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)

This study examined the effect of various extracellular glucose concentrations on the expression of a previously described 64,000-Mr islet cell autoantigen associated with insulin-dependent diabetes mellitus. The protein was precipitated from patient serums incubated with Triton X-100 lysates of [35S]methionine-labeled rat pancreatic islets that had been cultured in 5, 11, or 28 mM glucose for 6 h or 3 days. In both types of experiment, 28 mM glucose was the most efficient stimulator of 64,000-Mr autoantigen production. In contrast, the class I antigens of the major histocompatibility complex, precipitated by a rabbit polyclonal antiserum, were not influenced by differences in glucose concentrations. Our data indicate that expression of islet cell antigens may be increased during the course of hyperglycemia and suggest that the functional activity of islet cells influences their antigenicity.
Diabetes 1989 Oct
PMID:High-glucose stimulation of 64,000-Mr islet cell autoantigen expression. 267 61

Recent biochemical studies have shown that the cytoplasmic islet cell-antibody autoantigen has properties of a monosialoganglioside (GM). To characterize islet glycolipids and ascertain whether islets express unique gangliosides, we determined the pattern of ganglioside expression in whole human pancreas and isolated human islets using high-performance liquid chromatography (HPLC) and high-performance thin-layer chromatography (HPTLC). The major gangliosides detected in glycolipid extracts of whole human pancreas were GM3, GD3 (disialoganglioside), and in a lesser amount, a GD1a-comigrating ganglioside. In contrast to whole human pancreas, isolated human islets were found to predominantly express GM3, an acidic glycolipid comigrating with GM2, and a ganglioside with mobility between GM2 and GM1 by both HPLC and HPTLC. Quantitation of the major ganglioside UV peaks seen on HPLC gave the following results. In whole pancreas, GM3 represented 66.7% of total gangliosides detected; an asialoglycolipid comigrating with GM2, 2.0%; a ganglioside migrating between GM2 and GM1, 2.6%; GD3, 22.6%; and a GD1a-comigrating ganglioside, 6.1%. In isolated islets, these components were found at the following levels: GM3, 14.9%; GM2-comigrating glycolipid, 74.2%; a ganglioside migrating between GM2 and GM1, 9.8%; GD3, 1.1%; and the GD1a-comigrating ganglioside, not detectable.
Diabetes 1989 Nov
PMID:Ganglioside expression in human pancreatic islets. 269 76

Diabetes-prone biobreeding (BB) rats often develop lymphocytic thyroiditis. Intraperitoneal administration of silica to young BB rats (40-days-old) nearly completely prevented the development of lymphocytic thyroiditis as well as insulitis. Since silica is known to be toxic to macrophages, these data suggest that the presentation of autoantigen(s) on the specific target cells such as thyroid and pancreatic B cells by antigen-presenting cells (e.g., macrophages) would be the initial step in the development of organ-specific autoimmune diseases in diabetes-prone BB rats.
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PMID:Prevention of lymphocytic thyroiditis and insulitis in diabetes-prone BB rats by the depletion of macrophages. 284 11

Islet cell antibodies (ICA) are associated with insulin-dependent diabetes mellitus (IDD) and have been proposed as predictive markers for the disease. To determine whether ICA result from the activation of single autoreactive B-lymphocyte clones or are the result of polyclonal B-cell activation, we assayed ICA using polyvalent antisera specific to kappa or lambda light chains as well as monoclonal antibodies to IgG1, IgG2, IgG3 and IgG4 heavy chains by indirect immunofluorescence. Sera from 38 newly diagnosed IDD patients with IgG-ICA titers greater than 1:8 by end-point dilution were studied. ICA of both kappa and lambda light chains were present in all sera. The ICA were predominantly of the IgG1 subclass (38/38), although ICA were also found to be IgG2 in 53% (20/38), IgG3 in 29% (11/38) and IgG4 in 16% (6/38). The distribution of IgG heavy chains in ICA was compared to the ICA titer, age of onset of IDD and HLA-DR phenotype of the patient. No statistical correlation could be detected at a P value less than 0.05. Our findings more likely exclude the occurrence of a single aberrant lymphocyte clone secreting ICA that may have arisen by somatic mutation in individual patients. Rather, these results are consistent with the hypothesis that ICA arise by polyclonal B-lymphocyte activation as a result of a defect of immune regulation. Since human antibodies to protein antigens are found predominantly in the IgG1 subclass, our findings support the belief that the autoantigen involved in the stimulation of ICA formation is comprised, at least in part, of protein.
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PMID:Polyclonal nature of islet cell antibodies in insulin-dependent diabetes. 297 27

