Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent advances in knowledge of crystal structures of MHC class II molecules has advanced understanding of the molecular basis for interactions between peptides and HLA class II molecules. Polymorphism of HLA class II molecules influences structures of peptides bound to HLA class II molecules. To elucidate mechanisms for statistical association between particular HLA class II alleles and susceptibility to autoimmune diseases, it is important to identify self peptides presented by disease-susceptible HLA class II molecules and triggering disease-causative autoreactive T cells. In this study, we tried to identify self-peptides triggering autoimmune diseases including rheumatoid arthritis, insulin autoimmune syndrome, insulin dependent diabetes mellitus and infant-onset myasthenia gravis. Susceptibility to all of these diseases in the Japanese population are known to be strongly associated with particular HLA-DR-DQ haplotypes unique to Asians, and clinical features of some of these diseases are different between Caucasians and Asians including Japanese. We investigated differences in binding-peptide motifs between disease susceptible and non-susceptible HLA class II molecules and predicted candidates of autoimmune self-peptides carrying binding-motifs to disease-susceptible HLA class II molecules. Indeed the major epitope for insulin-autoreactive CD4+ T cell was successfully identified by this strategy. We also found heterogeneity in immunogenetic background between Western type and Asian type of multiple sclerosis. Our data indicated that our strategy is useful to identify autoimmune self-peptides, and it is suggested that not only disease-susceptible HLA class II but also self-peptides causing diseases are different between Caucasians and Asians. These differences may well correlate to different clinical manifestations of diseases between the two ethnic groups.
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PMID:[Binding-peptide motifs of HLA class II molecules susceptible to autoimmune diseases]. 920 Sep 22

RIP-LCMV transgenic mice that express the viral glycoprotein (GP) or nucleoprotein (NP) from lymphocytic choriomeningitis virus (LCMV) under control of the rat insulin promoter (RIP) in pancreatic beta-cells develop autoimmune diabetes (IDDM) after infection with LCMV. Previous reports have described that the viral infection activates naive, potentially autoreactive CD8+ cytotoxic T-lymphocytes (CTL) that are present in the periphery of these mice, thus leading to the breaking of immunological unresponsiveness to the viral self-antigen expressed on beta-cells. However, we find that adoptive transfer of such CTL that were active in vitro and in vivo into uninfected RIP-LCMV recipients rarely resulted in hyperglycemia nor in insulitis, despite their ability to home to the islets and induce peri-insulitis. These observations indicated that, in addition to activated autoreactive lymphocytes, other factor(s) were required for beta-cell destruction. The present study shows that upregulation of MHC class II molecules associated with the attraction/activation of antigen presenting cells (APCs) to the islets occurs as soon as 2 days after LCMV inoculation of transgenic mice, clearly before CD4+ and CD8+ lymphocytes are found entering the islets (days 6 and 7 after LCMV inoculation). In contrast, although some MHC class II upregulation is also found in islets of non-transgenic mice 2-4 days after LCMV infection, no insulitis or IDDM develops and MHC is downregulated to normal (pre-infection) levels by day 7-10 in these mice. Associated with the activation of APCs and MHC upregulation observed in transgenic mice, viral (LCMV) infection of islets was detectable 2 days post-viral inoculation in some mice. Thus, beta-cell destruction by activated autoreactive lymphocytes is a multifactorial process that is likely to require changes within the islet milieu or dysfunction of islets.
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PMID:Pathological changes in the islet milieu precede infiltration of islets and destruction of beta-cells by autoreactive lymphocytes in a transgenic model of virus-induced IDDM. 921 48

Susceptibility to IDDM is strongly associated with major histocompatibility complex (MHC) class II genotypes. Nonobese diabetic (NOD) mice develop a similar autoimmune diabetes and have a unique MHC class II I-A allele that is required for the development of diabetes. A number of groups have shown that the introduction of resistant MHC class II alleles as transgenes into the NOD mouse protects from diabetes. We made control transgenic NOD mice, expressing their own I-Abetag7 molecule as a transgene. One of two lines of these mice showed a reduced incidence of diabetes, without any change in T-cell proliferative response to a number of diabetes autoantigens or any change in insulitis severity. This line developed a subtle decrease in the percentage of splenic B-cells that progressed with age. This defect was not associated with any other phenotypic abnormalities. Our findings suggest that assessment of splenic B-cell number is necessary in interpretation of the effects of MHC class II transgenes on the development of diabetes in the NOD mouse.
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PMID:Reduction in diabetes incidence in an I-Ag7 transgenic nonobese diabetic mouse line. 939 82

