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)

Current knowledge of the phenotype of mononuclear cells accumulating in pancreatic islets in insulin-dependent diabetes (IDDM) and factors determining their homing into the pancreas is limited. Therefore, a pancreas obtained at the onset of IDDM was studied in detail. Cryostat sections were stained for mononuclear cell types, T cell receptor subtypes, and adhesion molecules of vascular endothelium and studied by immunofluorescence microscopy, and peripheral blood mononuclear cells were phenotyped using flow cytometry. Monocytes/macrophages (lysozyme- or CD 14-reactive cells) were identified among other mononuclear cell types in islet infiltrates. V beta 8-positive T cells were overrepresented, but T cells with other V beta s studied (V beta 5, V beta 5.1, V beta 6, V beta 12) were also found. The vascular endothelium of the islets and many small vessels nearby islets strongly expressed intercellular adhesion molecule-1, whereas vascular cell adhesion molecule-1 and E-selectin were totally absent. We conclude: (a) that increased expression of intercellular adhesion molecule-1 on vascular endothelium may increase endothelial adhesion of mononuclear cells and enhance their accumulation in the pancreas during diabetic insulitis; (b) that T cells with certain T cell receptors can be enriched in infiltrated pancreatic islets; and (c) that macrophages and antigen-specific CD 8-positive T cells are involved in pancreatic beta cell destruction at the onset of IDDM.
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PMID:Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. 138 78

It has been demonstrated, in certain autoimmune disease models, that pathogenic T cells express antigen receptors of limited diversity. It has been suggested that the T cells responsible for the pathogenesis of type I diabetes mellitus might similarly demonstrate restricted T cell receptor (TCR) usage. Recently, attempts have been made to identify the V beta subset(s) that initiates and/or perpetuates the antiislet response in a mouse model of spontaneous autoimmune diabetes (non-obese diabetic [NOD] mice). In studies reported here, we have bred NOD mice to a mouse strain that congenitally lacks approximately one-half of the conventional TCR V beta alleles. Included in this deletion are TCR V beta gene products previously implicated as being involved in the pathogenesis of NOD disease. By studying second backcross-intercross animals, we were able to demonstrate that this deletion of TCR V beta gene segments did not prevent the development of insulitis or diabetes.
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PMID:Genetic dissection of T cell receptor V beta gene requirements for spontaneous murine diabetes. 183 91

The effector mechanisms responsible for autoimmune beta cell destruction in insulin dependent (type 1) diabetes (IDD) remain elusive. In order to investigate whether T lymphocytes bearing the gamma-delta T cell receptor (gamma delta+ T cells) could be involved in this process, we measured percentages of peripheral blood gamma delta+ T cells in IDD patients, relatives of IDD probands and controls. High levels of gamma delta+ T cells strongly differentiated 23 relatives at high risk for IDD on the basis of positive islet cell autoantibodies (ICA positive relatives) from 59 controls (P = 0.0013), whereas 26 ICA negative relatives, 14 recent-onset and nine long term IDD patients could not be distinguished from controls on the basis of percentages of gamma delta+ T cells. These data suggest that increased levels of circulating gamma delta+ T cells correlate with the ongoing autoimmune process in pancreatic islets of subjects at high risk for IDD and may thus represent an additional marker for the development of the disease.
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PMID:Increased T lymphocytes bearing the gamma-delta T cell receptor in subjects at high risk for insulin dependent diabetes. 183 80

The analysis of HLA class II sequence variation in IDDM patients and controls, made possible by the PCR, has revealed that specific alleles are associated with IDDM. The HLA-DQ beta chain appears to play a role in determining genetic susceptibility and resistance, although polymorphisms in the DRB1, the DQ alpha, and the DP beta chain may also contribute. Although there is a correlation between susceptibility and the charge of DQ beta residue 57, the complex genetic epidemiology of IDDM cannot be accounted for by polymorphism at this position. As we have discussed previously (Horn et al, 1988a, 1988b; Erlich et al, 1990b), there are no unique class II sequences associated with IDDM, consistent with the view that 'normal' class II alleles confer susceptibility. Given the estimates of concordance of under 50% for monozygotic twins and approximately 15% (Tattersall and Pyke, 1972; Thomson, 1988) for HLA-identical sibs--it is not surprising that some unaffected individuals contain putative susceptibility alleles. Perhaps some environmental 'triggering' agent, such as viral infection, is required for the disease to develop in susceptible individuals. Other non-MHC-linked genes which contribute to susceptibility may account for the difference in concordance rates for monozygotic twins and for HLA-identical sibs. In the NOD (non-obese diabetic) mouse and the BB rat models for IDDM, non-MHC susceptibility loci have been identified and mapped (Colle et al, 1981; Hattori et al, 1986) but, in humans, the analysis of non-MHC candidate loci (i.e. the T cell receptor) has, thus far, failed to reveal any other susceptibility loci. In general, the HLA-linked genetic susceptibility to IDDM, as well as to other autoimmune diseases, appears to be associated with specific combinations of class II epitopes (e.g. alleles, haplotypes or genotypes) rather than with specific individual residues or epitopes. Understanding the role of these predisposing sequences will require structural analysis of the class II molecules as well as in vitro and in vivo functional studies of interactions with putative autoantigens and T cell receptors. In the meantime, DNA typing offers the potential for identifying individuals at high risk. These susceptible individuals could be monitored by immunological (e.g. anti-islet cell antibody) or by metabolic tests to detect the preclinical phase of IDDM.
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PMID:HLA class II sequences and genetic susceptibility to insulin dependent diabetes mellitus. 190 60

