins of the class II Major Histocompatibility Complex (MHC II) is pivotal to the initiation of an immune response. The primary functional requirement imposed on MHC II proteins is the ability to efficiently bind thousands of different peptides. Structurally, this is reflected in a unique architecture of binding interactions. The peptide is bound in an extended conformation within a groove on the membrane distal surface of the protein that is lined with several pockets that can accommodate peptide side-chains. Conserved MHC II protein residues also form hydrogen bonds along the length of the peptide main-chain. Here we review recent advances in the study of peptide-MHC II protein reactions that have led to an enhanced understanding of binding energetics. These results demonstrate that peptide-MHC II protein complexes achieve high affinity binding from the array of hydrogen bonds that are energetically segregated from the pocket interactions, which can then add to an intrinsic hydrogen bond-mediated affinity. Thus, MHC II proteins are unlike antibodies, which utilize cooperativity among binding interactions to achieve high affinity and specificity. The significance of these observations is discussed within the context of possible mechanisms for the HLA-DM protein that regulates peptide presentation in vivo and the design of non-peptide molecules that can bind MHC II proteins and act as vaccines or immune modulators. © 2002 John Wiley & Sons, Inc. Med Res Rev, 22, No. 2, 168,203, 2002; DOI 10.1002/med.10006 [source] Spatio-temporal variation in the strength and mode of selection acting on major histocompatibility complex diversity in water vole (Arvicola terrestris) metapopulationsMOLECULAR ECOLOGY, Issue 1 2009MATTHEW K. OLIVER Abstract Patterns of spatio-temporal genetic variation at a class II major histocompatibility complex (MHC) locus and multiple microsatellite loci were analysed within and between three water vole metapopulations in Scotland, UK. Comparisons of MHC and microsatellite spatial genetic differentiation, based on standardised tests between two demographically asynchronous zones within a metapopulation, suggested that spatial MHC variation was affected by balancing selection, directional selection and random genetic drift, but that the relative effects of these microevolutionary forces vary temporally. At the metapopulation level, between-year differentiation for MHC loci was significantly correlated with that of microsatellites, signifying that neutral factors such as migration and drift were primarily responsible for overall temporal genetic change at the metapopulation scale. Between metapopulations, patterns of genetic differentiation implied that, at large spatial scales, MHC variation was primarily affected by directional selection and drift. Levels of MHC heterozygosity in excess of Hardy,Weinberg expectations were consistent with overdominant balancing selection operating on MHC variation within metapopulations. However, this effect was not constant among all samples, indicating temporal variation in the strength of selection relative to other factors. The results highlight the benefit of contrasting variation at MHC with neutral markers to separate the effects of stochastic and deterministic microevolutionary forces, and add to a growing body of evidence showing that the mode and relative strength of selection acting on MHC diversity varies both spatially and temporally. [source] Pretreatment With Portal Venous Ultraviolet B Irradiated Donor Alloantigen Promotes Donor-Specific Tolerance to Rat Nerve Allografts,THE LARYNGOSCOPE, Issue 3 2001Eric M. Genden MD Abstract Objective To determine if a single intraportal inoculation of ultraviolet B-irradiated (UVB) donor splenocytes can prevent nerve allograft rejection and confer donor-specific immunotolerance to rat nerve allograft segments. Methods Age-matched, class I and class II major histocompatibility complex (MHC) mismatched Buffalo (RT1b) rats were transplanted with a syngeneic nerve isograft, a Lewis (RT1l) nerve allograft, or a Brown-Norway (RT1n) rat nerve allograft segment. Control Buffalo rats in group I received a 3.0-cm Lewis (RT11) sciatic-posterior tibial interposition nerve allograft without pretreatment;group II Buffalo rats received a syngeneic Buffalo nerve isograft without pretreatment. Group III Buffalo recipients were inoculated with 2.5 × 107 UVB-irradiated Lewis donor splenocyte cells by portal venous administration 7 days before transplantation with a 