Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of pancreatic B-cell destruction in type I (insulin-dependent) diabetes (IDDM) involves autoimmune phenomena based on genetic predisposition. The mechanism of action of the susceptibility genes is probably related to the function of the HLA molecules in the immune response. The genetic susceptibility is distinguished by increased frequency of the HLA antigens DR3 and DR4 and particularly their heterozygous combination DR3/DR4. Recent advances in molecular biology have resulted in a more precise definition of the genetic variants and corresponding amino acid sequences associated with IDDM. These markers may identify subjects at risk of developing the disease. However, the signs of islet-specific autoimmunity, e.g. islet-cell antibodies, which may be detected several years before the clinical onset of IDDM, are of greater predictive value. These and other arguments in favour of an autoimmune pathogenesis of type I diabetes have made preventive immunotherapy a goal for the future.
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PMID:[The role of genetic and immunological factors in the etiology of insulin-dependent diabetes]. 240 78

A major part of the T lymphocyte response to mumps and Coxsackie B4 virus appears to be restricted by HLA-DR associated restriction elements. This was further corroborated in inhibition experiments using monoclonal antibodies reactive with different HLA class II molecules. Only antibodies reactive with DR molecules significantly inhibited the response. The frequencies of DR restricted antigen-reactive T lymphocytes (ARTL) to mumps and Coxsackie B4 virus were then investigated, using a limiting dilution assay. A decreased frequency of DR3 restricted ARTL to mumps and Coxsackie B4 was found compared to ARTL restricted by other DR associated elements. In contrast, an increased frequency of DR4 restricted ARTL to mumps and Coxsackie B4 was found. The results were similar for healthy individuals and Type 1 diabetic patients. No correlation was found between DR restriction elements and the frequencies of ARTL to varicella-zoster or PPD. The studies indicate that HLA-DR3 and DR4, which are associated with Type 1 diabetes, have a different regulatory function on the proliferative T lymphocyte response to mumps and Coxsackie B4.
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PMID:T lymphocyte responses to Coxsackie B4 and mumps virus. II. Immunoregulation by HLA-DR3 and -DR4 associated restriction elements. 241 85

The proliferative T lymphocyte responses to two different mumps antigen preparations, S (nucleocapsid) and V (viral envelope), were characterized. Eight patients with Type 1 (insulin-dependent) diabetes mellitus were all found to be responders to S and V mumps antigen. Among the 64 healthy individuals, 52 were classified as responders to the S antigen and 50 responders to the V antigen. No difference was found between T lymphocytes from Type 1 diabetic patients and those from healthy individuals as regards the effect of indomethacin on the mumps-specific response. The majority of the mumps-specific T lymphocytes seemed to be restricted by epitopes on the HLA-DR molecules. The frequency of mumps antigen-reactive T lymphocytes (ARTL) was found to be low when the response was restricted by DR3-associated elements, and high when it was restricted by DR4-associated elements, compared to the frequency of ARTL when other DR-associated elements restricted the mumps-specific response. For the majority of the individuals tested, the DR-associated hypo- and hyper-responsiveness was found with both the S and the V mumps antigens.
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PMID:HLA control of the proliferative T lymphocyte response to antigenic determinants on mumps virus. Studies of healthy individuals and patients with type 1 diabetes. 241 8