The focus of this chapter is on the contribution of genes outside the HLA region to insulin dependent diabetes mellitus (IDDM) susceptibility. We review laboratory evidence for such genes from published studies and also present unpublished data from our recent research. The existence of genes predisposing to IDDM in the region of the insulin (INS) gene now appears established. Association analysis has demonstrated an increased frequency of class 1 alleles of the 5' INS polymorphism in diabetics compared with controls, and a new method of analysis (AFBAC) has shown that this association is not an artefact of population stratification. Interestingly, the effect of INS region susceptibility on IDDM cannot be detected by linkage analysis, suggesting that if a genetic marker locus is close to a disease susceptibility locus, association analysis may be a more sensitive method than linkage analysis for detecting the susceptibility locus. There is no convincing evidence that genes in the T cell receptor beta chain (TCRB) or alpha chain (TCRA) regions influence predisposition to IDDM, either directly, or indirectly through interaction with HLA region genes. However, we present new evidence for interaction between TCRB and immunoglobulin heavy chain (Gm) region genes in IDDM: diabetics who are positive for the IgG2 allotype G2m(23) have significantly different frequencies of a TCRB restriction fragment length polymorphism (RFLP) than those who are negative for the allotype. Gm region genes also appear to have indirect effects on IDDM susceptibility through interaction with HLA and INS region genes: DR3/4 and non-DR3/4 diabetics have significantly different frequencies of G2m(23), and INS1/1 and non-INS1/1 diabetics also have significantly different frequencies of this allotype. To our knowledge, there are no other studies of Gm-TCRB or Gm-INS interaction in IDDM susceptibility. Evidence for Gm-HLA interaction in IDDM has been published by several other groups of investigators, however the specific phenotypic interaction effects reported have differed. Nevertheless, pooled data from three studies of Gm/HLA haplotype segregation in affected sib pairs shows significantly increased sharing of Gm haplotypes in affected pairs who share both HLA haplotypes. The biological mechanisms underlying the direct (HLA, INS) and indirect (Gm-TCRB, Gm-HLA, Gm-INS) effects of these genetic regions on IDDM susceptibility remain to be elucidated.
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PMID:Non-HLA region genes in insulin dependent diabetes mellitus. 190 61

As we have discussed previously (Horn et al. 1988a; Erlich et al. 1989b; Horn et al. 1988b), there are no unique class II sequences associated with IDDM, which suggests that "normal" class II alleles confer susceptibility. Given the estimates of concordance--under 50% of monozygotic twins and approximately 15% (Tattersol, Pyle 1972 and Thomson 1988) for HLA-identical sibs--, it is not surprising that some unaffected individuals contain putative susceptibility alleles. Perhaps some environmental "triggering" agent, such as viral infection (Yoon, this volume), is required for the disease to develop in susceptible individuals. Other non-MHC linked genes which contribute to susceptibility may account for the difference in concordance rates for monozygotic twins and for HLA-identical sibs. In the nonobese diabetic mouse and the BB rat models for IDDM, non-MHC susceptibility loci have been identified and mapped (Hattori et al. 1986; Colle et al. 1981), but in humans the analysis of non-MHC candidate loci (i.e., the T cell receptor) has thus far failed to reveal any other susceptibility loci. In general, the HLA-linked genetic susceptibility to IDDM, as well as to other autoimmune diseases, appears to be associated with specific combinations of class II epitopes (e.g., alleles, haplotypes, or genotypes) rather than with specific individual residues or epitopes. Understanding the role of these predisposing sequences will require structural analysis of the class II molecules as well as in vitro and in vivo functional studies of interactions with putative autoantigens and T cell receptors. In the meantime, DNA typing offers the potential for identifying individuals at high risk for IDDM.
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PMID:HLA class II polymorphism and genetic susceptibility to insulin-dependent diabetes mellitus. 212 92

