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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 1 (insulin-dependent) diabetes mellitus results from an autoimmune disease which is directed to insulin-secreting islet cells. In man, it is closely associated to definite major histocompatibility complex alleles. The islets are infiltrated by inflammatory cells (insulitis). Anti-islet cell autoantibodies are present in most patients and represent a valuable marker for the autoimmune reaction. The major role of autoreactive T lymphocytes has been demonstrated in animal models of spontaneous insulin-dependent diabetes (the BB rat and the NOD mouse). Such pathophysiological concepts already have clinical applications. The presence of anti-islet cell antibodies identifies patients with type 1 diabetes of slow onset who initially present with non-insulin dependent diabetes. In the same respect it is now feasible to predict the possible occurrence of diabetes in 'at risk' subjects (such as siblings of a diabetic patient) on the basis of HLA typing and the presence of markers of anti-beta cell immunity. Lastly, both in animal models and in human diabetes, it has been demonstrated that immune intervention can alter the course of anti-islet autoimmunity. From these results one may hope in the future to get preventive treatment of type 1 diabetes before the onset of metabolic disturbances.
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PMID:[Type 1 diabetes mellitus, autoimmune disease: physiopathologic aspects and practical applications]. 206 84

Associations between a large number of diseases and markers within the major histocompatibility complex (MHC) have been described. In particular, susceptibility to several autoimmune disorders, including type I diabetes mellitus and rheumatoid arthritis, is linked to genes within the MHC and strong population associations are demonstrable between certain HLA class II alleles and these conditions. Genetic mapping of HLA susceptibility loci has traditionally relied on the use of phenotypic markers defined by alloantisera, cellular typing reagents and biochemical analysis of histocompatibility antigens. Polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) typing combines the ability to define the finest of HLA specificities, by analysis of the corresponding DNA sequences, with the possibility of study large populations of normal and affected individuals. The applications of this technology to characterizing precisely the MHC loci associated with susceptibility to autoimmune diseases such as rheumatoid arthritis, type I diabetes mellitus, coeliac disease and pemphigus vulgaris are reviewed here.
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PMID:PCR-SSO typing in HLA-disease association studies. 206 41

Insulin-dependent diabetes mellitus is characterized by the infiltration of lymphocytes into the islets of Langerhans of the pancreas (insulitis) followed by destruction of insulin-secreting beta-cells leading to overt diabetes. The best model for the disease is the non-obese diabetic (NOD) mouse. Two unusual features of the class II major histocompatibility complex (MHC) of the NOD mouse are the absence of I-E and the presence of unique I-A molecules (I-ANOD), in which aspartic acid at position 57 of the beta-chain is replaced by serine. This feature is also found in the HLA-DQ chain of many Caucasians with insulin-dependent diabetes mellitus. We have previously reported that the expression of I-E prevents the development of insulitis in NOD mouse. Here we report that the expression of I-Ak (A alpha kA beta k) in transgenic NOD mice can also prevent insulitis, and that this protection is seen not only when the I-A beta-chain has aspartic acid as residue 57, but also when this residue is serine. These results show that the single amino-acid substitution at position 57 of the I-A beta-chain from aspartic acid to serine is not sufficient for the development of the disease.
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PMID:Direct evidence for the contribution of the unique I-ANOD to the development of insulitis in non-obese diabetic mice. 197 76

Insulin-dependent diabetes mellitus (IDDM) is a disease with an autoimmune aetiology. The inbred non-obese diabetic (NOD) mouse strain provides a good animal model of the human disease and genetic analysis suggests that, as in man, at least one of the several genes controlling the development of IDDM is linked to the major histocompatibility complex. The NOD mouse does not express I-E owing to a deletion in the promoter region of the I-E alpha-chain gene, and the sequence of NOD I-A beta-chain in the first external domain is unique with His 56 and Ser 57 replacing Pro and Asp, respectively, at these positions. There has been considerable interest in the role amino acid 57 might have in conferring susceptibility to autoimmune diseases, including IDDM. The presence of a charged residue (such as Asp) at this position might affect the conformation of the peptide binding groove. But it could be assumed that Pro 56 gives rise to a different conformation of I-A beta-chain than does His 56. We therefore constructed transgenic NOD mice in which the transgene encoded a modified A beta nod with Pro 56, and studied its effect on the development of IDDM in this mouse strain. Previous studies have suggested that NOD mice expressing I-E as a result of the introduction of an I-E alpha-chain (E alpha) transgene are protected from the development of insulitis and hence IDDM. To explore further the protective effect of this molecule we constructed a second class of transgenic NOD mouse carrying an E alpha d transgene. Both transgenes protected the mice from IDDM, but this was not associated with a complete deletion of any T cells expressing commonly used T-cell receptor V beta genes.
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PMID:Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain. 197 76