T cells from an insulin-treated diabetic (ML, HLA DR1, w6) were stimulated in vitro with insulin, cloned at limiting dilution, and examined for their fine specificity and genetic restriction. T cell lines (TCL) derived from beef insulin stimulation were highly specific for epitopes on beef insulin, whereas pork insulin stimulation generated T cells that recognized determinants shared with beef insulin. Included among TCL reactive with pork insulin is one line (P2/9) that is autoreactive with human insulin. Antigen-presenting cells of known HLA type and monoclonal antibodies directed at class II major histocompatibility complex antigens were used to confirm the role of HLA-DR in restricting the response of insulin immune T cells. No preference or determinant selection within the donor's haplotypes was identified because either DR1 or DRw6 antigen-presenting cells could present the A loop of beef insulin. A TCL that recognized the A loop of beef insulin in association with DR1 was also alloreactive to HLA DR3, or a molecule closely linked to it, in the absence of insulin. A second T cell clone with insulin specificity and alloreactivity was also derived by allo stimulation of the donor's cells with DR3+ cells. When tested with a series of DR3+ stimulator cells, the alloreactivity was directed at diabetes-associated haplotypes. These data show that the T cell repertoire for insulin of a single diabetic donor encompasses that of multiple inbred animal strains and includes fine specificity for one to two amino acids, recognition of autologous insulin, and cross-reactivity with an allogeneic major histocompatibility complex antigen.
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PMID:Insulin-specific human T cells. Epitope specificity, major histocompatibility complex restriction, and alloreactivity to a diabetes-associated haplotype. 244 17

T cell autoreactivity to insulin in type I diabetic and related non-diabetic individuals was analyzed. Peripheral T lymphocytes from both insulin-treated diabetic and untreated non-diabetic members of four families were found to proliferate in vitro in response to human insulin. T cell autoreactivity to insulin therefore does not appear to be diagnostic of the onset of type I diabetes. Highest T cell responses to human insulin were usually detected in insulin-dependent type I diabetes patients treated with a mixture of beef and pork insulin than with self insulin, the greater the dose of animal insulin the higher the T cell response. The T cell repertoires for self insulin appear to be similar in diabetics and non-diabetics based on their patterns of T cell reactivity to beef insulin, port insulin, human insulin, and various peptide of human insulin. The autoreactive T cells analyzed recognize two conformational epitopes of human insulin formed by interactions between A chain and B chain residues. One epitope is associated with the A chain loop and is present in the A1-A14/B1-B16 peptide, and the other epitope consists mainly of B chain residues located in the A16-A21/B10-B25 peptide. These two epitopes are present in amphipathic alpha-helical regions of insulin. HLA-DR (DR3, DR4, and DR5) and HLA-DQ (DQw2/DQw3) Ag can restrict these T cell responses to human insulin epitopes. The ability to detect insulin-specific autoreactive T cells in healthy non-diabetic individuals supports the hypothesis that autoreactive lymphocytes do not necessarily elicit autoimmune disease if present in an environment in which their activity is immunoregulated.
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PMID:T cell autoreactivity to insulin in diabetic and related non-diabetic individuals. 245 92

Analysis of HLA haplotypes occurring in more than one, only one, or no diabetics in GAW5 multiplex insulin-dependent diabetes mellitus (IDDM) families suggested: 1) DR3, DR4, DRw6, and DRw8 are positively associated, and DR2 is negatively associated, with IDDM; 2) DR4 haplotypes are more diabetogenic than DR3 haplotypes; some DR3 haplotypes lacking B8/B18 are more diabetogenic than those carrying B8/B18; DR3 haplotypes with DR beta TaqI bands [2,5,10/11] are more diabetogenic than those without; DR4 haplotypes that carry DQw3.2 are more diabetogenic than those that do not; some DR2 haplotypes are diabetogenic rather than protective. Analysis of DR3 and DR4 transmission from DR3/X and DR4wX (X not equal to 3,4) healthy parents suggested: 3) no distortion of transmission to healthy children and 4) mothers transmit DR4 (and perhaps DR3) less often than fathers to diabetic children. Analysis of INS, GM, and HLA haplotype sharing in affected sib pairs suggested: 5) random segregation of INS haplotypes and 6) a tendency to increased sharing of GM haplotypes in affected sib pairs who were HLA-identical and DR3/4, compared with pairs who were not.
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PMID:Genes predisposing to IDDM in multiplex families. 249 98