We have investigated restriction fragment length polymorphism (RFLP) of HLA and non-HLA regions of the genome in the homogeneous Danish population. Insulin-dependent diabetes mellitus (IDDM) patients and healthy individuals were selected for being HLA-DR 3/4 heterozygous to evaluate the influence of genes other than DR on disease susceptibility. Five different probes were used: HLA alpha and beta DQ (chromosome 6), the Ins 310 genomic fragment which detects a polymorphic region 5' to the insulin gene (chromosome 11), and cDNA for the constant regions of the T cell receptor alpha and beta genes (chromosomes 14 and 7). Fifteen cells homozygous for the HLA-D region were used to obtain reference DNA patterns. This allowed us to describe four splits among the HLA-DQw3 haplotypes (DQw3.1 to DQw3.4). The two new haplotypes DQw3.3 and DQw3.4 do not code for the TA10 serological marker which is found on DQw3.1 positive cells. One-hundred per cent of IDDM patients were typed as DQw3.2 versus 68 per cent for controls (p = 0.003). However, our results do not indicate a role for the Ins 310 or for the alpha DX locus region in IDDM susceptibility, in contrast to previous reports by others. The restriction enzymes that we have used did not reveal significant differences between DNA patterns of patients and controls with probes for the constant region of the T cell receptor genes.
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PMID:Restriction fragment length polymorphism of HLA and non-HLA genes in DR3/4 heterozygous Danish insulin-dependent diabetic patients and healthy individuals: reassessment of the influence of alpha DX and insulin-linked polymorphic loci, and new splits of DQw3 haplotypes. 256 78

We investigated the T cell receptor constant beta chain (TCR C beta) genes of patients with insulin dependent diabetes mellitus (IDDM) using DNA restriction fragment length polymorphism (RFLP) analysis. Genomic DNA from patients and controls was digested with the restriction endonuclease Bg1 II and transferred to nylon filters using the Southern blot procedure. This enzyme identifies a polymorphic site between the two TCR C beta chain genes. We have found a highly significant increase in the frequency of the 10.0; 9.2 kilobase heterozygous phenotype in patients with IDDM (62.7% versus 42.0% in normal controls; P = 0.0006). In identical twin pairs, this association was most striking in those concordant for IDDM (79.2% versus 42.0% in controls; P = 0.0006).
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PMID:T cell receptor beta chain polymorphisms are associated with insulin-dependent diabetes. 289 59

Insulin-dependent diabetes mellitus (IDDM) is considered to be an autoimmune disease. Autoimmune diseases result from the breakdown of self-tolerance elicited by environmental factors on a susceptible genetic background. This reduced tolerance allows immunocompetent cells to attack normal structures present on an individual's tissues. The study of the T cells present in the islets of patients who died at the onset of the disease allowed the recognition of "superantigens" as etiopathogenetic factors in the development of IDDM. Since superantigens are the product of bacteria or viruses able to quickly stimulate a large number of the peripheral T cells sharing the same T cell receptor V beta segments once presented by certain HLA class II molecules, a number of observations in genetics, immunology, virology and epidemiology can now find a unifying explanation.
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PMID:Exposure to superantigens as an immunogenetic explanation of type I diabetes mini-epidemics. 758 94

Insulin dependent diabetes mellitus (IDDM) in the non-obese diabetic (NOD) mouse is the result of a cellular mediated autoimmune event that destroys pancreatic islet beta cells. This destruction is characterized by a progressive lymphocytic infiltration into the islets as well as circulating autoantibodies and T cells reactive with islet antigens. To gain a better understanding of the cells responsible for islet destruction we isolated lymphocytes from the islets of prediabetic NOD mice and conducted a comparative phenotypic analysis with the analogous subpopulations of lymphocytes isolated from peripheral blood and lymph node (LN) of the same mice. CD3+ cells were analysed for T cell receptor (TcR); cell bearing gamma delta TcR were consistently observed at a higher frequency in the infiltrating T cells than in the periphery. Lymphocytes were also characterized for the expression of CD4 and CD8 T cell markers and, within each population, for the expression of activation markers (CD25, CD69) and adhesion markers (CD51, CD54, CD11b, CD49e, L-selectin). Significantly increased levels of CD4+CD8+ double-positive and CD4-CD8- double-negative T cell populations were observed in the infiltrating lymphocytes as compared with peripheral lymphocytes. In addition, within both CD4 and CD8 subpopulations isolated from islet infiltrates, CD11b+ and CD49e+ cells were increased with respect to the same subset of cells isolated from the periphery. In contrast, the level of cells that expressed L-selectin was significantly higher in the periphery for both CD4+ and CD8+ cells than for infiltrating cells. These data describe the phenotype of islet reactive T cells in the NOD mouse and identify possible targets for therapeutic intervention.
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PMID:Differences in adhesion markers, activation markers, and TcR in islet infiltrating vs. peripheral lymphocytes in the NOD mouse. 761 49


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