The current paradigm of MHC and disease association is efficient binding of autoantigens by disease-associated MHC molecules leading to a T cell-mediated immune response and resultant autoimmune sequelae. Data presented here offer a different model for this association of MHC with autoimmune diabetes. This new explanation suggests that the association of MHC with autoimmunity results from "altered" thymic selection in which high-affinity self-reactive (potentially autoreactive) T cells escape negative selection. This model offers an explanation for the requirement of homozygous MHC class II expression in NOD mice (and in man) in susceptibility to IDDM.
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PMID:The association of MHC with autoimmune diseases: understanding the pathogenesis of autoimmune diabetes. 943 91

Insulin-dependent diabetes mellitus (IDDM) results from chronic, T-cell dependent, autoimmune destruction of the insulin-producing beta-cells in the Langerhans' islets of the pancreas. Non-obese diabetic (NOD) mice spontaneously develop IDDM that resembles human type I diabetes. The susceptibility to diabetes in the NOD strain is a complex polygenic trait that determines a phenotype of immune alterations. The unique MHC class II molecule expressed by NOD mice (I-Ag7) plays a major role in the development of disease. Recently, it has been reported that I-Ag7 molecules generate a lower proportion of compact alphabeta heterodimers, compared to other haplotypes. However, it is not clear whether this reflects an intrinsic defect of this molecule to bind peptide stably or is the result of abnormal processing and/or peptide loading into the I-Ag7 molecule. Our aim was to develop and characterize a suitable antigen-presenting cell (APC) that expressed I-Ag7 in the context of a non-diabetes-prone antigen processing and presentation machinery. Here, we report the generation of a mouse DAP.3 fibroblast cell line (DAP.3Ag7) that constitutively expresses high levels of I-Ag7. Using DAP.3 cells transfected with I-Ag7 or I-Ak, we show that the expression of compact dimers in the same cell type is proportionally less for I-Ag7 molecules than for I-Ak molecules, implying an intrinsic defect of the I-Ag7 molecule as the cause for the low generation of compact dimers. However, DAP.3Ag7 cells are able to process and present antigen, as indicated by I-Ag7-dependent IL-2 production by a GAD67-specific NDO T-cell hybridoma after stimulation with GAD and live, but not fixed, DAP.3Ag7 cells. The IL-2 response to GAD when presented by DAP.3Ag7 was significantly higher than the response to GAD presented by NOD splenocytes. Based on these data, we conclude that the low generations of compact dimers is an intrinsic feature of I-Ag7 molecules and not affected by other genes in the NOD background. The DAP.3Ag7 cell line should be a valuable tool with which to dissect the role of the I-Ag7 molecule in antigen presentation and T-cell activation in NOD mice, which clearly contributes to the development of IDDM.
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PMID:Development of an I-Ag7-expressing antigen-presenting cell line: intrinsic molecular defect in compact I-Ag7 dimer generation. 948 Jul 24

Insulin dependent diabetes mellitus (IDDM) is sometimes associated with extrapancreatic organ-specific autoimmune diseases, but whether this phenotype results from a peculiar genetic profile is still unclear. The allelic distribution of the major histocompatibility complex (MHC) class II genes (HLA-DRB1, DQA1, DQB1 and TAP) was analysed in 143 patients with IDDM alone by comparison with 82 IDDM patients with autoimmune thyroid disease (IDDM/AITD). The frequency of the DQB1*0301 IDDM-protective phenotype seemed to be lower in IDDM than in IDDM/AITD patients (16.8% vs 30.5% respectively, p = 0.02). By contrast, the frequency of the DRB1*04-DQB1*0302 IDDM-predisposing phenotype was higher in IDDM than in IDDM/AITD patients (91.3% vs 76.1% of DR4-positive patients respectively, p = 0.007), but these differences were not significant after correcting the p values, except in the case of the DRB1*0405-DQB1*0302 combination (21.3% vs 2.4% of DR4-positive patients, Pc = 0.05). Furthermore, all differences disappeared when patients were matched for age at IDDM-onset. Our data do not long give support for a particular role of MHC class II genes in favouring the occurrence of thyroid autoimmunity in IDDM patients, but rather suggest that some class II alleles or residues might determine the rapidity of progression to IDDM in genetically susceptible individuals. The involvement of non-MHC genes and/or environmental factors remains to be determined.
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PMID:Major histocompatibility class II genes polymorphism in insulin dependent diabetes mellitus with or without associated thyroid autoimmunity. 954 77

