Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004364 (autoimmune disease)
 24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes is an autoimmune disease that may be becoming more prevalent. It has a polygenic mode of inheritance with a major gene being present in the HLA DQ locus on chromosome 6. Inferential data suggest that environmental factors may be important to genetic penetrance albeit we still lack proof for involvement of often maligned viruses. Patients with IDD and their families are predisposed to organ-specific autoimmunities which should be routinely screened for. Autoantibodies to insulin, to a beta cell cytoplasmic lipid containing moiety and to a beta cell protein of 64KDa, which is believed to be the GABA forming enzyme GAD, can be used to predict IDD among relatives and probably the general population as well. Immunosuppressive therapy can modify the course of IDD after diagnosis and should be able to delay the clinical onset if given before diagnosis. Rigorous insulin therapy should also be given as needed to control hyperglycemia and avoid glucose toxicity to the islets. Such trials are now underway.
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PMID:Immunology of diabetes mellitus. 832 19

Glutamic acid decarboxylase (GAD; glutamate decarboxylase, L-glutamate 1-carboxy-lyase, EC 4.1.1.15), which catalyzes formation of gamma-aminobutyric acid from L-glutamic acid, is detectable in different isoforms with distinct electrophoretic and kinetic characteristics. GAD has also been implicated as an autoantigen in the vastly differing autoimmune disease stiff-man syndrome and insulin-dependent diabetes mellitus. Despite the differing GAD isoforms, only one type of GAD cDNA (GAD-1), localized to a syntenic region of chromosome 2, has been isolated from rat, mouse, and cat. Using sequence information from GAD-1 to screen a human pancreatic islet cDNA library, we describe the isolation of an additional GAD cDNA (GAD-2), which was mapped to the short arm of human chromosome 10. Genomic Southern blotting with GAD-2 demonstrated a hybridization pattern different from that detected by GAD-1. GAD-2 recognizes a 5.6-kilobase transcript in both islets and brain, in contrast to GAD-1, which detects a 3.7-kilobase transcript in brain only. The deduced 585-amino acid sequence coded for by GAD-2 shows less than 65% identity to previously published, highly conserved GAD-1 brain sequences, which show greater than 96% deduced amino acid sequence homology among the three species. The function of this additional islet GAD isoform and its importance as an autoantigen in insulin-dependent diabetes remain to be determined.
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PMID:Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10. 192 93

By using an immunoprecipitation assay, we analysed reactivity of autoantibodies to human recombinant GAD65 and GAD67 in sera from patients with autoimmune polyendocrine syndrome Type II (APS II) with and without Type 1 (insulin-dependent) diabetes mellitus (IDDM) compared to patients with organ-specific autoimmunity. Overall antibodies to GAD65 were correlated with IDDM in all study groups, whereas GAD67 antibodies were associated with IDDM when APS II coexists. Antibodies to GAD65 and GAD67 were detected in 13 (44.8%) and 7 (24.1%) out of 29 APS II patients with IDDM, but in only 4 (13.8%) and 2 (6.9%) out of 29 APS II patients without IDDM, respectively (p < 0.05). In short-standing IDDM (< 1 year), antibodies to GAD67 were significantly more frequent in patients with APS II (5 of 9 [55.6%] subjects) compared to matched diabetic patients without coexisting polyendocrinopathy (1 of 18 [5.6%] subjects) (p < 0.02). The levels of GAD65 (142 +/- 90 AU) and GAD67 antibodies (178 +/- 95 AU) were significantly higher in patients with polyglandular disease than in patients with isolated IDDM (91 +/- 85 AU and 93 +/- 57 AU) (p < 0.02). Interestingly, all 11 GAD67 antibody positive subjects also had GAD65 antibodies (p < 0.0001), and in 10 of 11 anti-GAD67 positive sera the GAD67 antibodies could be blocked by either GAD67 or GAD65, suggesting the presence of cross-reactive autoantibodies. No correlation was observed between GAD antibodies and age, sex or any particular associated autoimmune disease, besides IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Association between antibodies to the MR 67,000 isoform of glutamate decarboxylase (GAD) and type 1 (insulin-dependent) diabetes mellitus with coexisting autoimmune polyendocrine syndrome type II. 757 49

