Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 sera of type I (insulin-dependent) diabetic subjects are reported to contain autoantibodies against a 64,000-Mr protein identified in [35S]methionine biosynthetically labeled pancreatic islet cells. We have attempted to localize this autoantigen to the surface of the beta-cell and to define its properties. Sera from 10 newly diagnosed type I diabetic subjects, including five of the index sera originally used to identify the autoantigen, were shown to specifically precipitate a reduced protein of 67,000 Mr from Triton-solubilized, surface 125I-labeled cultured adult human islet and rat insulinoma (RINm5F) cells but not from fresh rat spleen cells. Further characterization revealed that this protein was bovine serum albumin (BSA) adsorbed to cells from fetal calf serum (FCS)-supplemented culture medium and precipitated by BSA antibodies present in many diabetic sera. No labeled proteins were specifically precipitated when surface 125I-labeled and solubilized human islet or RINm5F cells were precleared with anti-BSA immunoglobulins or when cells were first cultured in human serum. In contrast, a 64,000-Mr protein, clearly not BSA, was precipitated by diabetic globulins from human islets but not from RINm5F cells labeled with [35S]methionine. In addition, a protein of the same size as well as proteins of approximately 35,000, 43,000, 140,000, and 200,000 Mr were specifically precipitated by diabetic globulins from freshly isolated human islets solubilized in Triton X-100 and then labeled with 125I. These findings suggest that the 64,000-Mr antigen is not expressed on the surface of human islet cells, at least in culture, and therefore question its relevance as a target for islet cell surface antibodies in initiating beta-cell damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1987 Dec
PMID:64,000-Mr autoantigen in type I diabetes. Evidence against its surface location on human islets. 331 89

There is a high prevalence of islet cell antibodies (ICA) and autoantibodies detected against an islet cell protein of Mr 64,000 at the time of clinical diagnosis of insulin-dependent diabetes (IDDM). In view of the biphasic immune response after antigen presentation, the purpose of this study was to determine the presence of ICA and antibodies against the 64,000 islet antigen after separation of IgM from IgG to prevent interference between the two antibody classes. Plasma samples from 10 newly diagnosed IDDM children and 10 healthy controls were precipitated with polyethylene glycol (PEG), and the crude Ig was subjected to Sephacryl S-300 chromatography to separate IgM and IgG. ICA determined by indirect immunofluorescence on frozen sections of human pancreas showed reduced background immunofluorescence intensity in the purified fractions compared with crude plasma. The number of ICA-positive samples among the IDDM patients increased from 7/10 in plasma to 9/10 in the IgG fraction. There was an increase in the ICA titer in 6/9 of the positive samples. All purified IgM samples were ICA negative. Immunoprecipitation experiments by using Nonidet P-40 detergent lysates of [35S]methionine-labeled neonatal rat islets demonstrated that the 64,000 autoantibodies were in the IgG fraction. We found 7/10 IDDM samples to be positive, whereas all controls were negative. The background in the autoradiographic analysis was markedly reduced in the IgG fractions compared with immunoprecipitates with crude or PEG-purified plasma and the IgM fraction. ICA titers did not correlate to the ability of the IgG fraction to precipitate the 64,000 autoantigen. It is concluded that both the ICA and 64,000 autoantibodies are primarily of the IgG class at the time of clinical onset of IDDM, and that purification of IgG from human IDDM plasma facilitates the detection of the rat islet cell 64,000 antigen.
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PMID:Islet cell and 64K autoantibodies are associated with plasma IgG in newly diagnosed insulin-dependent diabetic children. 353 24

Cyclosporine is an 11 aminoacid cyclic peptide of fungal origin endowed with potent immunosuppressive activity. Unlike the conventional immunosuppressants, cyclosporine does not interfere with DNA metabolism, but it selectively and reversibly inhibits lymphocyte T-helper activation by inhibiting the production of interleukin-2 which plays a role in immune response development. Cyclosporine has little effect on lymphocytes B and does not modify the production of antibodies when it is in progress. The drug is effective in preventing spontaneous or autoantigen-induced auto-immune diseases in animals. The best studied models are experimental allergic encephalomyelitis, uveitis in the rat and spontaneous diabetes of BB rats. However, cyclosporine has no effect on diseases exclusively due to the pathogenic action of antibodies, such as spontaneous thyroiditis of the obese chicken. It is also possible to obtain a curative effect, this type of model being nearer to therapeutic conditions in humans than the previous models.
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PMID:[Cyclosporin and autoimmune diseases. 1: Experimental bases]. 355 Sep 87