Insulin-dependent diabetes mellitus (IDDM) is caused by the progressive autoimmune destruction of insulin-producing pancreatic beta cells. Although the pathogenesis of autoimmune IDDM has been extensively studied, the precise mechanisms involved in the initiation and progression of beta cell destruction remain unclear. Animal models used in the study of IDDM, such as the BioBreeding (BB) rat and the nonobese diabetic (NOD) mouse, have greatly enhanced our understanding of the pathogenic mechanisms involved in this disease. In these animals, macrophages and/or dendritic cells are the first cell types to infiltrate the pancreatic islets. Macrophages must be involved in the pathogenesis of IDDM early on, since inactivation of macrophages results in the near-complete prevention of insulitis and diabetes in both NOD mice and BB rats. The presentation of beta cell-specific autoantigens by macrophages and/or dendritic cells to CD4+ T helper cells, in association with MHC class II molecules, is considered the initial step in the development of autoimmune IDDM. The activated macrophages secrete IL-12, which stimulates Th1 type CD4+ T cells. The CD4+ T cells secrete IFN-gamma and IL-2. IFN-gamma activates other resting macrophages, which, in turn, release cytokines, such as IL-1beta, TNF-alpha, and free radicals, which are toxic to beta cells. During this process, IL-2 and other cytokines induce the migration of CD8+ peripheral T cells to the inflamed islets, perhaps by inducing the expression of a specific homing receptor. The precytotoxic CD8+ T cells that bear beta cell-specific autoantigen receptors differentiate into cytotoxic effector T cells upon recognition of the beta cell-specific peptide bound to MHC class I molecules in the presence of beta cell-specific CD4+ T helper cells. The cytotoxic CD8+ T cells then effect beta cell damage by releasing perforin and granzyme, and by Fas-mediated apoptosis. In this way, macrophages, CD4+ T cells, and CD8+ T cells synergistically destroy beta cells, resulting in the onset of autoimmune IDDM.
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PMID:Cellular and molecular mechanisms for the initiation and progression of beta cell destruction resulting from the collaboration between macrophages and T cells. 958 42

Susceptibility and resistance to type 1 diabetes are associated with MHC class II alleles that carry non-Asp and Asp at residue 57 of their beta chain respectively. The effect of Asp or non-Aspbeta57 may relate to a differential ability of distinct class II molecules to bind specific immuno-pathogenic peptides. Recent studies in man and mouse have revealed that some type 1 diabetes-predisposing non-Aspbeta57 class II molecules (i.e. DQ8, DR4Dw15 and I-Ag7) preferentially bind peptides with a negatively charged anchor residue at P9. It has been suggested that this is a common feature of type 1 diabetes-predisposing class II molecules. The molecular explanation for such a phenomenon could be that class II beta chains with Aspbeta57 form a salt bridge between Aspbeta57 and a conserved Arg of the a chain, whereas in non-Aspbeta57 molecules the Arg is unopposed and free to interact with negatively charged P9 peptide anchor residues. We have investigated the specificity of the P9 pocket of the type 1 diabetes-associated DQ2 molecule and in particular examined for charge effects at this anchor position. Different approaches were undertaken. We analyzed binding of a high-affinity binding ligand and P9-substituted variants of this peptide, and we analyzed the binding of a set of synthetic random peptide libraries. The binding analyses were performed with wild-type DQ2 and a mutated DQ2 with Ala at beta57 substituted with Asp. Our results indicate that the wild-type DQ2 (non-Aspbeta57) prefers large hydrophobic residues at P9 and that there is no particular preference for binding peptides with negatively charged residues at this position. The specificity of the P9 pocket in the mutated DQ molecule is altered, indicating that the beta57 residue contributes to determining the specificity of the P9 pocket. Our data do not lend support to the hypothesis that all non-Asp beta57 class II molecules predispose to development of disease by binding peptides with negatively charged P9 anchor residues.
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PMID:The P9 pocket of HLA-DQ2 (non-Aspbeta57) has no particular preference for negatively charged anchor residues found in other type 1 diabetes-predisposing non-Aspbeta57 MHC class II molecules. 972 10