We have biochemically treated (periodate, borohydride, neuraminidase, organic solvents) frozen sections of human pancreas and studied the reactivity of islet-cell-antibody-positive human sera and monoclonal antibodies. The autoantigen of pancreatic sections has the properties of sialic acid containing glycolipid.
Diabetes 1985 Jun
PMID:"Cytoplasmic" islet cell antibodies. Evidence that the target antigen is a sialoglycoconjugate. 298 50

Three mAb to variable region determinants of the alpha/beta-chain TCR were used to detect discrete populations of peripheral blood T cells. T cells sharing a TCR determinant defined by such an antibody presumably use the same or similar TCR V or J genes for their alpha- or beta-chains. Thus analysis with these mAb provides a tool to investigate TCR gene usage and expression. Since autoantigen specific T cells may play an important role in initiating autoimmune diseases, TCR were analyzed in different autoimmune diseases and control groups including rheumatoid arthritis, Graves disease, idiopathic thrombocytopenic purpura, psoriasis, SLE, insulin-dependent diabetes mellitus, and in nonautoimmune control diseases and normals. Purified T cells were stained by indirect immunofluorescence with three mAb to TCR variable regions: mAb S511 stains 1.8 +/- 0.9% (mean +/- 2 SD), mAb C37 stains 3.4 +/- 1.5% and mAb OT145 stains from 0 to 6% of T cells from normal donors. Several individuals were identified with expanded subsets of positive T cells. One patient with adult ITP followed during a 12-mo period consistently had elevated percentages of T cells staining with the mAb OT145 (15.9 to 24.5%). These cells were found to be exclusively CD8+. By Southern blotting DNA prepared from these OT145+, CD8+ cells, but not DNA from the patient's OT145- T cells, revealed a clonal rearrangement using a beta-chain C region probe. Thus this patient had a monoclonal expansion of CD8+, OT145+ cells. Hyperexpression of a TCR variable region, as defined by the available mAb, could not be associated with any of the diseases studied. Examination of T cells at the site of autoimmunity, such as T cells from rheumatoid arthritis synovial fluid, revealed normal percentages of cells staining with these mAb. Immunoperoxidase staining of psoriatic lesional skin showed no striking enrichment of T cells bearing one or the other TCR type.
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PMID:T cell antigen receptors in autoimmunity. 304 97

In insulin-dependent diabetes mellitus (IDDM) in humans and BB rats, islet cell autoimmunities associated with autoantibodies to a beta-cell protein of 64,000 Mr (64K) have been described. We report that sera from newly diagnosed nonobese diabetic (NOD) mice similarly contain an autoantibody that immunoprecipitates 64K autoantigen from detergent lysates of [35S]methionine-labeled murine islet cells. The autoantibody was detectable by weaning; it disappeared within weeks after diabetes onset and was absent in older nondiabetic NOD mice as well as all of three non-diabetes-prone control strains tested. The 64K beta-cell autoantigen may be a critical target in the immunopathogenesis of IDDM.
Diabetes 1988 Nov
PMID:Autoantibodies in nonobese diabetic mice immunoprecipitate 64,000-Mr islet antigen. 305 5