Although it has been confirmed that insulin dependent diabetes mellitus (IDDM) is a kind of autoimmune disease, islet cell autoantibodies (ICAs), insulin autoantibodies (IAA) and anti-GAD-glutamic acid decardaxylase antibodies have been found in the sera of patients with IDDM and immunotherapies have been used in some patients with IDDM, yet the manner in which the dysfunctional immunosystem acts on beta cells and causes damage to them remains to be clarified. Recently, possible involvement of the abnormal production of IL-6 in autoimmune symptoms was suggested in patients with cardiac myxomas, Castleman's disease and rheumatoid arthritis. However reports of IL-6 abnormal production in patients with IDDM are rare. In the present study, we examined whether or not an abnormal expression of IL-6 mRNA was present in mononuclear cells (PBMNCs) of the peripheral blood of patients with IDDM. We devised a highly sensitive, specific and semiquantitative protocol, ie, reverse transcription and polymerase chain reaction (RT-PCR). We have used such an assay to measure the relative expression levels of IL-6 mRNA in PBMNCs from 12 early IDDM patients (duration < 6 mon, 8.20 +/- 3.85 yr), 29 newly-diagnosed NIDDM patients (54.85 +/- 9.12 yr), 23 normal children (8.20 +/- 3.26 yr) and 12 normal adults (31.92 +/- 11.22 yr). In this assay significantly high expression levels of IL-6 mRNA were found in PBMNCs from patients with IDDM (P < 0.05). The relative levels were 0.91 +/- 0.19; 0.10 +/- 0.06; 0.43 +/- 0.08; 0.10 +/- 0.07, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression levels of IL-6 mRNA in PBMNCs from patients with IDDM, NIDDM and normals by RT-PCR procedure. 814 5

CD28 ligation delivers a costimulatory signal important in T cell activation. This study demonstrates that the disruption of the CD28/B7 pathway early in the nonobese diabetic mouse strain, using CD28-/- and CTLA41g transgenic mice, promoted the development and progression of spontaneous autoimmune diabetes. Functional analyses of T cells isolated from CD28-deficient mice demonstrated that the GAD-specific T cells produced enhanced Th1-type cytokines (IL-2 and IFN gamma) and diminished Th2-type cytokine, IL-4. Moreover, there was a significant decrease in serum levels of anti-GAD antibodies of the IgG1 isotype consistent with a profound suppression of Th2-type responses in these animals. Thus, the early differentiation of naive diabetogenic T cells into the Th2 subset is dependent upon CD28 signaling and extends our understanding of the importance of Th1/Th2 balance in the regulation of this spontaneous autoimmune disease.
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PMID:CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes. 880 83

The autoimmune disease insulin-dependent diabetes is thought to result from T-cell mediated destruction of pancreatic beta cells. We analysed the relation between humoral and cellular immunity to multiple islet cell antigens, including human insulin, glutamate decarboxylase GAD65, tyrosine phosphatase (ICA512/IA2), human pancreas and RIN cells in 28 patients with newly diagnosed type 1 diabetes and 9 antibody-positive (Ab+) relatives at high risk for type 1 diabetes. Of newly diagnosed patients, all showed reactivity to at least one recombinant islet cell antigen, by elevated cellular or humoral (or both) immune responses. Fifty-seven percent of patients and relatives showed T-cell reactivity to more than one islet cell antigen and 68% revealed humoral immunity to more than one islet cell antigen. Increased T-cell response to one single islet cell antigen was observed in 32% and positive antibody response in 25% of diabetic patients and relatives. Further-more, we found that T-cell reactivity to GAD was associated with T-cell reactivity to RIN cells, whereas reactivity to ICA512 and insulin was not associated with any other T-cell response. Likewise, antibody response to ICA512/IA2 correlated with antibodies to human pancreas (ICA), whereas antibody response to GAD or insulin was not related to any other antibody response. No positive or inverse correlation, however, was detected between T cell and humoral immunity, except for a positive association of antibodies and T-cell reactivity to insulin. Our data suggest that both humoral and cellular immune reactivity to multiple islet cell antigens are present in patients with newly diagnosed type 1 diabetes and in high risk relatives, but the two immune responses are individually activated.
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PMID:Relation between cellular and humoral immunity to islet cell antigens in type 1 diabetes. 881 82

A considerable body of data supports the hypothesis that type I diabetes is a chronic progressive autoimmune disorder. Individuals with very high probability of progressing to diabetes can now be readily identified. Assays for autoantibodies reacting with insulin (IAA), glutamic acid decarboxylase (GAD65AA), and the neuroendocrine tyrosine phosphatase ICA512/IA-2 (ICA512AA) allow for the identification of more than 95% of individuals developing type I diabetes. The expression of a single autoantibody does not indicate high risk for diabetes and in general, prediabetic individuals express a series of biochemically defined autoantibodies. Levels of such autoantibodies are usually stable over years of follow-up. Unusual variants of autoantibody expression (e.g. GAD-ICA with high titers of GAD65 autoantibodies as the sole autoantibody) have low prognostic significance. Given the presence of multiple autoantibodies, low first phase insulin secretion (following intravenous glucose) is the best predictor of time to diabetes onset. Measurement of autoantibodies can now be automated and applied to large populations such that screening and prediction in the general population is now feasible. We favor the hypothesis that insulin may be the primary autoantigen for type I diabetes, and therapies which after the immune response to insulin may lead to safe and effective preventive modalities.
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PMID:Chronic autoimmunity of type I diabetes. 885 79