Studies of the segregation of heterozygous immunoglobulin allotypes in families with several cases of insulin-dependent diabetes mellitus (IDDM) show that germline heavy-chain V (variable region) genes are not major genetic determinants for IDDM, but data for IDDM and Graves' disease together suggest involvement of kappa light-chain V genes. Absence of IDDM at birth, the semi-random age of onset, and the 50% discordance of identical twins suggest that somatic mutation of germline V genes is involved in the development of the pathogenetic anti-beta-cell clones. The effect of histocompatibility and other alloantigens on the prevalence of IDDM is readily accounted for by the effect of the "holes" they induce, by natural tolerance, in the immune response repertoire; these alterations apparently affect the chance of emergence of anti-beta-cell clones by the somatic mutations and network of interclonal deletions that constantly change the fringes of the repertoire. Histocompatibility antigens can also influence repertoire development by changing the specificity of conjoint presentation of foreign antigens by macrophages. Antigenic stimulation by particular environmental microorganisms is probably essential to the repertoire development necessary for the occurrence of IDDM. Additionally, beta-cell damage by local infection may play a part by facilitating autoantigen presentation to the immune system.
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PMID:A solution to the genetic and environmental puzzles of insulin-dependent diabetes mellitus. 614 51

Major histocompatibility complex (MHC) class II genes are the strongest susceptibility markers for many human autoimmune diseases. A perplexing aspect of this is that HLA alleles can confer either susceptibility or dominant protection. In nonobese diabetic (NOD) mice, the strongest known diabetes susceptibility locus is within the MHC and is presumed to be the H-2Ag7 product. When NOD mice carry a transgenic E alpha d molecule allowing expression of an H-2E heterodimer, diabetes is prevented. We investigated whether, as in human autoimmunity, a single class II heterodimer might protect from some autoimmune diseases while predisposing to others. NOD mice are susceptible to experimental autoimmune encephalomyelitis (EAE) induced by the proteolipoprotein (PLP) epitope 56-70. Susceptibility to EAE was analyzed in NOD mice which either have or lack transgenic H-2E expression. We found that H-2E expression in NOD mice has converse effects on diabetes and EAE: while diabetes is prevented, EAE is greatly exacerbated and leads to demyelination. Although PLP 56-70 could be presented both in the context of H-2A and H-2E, increased disease severity in H-2E transgenic mice could not be attributed either to an enhanced T cell proliferative response to PLP or to differences in determinant spread. However, cytokine analysis of the response revealed important differences between NOD mice and their H-2E transgenic counterparts: H-2E expression was associated with reduced interleukin-4 secretion and enhanced interferon-gamma (IFN-gamma) secretion by lymph node cells, while the response of central nervous system infiltrating T cells displayed a markedly enhanced IFN-gamma response. Thus, whether a particular class II molecule confers resistance or susceptibility to an autoimmune disease may depend on differential cytokine profiles elicited by particular class II/autoantigen complexes.
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PMID:Exacerbated autoimmunity associated with a T helper-1 cytokine profile shift in H-2E-transgenic mice. 748 54

