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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In insulin-dependent diabetes mellitus in humans, the BB rat and the NOD mouse, serum has been reported to contain autoantibodies that precipitate a 64,000 Mr protein from (32S) methionine labeled histoincompatible non-autoimmune rat or mouse islet cell proteins. Because experimental data reported recently have brought into question the role of the 64,000 Mr protein in targeting autoantibodies and hence initiate beta-cell destruction, we report differently designed experiments to clarify the apparent 64,000 Mr autoantigen enigma. Using an in vitro model of NOD mouse origin mimicking diabetic insulitis we found that target beta-cells induced a 6-fold increase in proliferative response of splenic L3T4+, Thy-1,2+ T cells. The magnitude of the proliferative response was not affected when target beta-cells were pretreated with 50% (vol/vol) partially purified immunoglobulins ((NH4)2SO4 precipitation at 33% saturation) from sera from newly diagnosed (less than 4d after onset) diabetic NOD mice. Cytofluorimetric analysis of beta-cells pretreated with partially purified immunoglobulins plus FITC-conjugated goat antimouse IgG as a second-step antibody were negative and thus gave no indication of an autoantigen-autoantibody complex formed on the surface of the beta-cells. We conclude from the experimental data that it remains still in question whether an autoantigen is targeted by an islet cell surface specific autoantibody and plays a role as a triggering event in the pathogenesis of diabetes in NOD mice.
Diabetes Res 1990 Jan
PMID:Autoantibodies in the sera from newly diagnosed diabetic nod mice: evidence against cross-reactivity with a putative beta-cell surface autoantigen. 209 91

Stiff-man syndrome is a rare disorder of the central nervous system of unknown pathogenesis. We have previously reported the presence of autoantibodies against glutamic acid decarboxylase (GAD) in a patient with stiff-man syndrome, epilepsy, and insulin-dependent diabetes mellitus. GAD is an enzyme selectively concentrated in neurons secreting the neurotransmitter gamma-aminobutyric acid (GABA) and in pancreatic beta cells. We subsequently observed autoantibodies to GABA-ergic neurons in 20 of 33 patients with stiff-man syndrome. GAD was the principal autoantigen. In the group of patients positive for autoantibodies against GABA-ergic neurons, there was a striking association with organ-specific autoimmune diseases, primarily insulin-dependent diabetes mellitus. These findings support the hypothesis that stiff-man syndrome is an autoimmune disease and suggest that GAD is the primary autoantigen involved in stiff-man syndrome and the associated insulin-dependent diabetes mellitus. Our findings also indicate that autoantibodies directed against GABA-ergic neurons are a useful marker in the diagnosis of the disease.
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PMID:Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. 213 82

There are a number of mechanisms which cooperate to produce and maintain T-cell tolerance. First, and perhaps most important, is the clonal deletion in the thymus of T cells with high affinity for self antigens. However, to ensure that a wide repertoire of T cells is available in the periphery to combat foreign antigens, the threshold of clonal deletion may be set low enough so that T cells whose TCR's have sub-threshold affinity for self antigens mature and migrate to the periphery. T cells which recognize self antigen-derived peptides not expressed or presented in the thymus will also fail to be deleted. For those self-reactive T cells which are not deleted in the thymus, other mechanisms may produce tolerance, including an undefined alteration of signalling pathways which produces clonal anergy, and lowering the avidity of the TCR for its ligand by downregulating coreceptor and accessory molecules. Active suppression of T-cell responses in another well-described phenomenon whose mechanism is undefined. From our observations with the model systems discussed here, we have observed three distinct mechanisms by which T-cell tolerance can be circumvented, allowing autoimmune phenomena to occur. These mechanisms may have relevance for different types of autoimmune diseases seen in humans. In gld mice, the autoimmune disease seems to be related to a global defect in T-cell differentiation and function, which allows for the expansion of autoimmune B cells. While we showed that clonal deletion of V beta-bearing T cells is appropriate in certain cases, aberrant lymphokine secretion by the abnormal T cells or disruption of immune system regulation are most probably responsible for allowing autoantibody production. While human lupus erythematosis shares much of the pathology of lpr and gld mice, there is no expansion of T cells with a similar phenotype in human lupus. There are environmental factors which must play a role in the development of human lupus, since the incidence of the disease does not follow an absolute genetic pattern. The escape from clonal deletion and subsequent reactivation of autoimmune T cells which we observed in V beta 8.1 TCR-transgenic mice can be a model for human autoimmune diseases such as multiple sclerosis and type I diabetes, in which T cells are directed against a specific autoantigen. According to this model, susceptibility loci for autoimmune disease such as the MHC would function by producing different repertoires of T cells which in some cases could gain autoreactivity following activation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms of autoimmunity in the context of T-cell tolerance: insights from natural and transgenic animal model systems. 215 Apr 1