The availability of cloned lines of T cells reactive with islet antigens has provided investigators with new tools to study how T cells contribute to autoimmune disease. T-cell clones isolated from the diabetes-prone nonobese diabetic (NOD) mouse are proving to be particularly valuable for analyzing pathogenesis and hold great promise for determining which T-cell subsets are involved in beta-cell destruction versus immunoregulation of the inflammatory process. Diabetogenic T-cell clones have been mostly of the CD4+, Th1 phenotype, but CD8+ T cell clones are also capable of transferring disease. In some cases, T-cell lines and clones (CD4+ and CD8+) have been found to have protective properties. In general T-cell antigen specificities have not been defined, as islet cells or lysates were used as the selecting antigen. However, there is an increasing number of reports of T cells specific for defined islet proteins, such as insulin and GAD, and some of these lines can induce disease. The variety of T-cell clones that have been produced indicate that there may a variety of conditions that lead to or protect against beta-cell destruction and provide further evidence that autoantigens are generated during development of disease.
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PMID:Autoreactive T-cell clones from the nonobese diabetic mouse. 901 59

In the Asian populations, it is not uncommon for adult patients with NIDDM to eventually lose beta-cell function and develop IDDM. Accepting that IDDM is an autoimmune disease, which occurs on a genetic background, it could by hypothesized that by measuring autoantibody prevalence and HLA DQ gene polymorphism, known important prediagnostic markers of IDDM, the prevalence of adult-onset IDDM in patients with previously undiagnosed NIDDM patients could be estimated. To do this, anti-GAD prevalence and HLA DQ A1 and DQ B1 polymorphisms after PCR amplification of genomic DNA were analyzed in 121 newly diagnosed diabetic patients of Yonchon cohort and compared to the results with those of 100 matched health control subjects. We also compared the results with those of other populations to assess the difference of genotype distribution. The overall prevalence of anti-GAD antibodies was 1.7% (2 of 121) in patients with previously undiagnosed NIDDM, whereas 1 of 100 controls had positive antibodies. Among those who were positive, their titer of antibodies to GAD were not high. No statistically significant differences in the distribution of either mean levels of anti-GAD or DQA1 and DQB1 alleles were found comparing NIDDM patients to controls. Interestingly, the frequency of DQB1*non-Asp-57 and DQA1*Arg-52 alleles in the Korean adult control population was similar to that of US Caucasians (DQB1*non-Asp-57: 0.431 vs. 0.475; DQA1*Arg-52: 0.492 vs. 0.463). The low prevalence of anti-GAD antibodies and HLA-DQA1 and DQB1 susceptibility alleles among recent-onset NIDDM patients, not different compared to controls suggests that diabetes in Korean adults is unlikely to have an autoimmune component to its pathogenesis.
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PMID:Low prevalence of immunogenetic markers of IDDM in adult Koreans with diabetes detected on OGTT. 901 68

Antibodies to glutamic acid decarboxylase-65 (GAD65) are present in a number of autoimmune disorders, such as insulin-dependent (type 1) diabetes mellitus (IDDM), stiff man syndrome, and polyendocrine autoimmune disease. Antibodies to GAD in IDDM patients usually recognize conformation-dependent regions on GAD65 and rarely bind to the second isoform, glutamic acid decarboxylase-67 (GAD67). In contrast, those present in stiff man syndrome and polyendocrine disease commonly target the second isoform (GAD67) and include antibodies that are less dependent on the conformation of the molecule. By immortalizing peripheral blood B cells with Epstein-Barr virus, we have generated three human IgG autoantibodies, termed b35, b78, and b96, to GAD65 from one patient with multiple autoantibodies to endocrine organs and Graves' disease. All three autoantibodies are of the IgG1 isotype, with islet cell activity, and do not react with GAD67. The regions on GAD65 recognized by the three autoantibodies have been investigated by immunoprecipitation with a series of chimeras, by binding to denatured and reduced antigens, and using protein footprinting techniques. Using chimeric GAD proteins, we have shown that b35 targets the IDDM-E1 region of GAD65 (amino acids 240-435) whereas both b78 and b96 target the IDDM-E2 region of GAD65 (amino acids 451-570). Furthermore, examination of binding to recombinant GAD65 and GAD67 by Western blotting revealed some differences in epitope recognition, where only b78 bound denatured and reduced GAD65. However, b35, b78, and b96 autoantibodies had different footprinting patterns after trypsin treatment of immune complexes with GAD65, again indicating different epitope recognition. Our results indicate that antibodies to GAD65 present in nondiabetic patients with multiple autoantibodies to endocrine organs show similarities to those in IDDM (by targeting IDDM-E1 and IDDM-E2 regions of GAD65) as well as subtle differences in epitope recognition (such as binding to denatured and reduced GAD65 and by protein footprinting). Thus, the GAD65 epitopes recognized by autoantibodies in different autoimmune diseases may overlap and be more heterogeneous than previously recognized.
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PMID:Human B cells secreting immunoglobulin G to glutamic acid decarboxylase-65 from a nondiabetic patient with multiple autoantibodies and Graves' disease: a comparison with those present in type 1 diabetes. 925 51


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