Glutamic acid decarboxylase (GAD) is a major islet cell autoantigen in insulin-dependent diabetes mellitus (IDDM), and autoantibodies are found in high frequencies in patients with recent-onset IDDM, stiff-man syndrome (SMS), and autoimmune polyendocrine syndrome type I (APS I). Antigens in autoimmune disorders are often enzymes, and autoantibody binding frequently inhibit their activity. In this study, we examined the reactivity of anti-GAD-containing sera from 7 patients with IDDM, 4 patients with SMS, and 5 patients with APS I. All sera immunoprecipitated GAD from [35S]methionine-labeled rat islet lysates and the sera from patients with SMS and APS I, but none of the IDDM patients' sera, identified the GAD protein in Western blots. Two of four SMS patients' sera and 5 of 5 APS I patients' sera, in contrast to 0 of 7 IDDM patients' sera, inhibited the enzymatic activity of GAD. When the various sera were tested with the GAD65 and GAD67 isoforms, produced separately by transient expression in COS cells, the enzymatic activity of GAD65 was inhibited by sera from patients with SMS and APS I, whereas no effect on the GAD67 activity was observed. Taken together, the results demonstrate that the GAD autoantibodies in these three disorders display marked differences in epitope recognition and indicate that, during the development of the diseases, the autoantigen is being presented to the immune system through separate pathogenetic mechanisms.
Diabetes 1994 Jan
PMID:GAD autoantibodies in IDDM, stiff-man syndrome, and autoimmune polyendocrine syndrome type I recognize different epitopes. 750 44

The smaller form of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD65) is a major autoantigen in two human diseases that affect its principal sites of expression. Thus, destruction of pancreatic beta cells, which results in insulin-dependent diabetes mellitus (IDDM), and impairment of GABA-ergic synaptic transmission in Stiff-Man syndrome (SMS) are both characterized by circulating autoantibodies to GAD65. Anti-GAD65 autoantibodies in IDDM are predominantly directed to conformational epitopes. Here we report the characterization of humoral autoimmune responses to GAD65 in 35 SMS patients, of whom 13 (37%) also had IDDM. All SMS patients immunoprecipitated native GAD65 and the main titers were orders of magnitude higher than in IDDM patients. Furthermore, in contrast to the situation in IDDM, autoantibodies in 35 of 35 (100%) of SMS patients recognized denatured GAD65 on Western blots. Two major patterns of epitope specificity were identified on Western blots. The first pattern, detected in 25 of 35 SMS patients (71%), of whom 11 had IDDM (44%), was predominantly reactive with a linear NH2-terminal epitope residing in the first eight amino acids of GAD65. Nine of nine individuals who were HLA-haplotyped in this group carried an IDDM susceptibility haplotype and HLA-DR3, DQw2 was particularly abundant. The second pattern, detected in 10 of 35 patients (29%) of whom two had IDDM (20%), included reactivity with the NH2-terminal epitope plus strong reactivity with one or more additional epitope(s) residing COOH-terminal to amino acid 101. The second epitope pattern may represent epitope spreading in the GAD65 molecule, but may also include some cases of epitope recognition associated with IDDM resistant HLA-haplotypes. The principal NH2-terminal linear epitope in GAD65 distinguishes the reactivity of SMS and IDDM autoantibodies and may be a determinant of pathogenicity for GABA-ergic neurons. The greater magnitude and distinct specificity of the humoral response to GAD65 in SMS may reflect a biased involvement of the T helper cell type 2 (Th2) subset of CD4+ T cells and antibody responses, whereas IDDM is likely mediated by the Th1 subset of CD4+ T cells and cytotoxic T cell responses.
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PMID:Higher autoantibody levels and recognition of a linear NH2-terminal epitope in the autoantigen GAD65, distinguish stiff-man syndrome from insulin-dependent diabetes mellitus. 751 42

The 65-kDa isoform of glutamic acid decarboxylase (GAD65) has been implicated in autoimmune diabetes in NOD mice, but the role of the 67-kDa GAD isoform (GAD67) is less clear. We found that immunization of 4-week-old NOD mice with purified recombinant mouse GAD67 prevented or significantly delayed the onset of diabetes. To further explore this phenomenon, we characterized anti-GAD67 immune responses in naive and GAD-immunized NOD mice. Anti-GAD67 antibodies titers were relatively low in naive mice at all ages, but a single immunization with GAD67 at 4 weeks induced high titers of anti-GAD antibodies by 6 weeks of age. In both 4-week-old and diabetic NOD mice, there were significant endogenous T-cell proliferative responses against purified recombinant mouse GAD67. These T-cell proliferative responses were blocked by anti-I-ANOD and anti-CD4 antibodies. To characterize the anti-GAD T-cell responses in the NOD mice, we established T-cell lines and T-cell clones which recognized GAD67, and we used recombinant subfragments of GAD to localize the predominant T-cell epitopes in GAD67. T-cells from naive NOD mice proliferated in response to all GAD subfragments, whereas T-cells from diabetic mice responded primarily to the COOH-terminal 83 amino acids of GAD67. These results suggest that GAD67 is an autoantigen in IDDM and immunization of prediabetic NOD mice with GAD67 can prevent the onset of diabetes.
Diabetes 1994 Dec
PMID:Immunization with the larger isoform of mouse glutamic acid decarboxylase (GAD67) prevents autoimmune diabetes in NOD mice. 752 93