Multiple injections of low doses of streptozotocin to susceptible strains of mice produce an experimental autoimmune diabetes mellitus. To investigate the possible initial role of macrophages in the development of insulitis, we studied the effect of macrophage-toxic silica administration on the development of in vitro cellular cytotoxic immune response against pancreatic beta-cells. Multiple streptozotocin-treated mice developed hyperglycemia at day 12 and their splenocytes showed cytotoxicity against cultured rat insulinoma cells. Mice given silica and streptozotocin together remained normoglycemic and their splenocytes showed no cytotoxicity. In contrast, in vitro depletion of macrophages from the splenocytes of mice given multiple streptozotocin alone did not abolish the cytotoxicity. These results show that macrophages themselves contribute little to the cellular cytotoxicity, but are necessary for the development of cytotoxic cells. From these results we suggest that there are at least two different steps in the development of insulitis; the presentation of beta-cell autoantigen by macrophages to helper-T cells, followed by the development of beta-cell-specific cytotoxic cells.
Diabetes Res Clin Pract 1990 Oct
PMID:Initial role of macrophage in the development of anti-beta-cell cellular autoimmunity in multiple low-dose streptozotocin-induced diabetes in mice. 217 96

DNA sequence analysis of major histocompatibility complex (MHC) class II genes from humans and rodents with type 1 (insulin-dependent) diabetes indicates that a portion of MHC-linked genetic susceptibility in humans is determined by the HLA-DQA1 and -DQB1 loci. In this article John Todd summarizes recent advances in these studies. The conformation of DQ molecules and their levels of expression may influence the efficiency of autoantigen presentation and the degree of pancreatic beta cells destruction during disease development. Certain DAQ1 and DQB1 alleles correlate with decreased susceptibility to disease. The penetrance of class II alleles that are correlated with positive susceptibility may be influenced by environmental factors such as bacterial and viral infections.
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PMID:Genetic control of autoimmunity in type 1 diabetes. 218 69

In order to investigate the role of insulin as a potential target autoantigen of cellular immunity in the prediabetic period, proliferative responses of T lymphocytes to human insulin were studied in nine islet-cell antibody (ICA) + first-degree relatives of patients with Type I diabetes (individuals at high risk for the development of Type I diabetes, or the 'prediabetic' group, which was never treated with insulin) and in 12 control individuals. Insulin autoantibodies were present in 6/9 (67%) of the prediabetic subjects and none of the controls. Peripheral blood lymphocytes were collected on Ficoll and incubated with human insulin, control antigens, or media alone for 5-6-day and 9-10-day incubation periods. Cells were pulsed with 3H-thymidine, harvested, and analysed in a scintillation counter. Results are expressed as stimulation index (SI = cpm with antigen/cpm without antigen), with a SI greater than or equal to 1.5 considered a positive response. Eight of nine (89%) prediabetic individuals responded positively to insulin after a 9-10-day incubation period, in contrast to four of 12 (33%) control subjects, P less than 0.05. The mean proliferative response to insulin after 9-10 days' incubation was 2.1 +/- 0.4 and 1.2 +/- 0.1, for the prediabetic and control groups, respectively. The proliferative response to insulin was not directly correlated with levels of insulin autoantibodies (r = -0.05, NS). These data suggest that most individuals at high risk for the development of Type I diabetes display a cellular immune response to insulin, and a subset of these individuals does not display a concomitant humoral immune response to insulin based on the presence or absence of insulin autoantibodies.
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PMID:Cellular immunity to human insulin in individuals at high risk for the development of type I diabetes mellitus. 220 45