Very little is known about the genes involved in the pathogenesis of IDDM. One component is known to be linked to the major histocompatibility complex, but the other components are unknown. We know from the major animals models of IDDM, both the NOD mouse and the BB rat, that the disease is under multigenic control. However, due to the size and complexity of the mammalian genome as well as to the lack of useful clues, the location and identity of the other genes remains a mystery. This is compounded by the fact that well-characterized genetic markers are not available for all regions of the mammalian genome, and it is likely that at least some of the genes of interest are located in these regions. The testing of pedigrees for the linkage of RFLP with the genetic factors involved in IDDM promises to be the most effective means of mapping, and ultimately identifying, these genes. However, the number of genes which are theoretically necessary to test for linkage makes even this approach impractical. Here, we have described here how the amount of work and time can be significantly reduced by utilizing repetitive DNA sequences as probes for the linkage of random RFLPs to diabetes. With each screening, one can simultaneously test multiple unlinked loci in the genome. Preliminary results which show promising linkage to two of the genetic components have been presented, thereby supporting the usefulness of this approach.
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PMID:The genetics of insulin-dependent diabetes in the BB rat. 219 68

INSULIN-dependent (type I) diabetes mellitus (IDDM) follows an autoimmune destruction of the insulin-producing beta-cells of the pancreas. Family and population studies indicate that predisposition is probably polygenic. At least one susceptibility gene lies within the major histocompatibility complex and is closely linked to the genes encoding the class II antigens, HLA-DR and HLA-DQ (refs 3, 4). Fine mapping of susceptibility genes by linkage analysis in families is not feasible because of infrequent recombination (linkage disequilibrium) between the DR and DQ genes. Recombination events in the past, however, have occurred and generated distinct DR-DQ haplotypes, whose frequencies vary between races. DNA sequencing and oligonucleotide dot-blot analysis of class II genes from two race-specific haplotypes indicate that susceptibility to IDDM is closely linked to the DQA1 locus and suggest that both the DQB1 (ref. 7) and DQA1 genes contribute to disease predisposition.
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PMID:Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. 249 58

The selective destruction of the pancreatic islet beta cells in type 1 diabetes mellitus is thought to be mediated by a cellular autoimmune process, possibly triggered by virus infection in genetically susceptible individuals. Because of the potentially important role of cell-cell adhesion in the immune response, we investigated whether cytokine products of mononuclear cells, or virus infection, induced the expression of intercellular adhesion molecule 1 (ICAM-1) on human endocrine islet cells. By flow cytofluorimetry, control islet cells did not express detectable ICAM-1. However, after a 72-hr exposure of islets to interferon gamma (IFN-gamma) and/or tumor necrosis factor alpha (TNF-alpha) (each at 250 units/ml), ICAM-1 was induced on greater than 85% of islet cells. IFN-gamma was 50% more potent than TNF-alpha; together, their effects were additive. Class I major histocompatibility complex (MHC) protein expression, detected on control islet cells, was also stimulated by IFN-gamma and/or TNF-alpha. In contrast, infection with reovirus type 3 did not induce ICAM-1 on islet cells, although it stimulated the expression of class I MHC proteins. By double-label indirect immunofluorescence microscopy, ICAM-1 expression was identified on both beta (insulin-secreting) and delta (somatostatin-secreting) islet cells. Monoclonal antibody to ICAM-1 precipitated protein of Mr 97,000 from [35S]methionine-labeled islets exposed to IFN-gamma and TNF-alpha, but not from control islets. RNA blot analysis revealed a major species of 3.3 kilobases and a minor species of 2.2 kilobases induced in islets exposed to the cytokines. These findings have implications for the molecular mechanisms of beta-cell destruction in type 1 diabetes, in that expression of ICAM-1 by beta cells may facilitate adhesion of antigen-targeted immune cells.
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PMID:Intercellular adhesion molecule 1 is induced on isolated endocrine islet cells by cytokines but not by reovirus infection. 249 83