During development of IDDM mononuclear cell infiltration is seen in the islets of Langerhans in both man and rodent models. This process is not synchronized in time and space. To create a synchronized model for investigation of the cellular and molecular events during IDDM development, we isolated and transplanted 200 neonatal BB-DP rat islets under the kidney capsule of 30 day old BB-DP rats. Islet transplantations were also carried out from Wistar Furth (WF) to WF rats, from WF to Wistar Kyoto (WK) rats and from WK to BB-DP rats to compare disease occurrence in an islet syngraft with changes in islet syngrafts or allografts in non-diabetes prone recipients and with changes in islet allografts in diabetes prone recipients, respectively. Pancreata and grafts were harvested at pre-scheduled time points before onset of diabetes and at onset of diabetes, and stained for insulin, MHC class I, MHC class II, alphabeta-TCR, CD4, CD8 or ED1. Diabetes incidence in the syngrafted BB-DP rats was 75% at 78 +/- 5 days of age. The incidence and time of onset of IDDM was unaffected by islet syngrafting. Positive correlations were found between the percentage of infiltrated islets in situ and the number of infiltrating cells in the islet syngraft from the same BB-DP rats (p = 0.003-p < 0.0001, r = 0.5-0.7). The number of infiltrating cells regardless of cell type in the graft was inversely correlated to the graft insulin content (p = 0.0003-p < 0.0000, r = -0.6 to -0.8). The graft insulin content was 70% and 90% in BB-DP rats before onset of diabetes and BB-DP rats not developing diabetes respectively, and 30% in the diabetic rats (p < 0.01). Interestingly only 5% of the allografted BB-DP rats developed diabetes. No correlation was found between the number of infiltrating cells in the graft and islets in situ in the BB-DP rats not developing diabetes. Only baseline infiltration was seen in grafts from syngrafted WF rats. In allografted WF islet to WK rats graft rejection was seen 12 days after transplantation. No correlation was found between the number of infiltrating cells in the graft and islets in situ. In conclusion the cellular infiltration in syngeneic but not allogeneic islets grafted to 30 day old BB-rats mirrors that seen in islets in situ. Syngeneic islet grafting in BB-DP rats may be useful for studying the cellular and molecular events during the development of IDDM.
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PMID:Syngeneic islet transplantation in prediabetic BB-DP rats--a synchronized model for studying beta-cell destruction during the development of IDDM. 977 79

MHC class II molecules function by selective binding of antigenic peptides, thereby both shaping the T-cell receptor (TCR) repertoire in the thymus and influencing presentation of immunogenic peptides to CD4+ T cells in the periphery. The strong association between a number of human autoimmune diseases (type 1 diabetes, rheumatoid arthritis, and multiple sclerosis) and certain HLA-DR/DQ alleles suggests that it may be possible to alter pathological autoimmune responses by deliberate introduction of autoantigenic peptides in a "tolerogenic" manner. Since there are likely to be differences in epitope selection and epitope spreading in different patients over time, this approach requires identification of all the immunogenic CD4+ T-cell epitopes (dominant, subdominant, or cryptic) of an autoantigen which elicit T-cell responses restricted to the HLA-DR/DQ alleles predisposing to these autoimmune diseases. This paper describes a new approach for the identification of immunogenic peptide epitopes of human autoantigenic proteins using HLA-DR and DQ transgenic mice. These mice are engineered to select a full TCR repertoire which can identify immunogenic peptide epitopes similar or identical to human subjects of the same HLA-DR/DQ genotype. This experimental system also allows comparison of autoantigenic immune responses restricted to disease-susceptible and disease-resistant HLA-DR/DQ alleles.
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PMID:Identification of autoantigen epitopes in MHC class II transgenic mice. 979 71


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