3.0-cm sciatic-posterior tibial nerve allograft from a Lewis (RT11) or a third party Brown-Norway rat (RT1n) donor (group IV). Nerve graft regeneration was assessed with walking track analysis, nerve conduction studies, retrograde neural tracing, nerve graft histology, and morphometry. Recipient immune tolerance was assessed through in vitro immunological assessment. Results Pretreatment with UVB-irradiated donor splenocytes 7 days before transplantation prevented nerve allograft rejection. Pretreated animals receiving a nerve allograft recovered limb function, and demonstrated morphological, histological, and electrophysiologic parameters of nerve regeneration similar to that measured in rats receiving a nerve isograft. In vitro immunological assessment by mixed lymphocyte culture (MLC), cytotoxic T lymphocyte (CTL) assay, limiting dilution analysis (LDA) of helper (pTH) and cytotoxic (pCTL) precursor frequencies, and IL-2 production demonstrated a marked donor-specific suppression in allografted animals pretreated with intraportal UVB-irradiated donor splenocytes. These assessments correlated with indefinite acceptance of donor nerve allografts. Conclusions A single pretreatment with a single intraportal dose of UVB-modified donor antigen specifically induces tolerance to peripheral nerve allografts in rats. [source] Constitutive overexpression of BAFF in autoimmune-resistant mice drives only some aspects of systemic lupus erythematosus,like autoimmunityARTHRITIS & RHEUMATISM, Issue 8 2010William Stohl Objective To determine whether overexpression of BAFF can promote systemic lupus erythematosus (SLE),like autoimmunity in mice that are otherwise autoimmune-resistant. Methods We used class II major histocompatibility complex (MHC),deficient C57BL/6 (B6) mice as a model of resistance to SLE and Sles1 -bearing B6 mice as a model of resistance to the autoantibody-promoting capacity of the Sle1 region. We generated BAFF-transgenic (Tg) counterparts to these respective mice and evaluated lymphocyte phenotype, serologic autoimmunity, renal immunopathology, and clinical disease in the BAFF-Tg and non-Tg mouse sets. Results Although constitutive BAFF overexpression did not lead to B cell expansion in class II MHC,deficient B6 mice, it did lead to increased serum IgG autoantibody levels. Nevertheless, renal immunopathology was limited, and clinical disease did not develop. In B6 and B6.Sle1 mice, constitutive BAFF overexpression led to increased numbers of B cells and CD4+ memory cells, as well as increased serum IgG and IgA autoantibody levels. Renal immunopathology was modestly greater in BAFF-Tg mice than in their non-Tg counterparts, but again, clinical disease did not develop. Introduction of the Sles1 region into B6.Sle1.Baff mice abrogated the BAFF-driven increase in CD4+ memory cells and the Sle1 -driven, but not the BAFF-driven, increase in serum IgG antichromatin levels. Renal immunopathology was substantially ameliorated. Conclusion Although constitutive BAFF overexpression in otherwise autoimmune-resistant mice led to humoral autoimmunity, meaningful renal immunopathology and clinical disease did not develop. This raises the possibility that BAFF overexpression, even when present, may not necessarily drive disease in some SLE patients. This may help explain the heterogeneity of the clinical response to BAFF antagonists in human SLE. [source] Presentation of arthritogenic peptide to antigen-specific T cells by fibroblast-like synoviocytesARTHRITIS & RHEUMATISM, Issue 5 2007Chinh N. Tran Objective To assess the ability of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) to function as antigen-presenting cells (APCs) for arthritogenic autoantigens found within inflamed joint tissues. Methods Human class II major histocompatibility complex (MHC),typed FLS were used as APCs for murine class II MHC,restricted CD4 T cell hybridomas. Interferon-, (IFN,),treated, antigen-loaded FLS were cocultured with T cell hybridomas specific for immunodominant portions of human cartilage gp-39 (HC gp-39) or human type II collagen (CII). T cell hybridoma activation was measured by enzyme-linked immunosorbent assay of culture supernatants for interleukin-2. Both synthetic peptide and synovial fluid (SF) were used as sources of antigen. APC function in cocultures was inhibited by using blocking antibodies to human class II MHC, CD54, or CD58, or to murine CD4, CD11a, or CD2. Results Human FLS could present peptides from the autoantigens HC gp-39 and human CII to