Type I diabetes, an autoimmune disease that occurs in humans and animals, is characterized by the destruction of insulin-secreting islet beta-cells of the pancreas. Antibodies directed toward multiple islet protein can be detected before diagnosis of type I diabetes; however, the identity of the inciting autoantigen(s) that targets beta-cells for destruction has not been defined. Autorecognition of many self-proteins by CD4+ T lymphocytes is restricted by the products of class II immune response genes of the major histocompatibility complex (MHC), and in human type I diabetes such a MHC association has been described. The present study uses a rat MHC class II (RT1.Bl) peptide binding motif to predict potentially autoreactive CD4+ T cell epitopes in two key islet beta-cell constituents: the enzyme glutamic acid decarboxylase (GAD) and the insulin precursor hormone proinsulin (PI). Seventeen-amino-acid-long peptide fragments of GAD and PI containing the binding motif were synthesized and used to generate peptide-specific, MHC class II-restricted, CD4+ T cell lines. Once established, the T cell lines specific for rat islet GAD and PI were adoptively transferred to naive, MHC-compatible rats. At 10 days after transfer, insulitis had developed in rats receiving PI-specific T cells, whereas no insulitis was observed in pancreata of rats receiving GAD-specific T cells. Of particular interest is the finding that the pathogenic T cell epitope identified in PI spans the endogenous cleavage site between the B-chain and C-peptide of insulin. Moreover, the PI-specific T cells were able to react specifically with material produced in vitro by a rat insulinoma cell line. These results demonstrate that pathogenic T cell epitopes can be located in portions of molecules that are subsequently degraded during normal enzymatic processing. As PI is found highest concentrations in the beta-cells of pancreatic islets, it is possible that this molecule and not its individual degradation products (ie, insulin and C-peptide) might serve as an autoantigen in the pathogenesis of type I diabetes.
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PMID:Experimental autoimmune insulitis. Induction by T lymphocytes specific for a peptide of proinsulin. 754 75

Identification of islet autoantigens offers the possibility that antibody tests other than islet cell antibodies may be used for assessing risk of insulin-dependent diabetes mellitus (IDDM). The aim of this study was to determine the combination of islet autoantibody markers that could identify most future cases of IDDM. Islet cell antibodies, antibodies to glutamic acid decarboxylase (GAD)65, 37,000/40,000 M(r) islet tryptic fragments, carboxypeptidase-H, and islet cell autoantigen (ICA)69 were measured in sera from 100 newly-diagnosed IDDM patients, 27 individuals prior to onset of IDDM, and 83 control subjects. Islet cell antibodies were detected in 88% of IDDM patients and 81% with pre-IDDM, GAD65 antibodies in 70% of IDDM patients and 89% with pre-IDDM, and antibodies to 37,000/40,000 M(r) islet tryptic fragments in 54% of IDDM patients and in 48% with pre-IDDM. The latter were found only in conjunction with islet cell antibodies and were more frequent in young onset cases. All 20 IDDM patients and the 3 pre-IDDM subjects who had islet cell antibodies without GAD65 antibodies had antibodies to 37,000/40,000 M(r) islet tryptic fragments, and all but one had disease onset before age 15 years. No sera strongly immunoprecipitated in vitro translated ICA69 or carboxypeptidase-H; 4% of patients had anti-ICA69 and 11% anti-carboxypeptidase-H levels above those of the control subjects. The findings suggest that none of the single antibody specificities are as sensitive as islet cell antibodies, but that a combination of GAD65 antibodies and antibodies to 37,000/40,000 M(r) islet tryptic fragments has the potential to identify more than 90% of future cases of IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Islet autoantibody markers in IDDM: risk assessment strategies yielding high sensitivity. 755 84


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