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)

Recently it has been reported that 57th amino acid of DQ beta antigen was a non-aspartic acid in the most Caucasian patients with insulin-dependent diabetes mellitus (IDDM). Using serological analysis, HLA-DQ antigens show a strong association with IDDM rather than the HLA-DR antigens. In the Caucasian population, IDDM is associated with DQw2 and DQw3 antigens. However, in the Japanese population, DQw4 and DQw9 antigens are strongly associated with IDDM. In order to determine the possible significance of the 57th amino acid of DQ beta chain for the susceptibility to IDDM in Japanese, we performed DNA Sequence analysis of HLA-DQB from Japanese IDDM patient, its same HLA genotyped healthy sibling and B cell line with Japanese IDDM associated haplotype. The results revealed that all of the 57th amino acid are aspartic acid which is thought to contribute to develop IDDM resistance in Caucasian. Furthermore we could not find any other amino acid sequence of DQ beta chain which might contribute to the susceptibility of the Japanese IDDM.
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PMID:[DNA sequence analysis of HLA-DQB genes associated with insulin-dependent diabetes mellitus in Japanese]. 222 93

Analysis of the frequencies of class II HLA-DR and HLA-DQ alleles by serological and DNA typing in 49 Japanese patients with type 1 (insulin-dependent) diabetes and 31 Japanese controls indicates the following. (i) Susceptibility is more strongly associated with the HLA-DQ subregion than with the HLA-DR subregion. (ii) Of the class II alleles detected, the A3 allele of the DQA1 locus was the most strongly associated with disease. Ninety-six percent of the patients were positive for the A3 allele compared to 53% of the controls (P = 0.001; relative risk = 19.7; confidence limits = 3.72-188.64). (iii) The DQw8 allele of the DQB1 locus, which is associated with susceptibility to type 1 diabetes in Caucasians and Blacks, was not increased in frequency in Japanese patients (22%) versus controls (19%). (iv) Asp-57-encoding DQB1 alleles are associated with reduced susceptibility to type 1 diabetes in Caucasians. The major predisposing haplotypes in Japanese are DR4 and DR9. By DNA sequence analysis, both of these Japanese haplotypes have Asp-57-encoding DQB1 alleles. Oligonucleotide dot blot analysis showed that all, except 1, of the 49 Japanese patients and all of the 31 controls have at least one Asp-57-encoding DQB1 allele. In addition, 40% of the patients were homozygous for Asp-57-encoding DQB1 alleles versus 35% of the controls. The high frequencies of Asp-57-encoding DQB1 alleles in this ethnic group may account for the rarity of type 1 diabetes in Japan.
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PMID:The A3 allele of the HLA-DQA1 locus is associated with susceptibility to type 1 diabetes in Japanese. 230 May 72

Restriction fragment length polymorphism using an HLA-DQ beta-chain genomic probe showed that 63 children with insulin-dependent (type 1) diabetes mellitus (IDDM) were all (100%) positive for the BamH1 fragments 12 kb and/or 4 kb compared to 98% (62/63) for HLA-DR3 and/or 4 and 75% (47/63) for HLA-B8 and/or 15. The 36 (56%) DR3-positive children were all 4-kb-positive; however, a total of 44 (70%) children were 4-kb-positive (P less than 0.02). The 55 (87%) DR4-positive children were all 12-kb-positive, but a total of 56 (89%) were 12-kb-positive (NS). The heterozygosity at the HLA region increased from 11/63 (18%) for HLA-B8/15 to 29/63 (46%) for HLA-DR3/4 (P less than 0.0004) and to 37/63 (59%) for the HLA-DQ 4 kb/12 kb fragments (P less than 0.02). The test of an equal probability of a positive result under the adjacent pair of tests indicates that the increased risk of developing IDDM in association with HLA-DQ is to a great extent due to heterozygosity at this locus. There were no differences between the 4 kb/12 kb and the DR3/4-positive IDDM children with respect to fasting or meal-stimulated C peptide, insulin requirement, or levels of insulin antibodies formed during the first 12 months of insulin therapy. Our results support the hypothesis that HLA-DQ is closely associated with an increased risk of childhood IDDM, and when typed for at this locus parameters of the clinical course were homogeneous, suggesting that factors other than HLA-DQ may determine previously observed differences between IDDM children in clinical or functional parameters.
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PMID:HLA heterozygosity in insulin-dependent diabetes is most frequent at the DQ locus. 233 66