Evidence from epidemiological and histopathologic studies in humans with autoimmune type 1 (insulin-dependent) diabetes suggests that beta-cell destruction within the islets of Langerhans progresses through a number of stages. In this review we draw on recent experimental evidence in an attempt to define the molecular pathology of these stages. Stage 1 is postulated to be initiated by modification of the beta cell by virus, chemical or other factors, leading to the production of interferon-alpha, hyperexpression of major histocompatibility complex (MHC) class I molecules and induction of MHC class II molecules. Experiments in transgenic mice suggest that overexpression of MHC molecules is in itself detrimental to beta-cell function. Shedding of antigen(s) from dying beta cells in combination with hyperexpression of MHC molecules may be a powerful immunogenic stimulus. Stage 2 commences with infiltration of the islets by immuno-inflammatory cells (termed insulitis). It is proposed that production of cytokines from the infiltrating cells induces "phenotypic switching" in beta cells, with further upregulation of MHC molecules and the induction of intracellular adhesion molecule-1 expression and interleukin-6 production. Together, these properties are seen as a prerequisite for the presentation of autoantigen by beta cells to adherent T lymphocytes and autoimmune activation. The final stage encompasses autoimmune-mediated destruction of the beta cells by the targeted delivery of cytotoxic cytokines and other mediators.
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PMID:Molecular pathology of type 1 diabetes. 223 44

Family and population studies indicate that predisposition to insulin-dependent (type I) diabetes mellitus (IDDM) is polygenic. It has been shown that the absence of the aspartic acid in position 57 (Asp57) of the DQ beta chain is positively correlated to IDDM. However, Asp57-negative haplotypes do not always confer susceptibility and conversely, some Asp57-positive haplotypes seem to be disease associated. It has been suggested that other HLA class II sequences, probably belonging to the HLA DQA1 gene, confer susceptibility to IDDM. This report, based on extensive oligonucleotide dot blot hybridization of PCR-amplified DQA1 and DQB1 genes, reinforces the importance of the Asp57-negative DQ beta chain, but also introduces the possibility that a DQ alpha chain bearing an arginine in position 52 (Arg52) confers susceptibility to IDDM. A molecular model of susceptibility to IDDM is proposed. This model strongly suggests that the disease susceptibility correlates quantitatively with the expression at the cell surface of a heterodimer, composed of a DQ alpha-chain bearing an Arg52 and a DQ beta chain lacking an Asp57. In view of the respective positions of the two residues and their charge, we might anticipate that both residues DQ beta Asp57 and DQ alpha Arg52 are critical for modulation of susceptibility, presumably via viral-antigenic peptide and/or autoantigen presentation.
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PMID:A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus. 231 83

Noninsulin dependent diabetes mellitus (NIDDM) is associated with an entirely different set of genetic alterations from insulin-dependent diabetes mellitus (IDDM). Over 90% of IDDM carry HLA type DR3, DR4 or both. Several theories have been proposed to explain how the genetic alterations are translated into a beta cell destructive process. All involve the elaboration of a beta cell autoantigen. A major current research focus is on the development of pharmacologic approaches to the control of the beta cell destructive process (cyclosporine A). This has led to a shift in interest to the early identification of individuals at risk for IDDM. Many questions remain to be answered. In our paper emphasis is placed on epidemiological research. In Allegheny County, Pennsylvania, we have found an incidence of 1.73 cases/1000 (incidence rate of 15/100,000/year). There were marked geographical variations (incidence rate of 1/100,000/year in Asian countries, of 40/100,000/year in Finland). This suggests that there are major environmental determinants leading to expression of disease in genetically susceptible individuals. There are no geographical differences in the main age of onset, the sex ratio and the clinical patterns in the initial course of newly detected IDDM. In all parts of the world islet cell antibodies are positive in 60-80% of newly diagnosed IDDM. Migration of children from their native homeland with a low incidence rate to a country with high incidence rate was accompanied by an increase of incidence. The following potential environmental factors have been considered: viral infections, environmental toxins, nutrients, and stress. In our view IDDM occurs in genetically susceptible individuals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:What do epidemiologic observations tell us about the etiology of insulin dependent diabetes mellitus? 240 77

Autoimmunity is paradoxically a physiologic phenomenon. One finds in normal sera natural autoantibodies that are encoded by germ line genes. Autoimmunity is at the origin of common and severe diseases such as diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus and perhaps psoriasis and Crohn's disease. The disease may be due according to cases to exacerbation of physiologic autoimmunity or to appearance of autoreactive clones producing autoantibodies encoded by mutated genes. The respective role of triggering environmental factors and genetic predisposition (HLA and non HLA genes) is not determined. New immunotherapeutic methods, particularly cyclosporine, monoclonal antibodies (against T cells, CD4 and T cell receptor molecules and Ia antigens) and autoantigen-specific vaccination open new major therapeutic perspectives that presage major improvement in the prognosis of these diseases.
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PMID:[Evolution of the concept of autoimmunity and its therapeutic implications]. 267 84


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