A major problem in standardization of the islet cell cytoplasmic antibody (ICA) assay is variation in sensitivity of the different human pancreas substrates used in individual laboratories. To circumvent this problem, we have developed an assay that utilizes Wistar-Furth rat pancreas as substrate, an anti-islet monoclonal antibody (A2B5) to identify islets and fluorescein-conjugated protein A to identify patient autoantibodies. Sera from 85 control subjects, 27 type I diabetics, and 17 subjects at high risk for developing type I diabetes were assayed in parallel with our standard ICA assay on human pancreas substrate and with Wistar-Furth rat pancreas as substrate. Two sera from control subjects (2 of 85) were ICA positive with rat pancreas compared to 1 of 85 with human pancreas substrate. Sera from 11 of 27 type I diabetics and 15 of 17 sera from high-risk subjects were ICA positive with either rat or human pancreas substrate. A correlation between the specific islet fluorescence readings on human and rat pancreas sections was found with sera from high-risk and control subjects. Furthermore, end-point titers of an ICA-positive serum were identical with both assays. Finally, incubation of an ICA-positive serum with glycolipids, extracted from either human or Wistar-Furth rat pancreas, blocked subsequent ICA binding. These findings suggest that Wistar-Furth rat pancreas expresses an identical or similar autoantigen to human pancreas.
Diabetes 1987 Aug
PMID:Expression of cytoplasmic islet cell antigens by rat pancreas. 310 88

With biochemical and enzymatic treatment of frozen sections of pancreas, we have previously shown that cytoplasmic islet cell antibodies (ICAs) react with carbohydrate determinants of islet cell glycoconjugates. As a first step toward purifying these glycoconjugates, human pancreas tissue was extracted in a mixture of chloroform and methanol, and the glycolipids were obtained by effecting a Folch partition. The protein pellet, lipid fraction, and glycolipid fraction so obtained were assessed for their ability to block the binding of ICAs to frozen sections of human pancreas, the effect being quantitated with a photometer. Only the glycolipid extract could block ICA binding, and blocking was dose dependent. Subfractionation of the glycolipid extract by hydrophobic interaction on C18 cartridges demonstrated that blocking activity resided in the fraction bound and eluted with methanol, consistent with the autoantigen being a glycolipid. Furthermore, the binding of an anti-islet cell ganglioside monoclonal antibody, 3G5, could be blocked with these extracts, whereas the binding of an anti-islet cell protein monoclonal antibody, 4F2, was unaffected. The major gangliosides of the pancreas were seen to be GM3 and GD3 by thin-layer chromatography (TLC). Fractions scraped and eluted from TLC plates were tested for their ability to block ICA binding to pancreatic sections. Neither GM3- nor GD3-containing fractions could block ICA binding; however, a fraction containing minor pancreatic gangliosides (including GM2) of monosialoganglioside mobility was a potent inhibitor of ICA binding to pancreas sections. TLC of a chloroform-methanol extract of human islets demonstrated that islets differentially express monosialogangliosides (especially GM2).
Diabetes 1988 May
PMID:Binding of cytoplasmic islet cell antibodies is blocked by human pancreatic glycolipid extracts. 328 49

Antigen expression is studied corresponding to a monoclonal autoantibody (IC2) derived from a hybridoma of rat myeloma Y3 cells and splenocytes of the diabetic BB rat. The selective reactivity of IC2 with islet cells has earlier been proven. We studied the possible specificity for beta islet cells, and the possible variation in autoantigen expression. Islet cells were isolated by cautious collagenase and dispase treatment. The cells were labelled with IC2 alone or together with anti-insulin immunoglobulin in double-labelling experiments. Extensive series of cells were examined by immunofluorescence microscopy, and some samples also by flow cytometry. In double-labelling examinations we found that only anti-insulin positive cells could bind the IC2 antibody, thus showing beta-cell selectivity. On the other hand, not all anti-insulin positive cells were IC2-positive. Since insulin treatment has been shown to decrease the incidence of diabetes in the BB rat, islet cells were examined after reduced beta-cell strain. Islet cells from Lewis and Wistar Furth rats display 21.4 +/- 1.4% IC2-positive cells, while islet cells from 24-hour fasting animals showed 7.0 +/- 1.4% (p less than 0.0001). Similar results were seen for BALB/c mice (25.0 +/- 1.8% vs. 13.7 +/- 2.3%, p less than 0.002). Also, after a week of insulin treatment, autoantigen expression was significantly decreased. Thus, the IC2 antibody is beta-cell-specific, and expression of the corresponding cell surface antigen depends on the functional state of the beta-cells.
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PMID:Antigen expression of the pancreatic beta-cells is dependent on their functional state, as shown by a specific, BB rat monoclonal autoantibody IC2. 328 66


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