There is evidence that certain alleles at the HLA-DQ locus are correlated with susceptibility to insulin-dependent diabetes mellitus (IDDM) and in particular that DQ beta-chain alleles containing aspartic acid at position 57 are protective. The availability of a large group of patients with IDDM enabled us to assess the role of HLA-DQ alleles in susceptibility to the disease in order to confirm and extend recent observations derived from studies of smaller numbers of patients. Using allele-specific oligonucleotide probes and the polymerase chain reaction, we studied 266 unrelated patients with IDDM and 203 unrelated normal subjects for eight HLA-DQ beta-chain alleles. Two major findings emerged from these studies. First, the presence of an HLA-DQw1.2 allele was protective. Only 6 of the 266 patients with IDDM (2.3 percent) were positive for HLA-DQw1.2, as compared with 74 of the 203 normal subjects (36.4 percent; P less than 0.001). Thus, persons with the HLA-DQw1.2 allele, which is one of the polymorphic forms of the beta chain of the HLA-DQ molecule, rarely had IDDM, no matter which other HLA-DQ beta-chain allele they inherited ("dominant protection"). Second, the presence of the HLA-DQw8 allele increased the risk of IDDM. The relative risk of IDDM was 5.6 in persons homozygous for HLA-DQw8, and it was similar in persons with the HLA-DQw1.1/DQw8 or HLA-DQw2/DQw8 haplotype ("dominant susceptibility"). However, the relative risk of IDDM in persons who had the HLA-DQw1.2/DQw8 haplotype was 0.37, demonstrating that the protective effect of HLA-DQw1.2 predominated over the effect of HLA-DQw8. We conclude that the presence of the HLA Class II antigen DQw1.2 is strongly protective against the development of IDDM, and that complete HLA-DQ typing is necessary for accurate assessment of susceptibility to IDDM.
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PMID:Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus. 234 40

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

We evaluated the expression of factor VIII and class II histocompatibility antigens on frozen sections of normal human and rat pancreases. The immunohistologic studies were performed with directly fluoresceinated anti-human factor VIII and monoclonal antibodies A2B5, 3G5 (anti-islet), L-243, I-2, OK1 (anti-human Ia-DR), Leu-10 (anti-human HLA-DQ), anti-human HLA-DP, and OX6 (anti-rat Ia). Islet endothelial cells of humans and Wistar, CD, and BB diabetes-prone rats could be distinguished from intra-acinar endothelial cells by markedly enhanced factor VIII immunoreactivity. Factor VIII-antibody staining of islet endothelial cells was specifically absorbed by prior incubation of anti-human factor VIII antibody with normal human plasma but not by incubation with factor VIII-deficient plasma. By double indirect immunofluorescence, normal human pancreatic ductal epithelium expressed Ia in five of six pancreases studied.
Diabetes 1988 Apr
PMID:Selective localization of factor VIII antigenicity to islet endothelial cells and expression of class II antigens by normal human pancreatic ductal epithelium. 245 9