antigen-specific MHC-restricted T cell hybridomas. This response required pretreatment of FLS with IFN,, showed MHC restriction, and was dependent on human class II MHC and murine CD4 for effective antigen presentation. Furthermore, FLS were able to extract and present antigens found within human SF to both the HC gp-39 and human CII T cell hybridomas in an IFN,-dependent and MHC-restricted manner. Conclusion RA FLS can function as APCs and are able to present peptides derived from autoantigens found within joint tissues to activated T cells in vitro. In the context of inflamed synovial tissues, FLS may be an important and hitherto overlooked subset of APCs that could contribute to autoreactive immune responses. [source] Rheumatoid arthritis association with the FCRL3 ,169C polymorphism is restricted to PTPN22 1858T,homozygous individuals in a Canadian populationARTHRITIS & RHEUMATISM, Issue 12 2006William G. Newman Objective Variants in genes encoding the Fc receptor,like 3 (FcRL-3) and the class II major histocompatibility complex (MHC) transactivator proteins have been associated with an increased risk of rheumatoid arthritis (RA) in Japanese and Nordic populations, respectively. The aim of this study was to investigate these associations in a Canadian Caucasian cohort of RA cases and healthy controls. Methods A total of 1,187 RA patients and 462 healthy controls were genotyped for FCRL3 and MHC2TA gene variants associated with RA. Epistasis between the FCRL3 ,169C and the PTPN22 1858T variants was also examined. Results An association was detected between RA and both the FCRL3 ,169C allele (OR 1.19, P = 0.023) and the homozygous genotype (OR 1.41, P = 0.027), but association of the MHC2TA promoter region variant (,168G) with RA was not replicated. Stratification of the RA cohort by PTPN22 genotypes revealed the FCRL3 risk variant and RA association was stronger in the patient subgroup lacking PTPN22 1858T variants (P = 0.004) and was not detectable in the subgroup with PTPN22 1858T variants (P = 0.52). The PTPN22 association with RA was greater in the absence than in the presence of the FCRL3 ,169C allele (P = 0.0008 versus P = 0.001). The PTPN22 1858T variant also increased the risk of autoimmune thyroid disease (AITD) in the RA patients, whereas the FCRL3 risk variant was protective against AITD. Conclusion Our findings support an association of RA with an FCRL3 functional polymorphism and reveal that this association is stronger in the absence of PTPN22 risk genotypes. These findings support a genetic heterogeneity across RA populations, suggesting that both the FCRL3 and PTPN22 genes play roles in RA susceptibility, but in different individuals. [source] IK cytokine ameliorates the progression of lupus nephritis in MRL/lpr miceARTHRITIS & RHEUMATISM, Issue 11 2006Masatake Muraoka Objective IK cytokine has been isolated as a factor that inhibits interferon-, (IFN,),induced expression of class II major histocompatibility complex (MHC) antigens. Aberrant expression of class II MHC antigens has reportedly been recognized in the target organs of autoimmune diseases and been associated with disease activity. In this study, we investigated whether IK cytokine can ameliorate the progression of lupus nephritis in MRL/lpr mice. Methods A truncated IK analog was prepared and transfected into a nonmetastatic fibroblastoid cell line, and then injected subcutaneously into MRL/lpr mice at ages 8 weeks (before the onset of lupus nephritis) and 12 weeks (at the early stage of the disease). Results An IK cytokine, when it was translated from methionine at position 316, acted as a secretory protein. This truncated IK cytokine (tIK) reduced IFN,-induced class II MHC expression in various cells through decreased expression of class II MHC transcription activator. Treatment of MRL/lpr mice with tIK significantly reduced renal damage as compared with control mice. A significant decrease in macrophage and T cell infiltration was found in the kidneys of tIK-treated mice, resulting in decreased production of IFN, and interleukin-2. Mice treated with tIK also showed significant reduction of anti-DNA antibodies and circulating immune complexes. A specific reduction of class II MHC expression was observed on B cells and monocytes as well as in the kidney. Conclusion We prepared a potent IK analog and demonstrated its ability to ameliorate the progression of lupus nephritis. This agent may therefore provide a new therapeutic approach for lupus nephritis. [source] | ||||||||||