Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus (IDDM) is associated with the formation of autoantibodies against different antigens in the islets of Langerhans, so-called islet cell antibodies (ICA). The expression of a major autoantigen, the beta-cell specific enzyme glutamic acid decarboxylase (GAD), is glucose-dependent in vitro and correlated to insulin release in vitro. In this study the expression of islet autoantigens was examined in vivo and the relationship between beta-cell function and islet cell surface antibody (ICSA) reactivity was tested. Rats were fed for 10 days with glipizide or diazoxide, in order to stimulate or inhibit insulin release, respectively. Frozen sections of pancreata were incubated with ten ICA-positive IDDM sera and analyzed by indirect immunofluorescence. Two sera with a "beta-cell restricted" staining, five with an "all-islet cell" staining and three with a "mixed" pattern were employed. In all three groups, the highest end-point titres were obtained when pancreata of rats treated with glipizide were used. Intermediate titres were seen in control animals and the lowest titres were observed on pancreata from diazoxide-treated rats, regardless of the serum used. In contrast to these observations, no correlation between ICSA reactivity and islet cell activity could be demonstrated. Conflicting results concerning ICSA in previous reports and our failure to show a glucose regulation of ICSA reactivity, indicate that ICSA is a phenomenon with a low degree of specificity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of beta-cell activity and its influence on islet cell antibody (ICA) and islet cell surface antibody (ICSA) reactivity. 800 13

Early therapy made possible by the predictive tests discussed above, using selective or even antigen-specific therapy, opens the way to more radical and much more innocuous therapeutic approaches of major AIDs. It should be realized, however, that before the putative autoantigens have been identified, immunotherapy must be based on nonantigen-specific agents. The results recently obtained in NOD mice indicate that the goal of nontoxic, long-lasting immune protection from the disease is feasible if treatment is started early enough. In some cases (anti-T cell monoclonal antibodies), it appears that specific unresponsiveness can be induced even in the absence of a concomitant administration of the autoantigen. In the case of IDDM, one must convince clinical diabetologists, patients, and their families that immunoprevention of the disease will only be achieved if research on both prediction and immunotherapy proceeds hand in hand: prediction programs are difficult to run without proposing access to preventive therapy, and the search for therapy cannot be successful without access to prediabetics or patients with preclinical diabetes and they can only be identified in prediction clinics. In brief, the two research approaches, prediction and specific therapy, have to be carried out in parallel until their convergence allows the final immunoprevention of the disease.
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PMID:Predictive medicine in autoimmune diseases: from the identification of genetic predisposition and environmental influence to precocious immunotherapy. 805 Jan 86

The diabetic syndrome in the DP-BB rat results from progressive beta-cell destruction by autoimmune responses. However, the initial events causing the autoimmune destruction of beta cells remain largely unknown. Our recent experimental results suggest that the delayed expression of a beta-cell-specific autoantigen may result in the initiation of beta-cell-specific autoimmunity. The present investigation was initiated to identify such an autoantigen. Islets were isolated from DP-BB rats of several different ages, and protein extracts from the membrane fraction of the islet preparations were immunoprecipitated with sera from diabetic DP-BB rats. We have found that a membrane-bound islet cell-specific 38 kDa autoantigen is not expressed early in the life of DP-BB rats, but is delayed-expressed by approximately 30 days of age, the time at which immunological effectors begin to recognize beta cells. In contrast, a 64 kDa islet cell protein is expressed from birth in DP-BB rats. On the basis of these observations, we suggest that delayed expression of a gene encoding for the membrane-bound islet cell-specific 38 kDa autoantigen may result in a breakdown of self-tolerance, leading to beta-cell-specific autoimmune IDDM in the BB rat.
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PMID:Studies on autoimmunity for initiation of beta-cell destruction. X. Delayed expression of a membrane-bound islet cell-specific 38 kDa autoantigen that precedes insulitis and diabetes in the diabetes-prone BB rat. 805 82

GAD is a major islet cell autoantigen in human type 1 diabetes mellitus. Autoantibodies are preferentially directed against the 65-kD isoform of the enzyme which is the only form expressed in human islets of Langerhans. The NOD mouse is a spontaneous model of type 1 diabetes, frequently employed in studies dealing with the immunopathogenesis of the disease. In the present study the reactivity of sera from 34 prediabetic and 15 diabetic NOD mice was tested against GAD protein present in islets of Langerhans and cerebellum, and against recombinant, semi-purified GAD-65 and GAD-67. A rabbit antiserum (K2) raised against GAD-67 could readily recognize the recombinant GAD-67 and the isoform present in rat and mouse islets and mouse brain. A MoAb (GAD-6) specific for the GAD-65 isoform reacted against the recombinant GAD-65 and the isoform present in rat islets and mouse brain, whereas no reactivity was observed when using mouse islets. However, when testing the NOD mice sera by immunohistochemistry, immunoprecipitation and Western blot, no reactivity against any of the isoforms of GAD could be detected. Using reverse transcription polymerase chain reaction (PCR), GAD-67 mRNA could be detected in mouse and rat islets and in mouse brain. GAD-65 mRNA could also be detected in rat islets and mouse brain, but apparently a much lower copy number is present in mouse islets. These findings stress important differences in the immune response occurring in the animal model NOD mouse compared with human type 1 diabetes, and emphasize that human and animal type 1 diabetes possibly represent the final outcome of several different etiological factors.
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PMID:Absence of autoantibodies against glutamate decarboxylase (GAD) in the non-obese diabetic (NOD) mouse and low expression of the enzyme in mouse islets. 814 57