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

Basal and yellow fever vaccination-induced 2',5'-oligoadenylate synthetase (2',5'A) activity was determined in blood mononuclear cells (peripheral blood lymphocytes [PBLs]) from insulin-dependent diabetes mellitus (IDDM) and matched control subjects. The live attenuated yellow fever vaccine represented a primary stimulus in all subjects. First, basal 2',5'A activity increased severalfold in response to yellow fever vaccination. In IDDM subjects, this increase was significantly lower (P = .025). Second, the 2',5'A activity increased proportionately to the higher basal 2',5'A activity in IDDM subjects. In control subjects, the increase in 2',5'A activity was not dependent on the basal activity. There was no relationship between basal or stimulated 2',5'A activity and age, sex, duration of IDDM, age at onset of IDDM, metabolic control, or HLA-DQ beta-chain gene polymorphism. There is a direct relationship between 2',5'A activity and latent viral infections associated with the presence of double-stranded RNA and with cellular interferons (IFNs) formed in response to viral infections. The higher basal 2',5'A activity (P = .05) in relation to the stimulated activity may therefore signify a latent infection or the presence of double-stranded RNA in PBLs of IDDM subjects. In vitro stimulation of PBLs showed increased IFN sensitivity in IDDM subjects. Analysis of 2',5'A activity is proposed to be a sensitive measure of the activation of the IFN system and the level of latent infectivity.
Diabetes 1989 Dec
PMID:Association of IDDM and attenuated response of 2',5'-oligoadenylate synthetase to yellow fever vaccine. 257 56

The particular susceptibility to insulin-dependent diabetes mellitus (IDDM) conferred by HLA-DR3,4 heterozygosity has been suggested to be an effect of transcomplementation of HLA class II molecules. To test this hypothesis of special IDDM-specific hybrid determinants and to evaluate the T-cell repertoire towards a specific antigen in IDDM patients we generated a total of 352 PPD-specific T-cell lines by the soft-agar cloning technique and studied their restriction by HLA class II molecules. Of these lines, 227 were from nine IDDM patients, of whom six were DR3,4 heterozygotes, and 125 from 10 healthy controls. Forty-six T-cell lines elicited specific responses in at least two experiments and in addition to T-cell lines demonstrating class-II-restricted PPD specificity, lines with an alloreactivity occurred. HLA-DQ-restricted PPD-specific T-cell lines were not identified and a possible DP restriction (DPw2) was only observed with one line. These data indicate that PPD is preferentially presented to T cells in the context of HLA-DR/Dw. Presentation of PPD by hybrid molecules in IDDM patients or by IDDM-specific class II epitopes recognized by the T-cell lines was not demonstrated. By restriction fragment length polymorphism analysis using a probe for the joining region of the T-cell receptor gamma gene, T-cell lines generated by the soft-agar cloning technique were found to be oligoclonal. It is concluded that soft-agar cloning should be followed by subsequent limiting dilution in order to assure monoclonality. Different preparations of antigen-presenting cells (APC) were tested. In several cases the T-cell lines were not able to respond to PPD presented by Epstein-Barr-virus-transformed lymphoblastoid cell lines (LCL). It was demonstrated that lipopolysaccharides (LPS) of E. coli potently reduce the proliferative response of antigen-specific and alloreactive T cells when T-cell-depleted peripheral blood mononuclear cells (E- cells) were used as APC, whereas only limited inhibition was observed when LCL were used as APC in the presence of LPS. This effect of LPS is suggested to be mediated by increased prostaglandin secretion by monocytes among the E- cells since indomethacin abolished the effect of LPS. This observation may have implications for T-cell cloning procedures since we have found that most commercially available culture media are heavily contaminated with endotoxin.
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PMID:Characterization of PPD-specific T-cell lines generated in type I (insulin-dependent) diabetic and healthy individuals. 258 37

The discovery of the key role played by the immune system in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) opens up new possibilities for its early diagnosis, at the stages preceding its clinical manifestation. Analysed are the markers of genetic susceptibility to IDDM associated with some major histocompatibility complex antigens (specifically with HLA-DR 3, HLA-DR4, and HLA-DQ), of the cellular and humoral anti-islet autoimmunity, as well as the origin of the islet-cell autoantigens. The markers' significance for the diagnosis and prognosis is discussed.
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PMID:[Molecular biological aspects of the pathogenesis of diabetes mellitus]. 266 69


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