Analysis of the Fifth Genetic Analysis Workshop (GAW5) insulin-dependent diabetes mellitus (IDDM) data leads to the following conclusions: 1) With a maximum-likelihood affected sib pair method, there is strong evidence for linkage with HLA and no evidence for linkage with INS, Gm, or Km. 2) Susceptibility as defined by HLA genotypes is very complex. Each DR allele has a unique susceptibility, and DR3 and DR4 haplotype associations for DR 3/4 genotypes are different from those for 3/X and 4/X. 3) Risk is substantially higher in sibships with an affected father compared to those with an affected mother. This excess cannot be attributed to transmission distortion at HLA.
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PMID:Genetics of IDDM: evidence for complex inheritance with HLA. 249 1

Characteristics of a multiplex sample of families with insulin-dependent diabetes mellitus (IDDM) are studied and contrasted with similar characteristics in other, more conventionally sampled data sets. Some characteristics remain consistent with earlier observations including the high frequency of human leukocyte antigen (HLA) DR3,4 in affected individuals and the greater than expected percentage of HLA haplotype sharing among affected sib pairs. In other respects, however, differences are seen between this sample and others. "Control" haplotypes, i.e., those not transmitted to the first affected offspring, had a higher frequency of DR3 and DR4 than expected, and a rather high frequency of affected parents was observed. Differences between the first affected and later affected offspring reported in other samples were absent from these families. No effect of the sampling scheme and the resulting distribution of parental phenotypes could be shown to explain this difference.
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PMID:Characteristics of a multiplex IDDM sample: unexplained differences with other samples. 249 6

Serological HLA typing of 92 insulin-dependent diabetes mellitus (IDDM) patients and 300 healthy controls was performed by the immunomagnetic typing technique. We found an increased risk of IDDM among DR4/w8 heterozygotes, similar to that seen for DR3/4 heterozygotes. The DQ alleles of these DR4/w8 patients were therefore established. When hybridized with a cDNA DQB probe, BamHI-digested DNA from eight out of the nine DR4/w8 patients revealed only one single 10.8-kb DQB1-specific fragment typical of DQw4 and DQw8. DNA from all DR4/w8 patients also hybridized to an oligonucleotide probe corresponding to amino acids (aa) 23-30 of the beta chain of DQw8. However, using the oligonucleotide probe, the staining intensity was found to be only half of that seen when DNA from DQw8 homozygotes was used instead, suggesting that the eight DR4/w8 patients had DQw8 in a single dose and carried the DQw4 allele at the DRw8 haplotype. Therefore, eight of nine DR4/w8 IDDM patients seemed to be DR4,DQw8/DRw8,DQw4, which, thus, may be associated with susceptibility to develop IDDM. One common explanation of IDDM susceptibility for DR4,DQw8/DRw8,DQw4 and DR3,DQw2/DR4,DQw8 heterozygotes may be that they share similar DQ alpha beta epitopes encoded by DQA and DQB genes in trans.
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PMID:An increased risk of insulin-dependent diabetes mellitus (IDDM) among HLA-DR4,DQw8/DRw8,DQw4 heterozygotes. 256 83

A scheme is outlined for analyzing the genotypic contributions of two unlinked loci in producing a disease, using DR and the 5' insulin locus (INS) in insulin-dependent diabetes mellitus (IDDM) as examples. Although genotypes of both DR and INS play roles in IDDM susceptibility, both the relatively small size of the Genetic Analysis Workshop 5 (GAW5) data set and the apparently limited magnitudes of the contributory effects prevent the identification of the exact nature of the association of these two loci in disease causation. The Gm allotypes showed no association with IDDM, either alone or in combination with other variables. Association of reactivity among the six strains of Coxsackie B virus is described, with no evidence of associations with DR type and IDDM found. The unaffected offspring segregated DR alleles according to expectations, while the segregation of affected alleles revealed the various contributions of DR alleles to IDDM pathogenesis, with the suggestion that DR4 from fathers is more diabetogenic than that from mothers. Lastly, a method is described for revealing the accuracy of typing in family data, and applied to RFLP variants subdividing DR3.
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PMID:Clues to IDDM pathogenesis from genetic and serological traits in multiply affected families. 256 54


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