Insulin-dependent diabetes mellitus (IDDM) is caused by a specific loss of the insulin-producing beta cells from pancreatic Langerhans islets. It has been proposed that aberrant expression of major histocompatibility complex (MHC) class II molecules on these cells could be a triggering factor for their autoimmune destruction. This proposal was tested in transgenic mice that express allogeneic or syngeneic class II molecules on the surface of islet cells at a level comparable with that normally found on resting B lymphocytes. These animals do not develop diabetes, nor is lymphocyte infiltration of the islets observed. This immunological inactivity does not result from tolerance to the "foreign" class II molecules.
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PMID:Transgenic mice with I-A on islet cells are normoglycemic but immunologically intolerant. 249 48

Insulin-dependent diabetes mellitus is widely believed to be an autoimmune disease. Recent onset diabetics show destruction of insulin-secreting pancreatic beta-cells associated with a lymphocytic infiltrate (insulitis), with autoantibodies to beta-cells being found even before the onset of symptoms. Susceptibility to the disease is strongly influenced by major histocompatibility complex (MHC) class II polymorphism in both man and experimental animal models such as the non-obese diabetic (NOD) mouse. As MHC class II molecules are usually associated with dominant immune responsiveness, it was surprising that introduction of a transgenic class II molecule, I-E, protected NOD mice from insulitis and diabetes. This could be explained by a change either in the target tissue or in the T cells presumed to be involved in beta-cell destruction. Recently, several studies have shown that I-E molecules are associated with ontogenetic deletion of T cells bearing antigen/MHC receptors encoded in part by certain T-cell receptor V beta gene segments. To determine the mechanism of the protective effect of I-E, we have produced cloned CD4+ and CD8+ T-cell lines from islets of recently diabetic NOD mice. These cloned lines are islet-specific and pathogenic in both I-E- and I-E+ mice. Both CD4+ and CD8+ cloned T cells bear receptors encoded by a V beta 5 gene segment, known to be deleted during development in I-E expressing mice. Our data provide, therefore, an explanation for the puzzling effect of I-E on susceptibility to diabetes in NOD mice.
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PMID:An explanation for the protective effect of the MHC class II I-E molecule in murine diabetes. 250 22

Insulin-dependent diabetes mellitus (IDDM, type I) is an autoimmune disorder exhibiting a strong association with particular haplotypes of the major histocompatibility complex (MHC). We have previously shown that the u haplotype of the rat MHC (RT1) is absolutely required for expression of IDDM in the BB rat model of the disease. To define the precise regions of the RT1 contributing to disease occurrence and to address the mechanism by which the associated haplotype participates in disease pathogenesis, we have transferred recombinant haplotypes bearing the IDDM-associated MHC in defined regions onto the BB rat genetic background. In this report, we present data from two breeding studies utilizing the r8 haplotype (RT1AaBuDuEuCu) that demonstrate that (1) the RT1A locus is not involved in the disease association, (2) the MHC genes determining disease susceptibility are not unique to the BB rat, and (3) IDDM resistance genes are found outside the MHC. We also present evidence that the immunoregulatory defect characteristic of BB rats enhances the incidence of IDDM although it is not absolutely required for disease expression. We were able to track the transmission of the recombinant haplotypes in diabetic progeny using a combination of monospecific alloantisera and restriction fragment length polymorphism analysis using locus-specific MHC gene probes.
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PMID:Susceptibility and resistance genes to insulin-dependent diabetes mellitus in the BB rat. 251 27


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