Knowing the autoantigen target(s) in an organ-specific autoimmune disease is essential to understanding its pathogenesis. Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by lymphocytic infiltration of the islets of Langerhans (insulitis) and destruction of insulin-secreting pancreatic beta-cells. Several beta-cell proteins have been identified as autoantigens, but their importance in the diabetogenic process is not known. The non-obese diabetic (NOD) mouse is a murine model for spontaneous IDDM. Here we determine the temporal sequence of T-cell and antibody responses in NOD mice to a panel of five murine beta-cell antigens and find that antibody and T-cell responses specific for the two isoforms of glutamic acid decarboxylase (GAD) are first detected in 4-week-old NOD mice. This GAD-specific reactivity coincides with the earliest detectable response to an islet extract, and with the onset of insulitis. Furthermore, NOD mice receiving intrathymic injections of GAD65 exhibit markedly reduced T-cell proliferative responses to GAD and to the rest of the panel, in addition to remaining free of diabetes. These results indicate that the spontaneous response to beta-cell antigens arises very early in life and that the anti-GAD immune response has a critical role in the disease process during this period.
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PMID:Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. 823 29

Insulin-dependent diabetes mellitus (IDDM) is thought to result from chronic, cell-mediated, autoimmune islet damage. Our aim was to identify the earliest T-cell autoantigen in IDDM, reasoning that this antigen could be causally involved in the initiation of the disease. Identification of the earliest beta-cell-specific autoantigen is extremely important in allowing advances in prevention and treatment of initial events in the development of inflammatory insulitis that precedes beta-cell destruction and overt diabetes. Therefore, we analyzed the proliferative responses of peripheral T-cells from young, female nonobese diabetic (NOD) mice to extracts of pancreatic beta-cell lines. We were able to demonstrate that T-cells responsive to beta-cell antigens exist in the peripheral lymphoid tissue of these mice in the absence of deliberate priming before the manifestation of histologically detectable insulitis. T-cell lines and clones isolated from the peripheral lymphatic tissues of young, unimmunized, female NOD mice were also shown to react with extracts of beta-cells. Fractionation of the beta-cell extracts showed that these T-cell clones recognized multiple beta-cell-specific autoantigens but none of the previously reported putative autoantigens (glutamic acid decarboxylase [GAD]65, GAD67, Hsp65, insulin, ICA 69, carboxypeptidase-H, and peripherin). Thus, we can conclude that these responses are specific for novel beta-cell autoantigens. Finally, NOD T-cell proliferative responses were also seen to an extract of human islets suggesting potential shared antigenic determinants between human and mouse beta-cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isolation of nonobese diabetic mouse T-cells that recognize novel autoantigens involved in the early events of diabetes. 826 14

Glutamic acid decarboxylase (GAD) catalyzes formation of gamma-aminobutyric acid from glutamic acid and is a major autoantigen in insulin-dependent diabetes mellitus. Its two isoforms, GAD65 and GAD67, are encoded by two separate genes. We prepared human islet cDNA library and screened it with cDNA probes of rat brain GAD67. We cloned the cDNA for GAD67, the large isoform of glutamic acid decarboxylase, and determined its nucleotide sequence. Sequencing of the resulting clone identified a 1,785 residue open-reading frame encoded a 594 amino acid polypeptide that showed a 99.4% similarity with GAD67 from human brain. The bacterially expressed human islet GAD67 protein was enzymatically active and immunoreactive. The isolation of cDNA for this additional islet GAD isoforms will be important in studying the etiology and pathogenesis of IDDM.
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PMID:Cloning and expression of large isoform of glutamic acid decarboxylase from human pancreatic islet. 850 3

The autoimmune nature of insulin-dependent diabetes mellitus (type 1 diabetes) has been definitively established during the past ten years only, owing essentially to the development of the NOD and the BB rat models. Three of the four criterias required for defining an autoimmune disease have been demonstrated in these animal models. IDDM is accompanied by immunological stigmatas including circulating autoantibodies and insulitis (lymphocytic infiltration of the islets of Langerhans), it is attenuated or prevented by immunosuppressors and it is transferable from diabetic to non-diabetic mice or rats, via T lymphocytes. Only the fourth criterium, namely the induction of the disease by immunization with an autoantigen, has so far not been met. As is the case for many, if not most, autoimmune diseases, the pathogenesis of IDDM is, however, far from being totally understood. Many aspects including the circumstances favoring escape from self-tolerance, the role of the genetic background, the nature of the pancreatic antigens involved in the initiation and perpetuation of the disease, the effector mechanisms responsible for the elimination of the insulin cells and, most importantly, the conditions for restoring tolerance are at the forefront of immunopathologists' concerns. We provide in this review an account of the present situation in these different areas of research. There is no doubt that a cure or a prevention of the disease will be available in the forseeable future. Experiments on animal models have already initiated several clinical trials and epidemiological studies, and this is probably only the beginning of a long list.
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PMID:The contribution of animal models to the understanding of the pathogenesis of type 1 diabetes. 855 97

Cell-mediated autoimmune attack directed against islet proteins of approximately 38 kD in size has been associated with type 1 diabetes. A novel murine cDNA encoding an antigen of this size was cloned using a screening procedure based on the proliferative response of a human diabetic T cell clone (1C6) to a recombinant antigen epitope library. Membrane preparations from COS 7 cells transfected with the full-length 1,267-bp cDNA elicited a proliferative response from the reporter T cells comparable to that of the defined peptide epitope and native insulinoma antigen. In vitro translation and transfection experiments suggested that the protein is initially synthesized as a 44-kD protein and then processed to the native 38-kD form through the proteolytic removal of a 54-aa NH2-terminal mitochondrial targeting sequence. Differential centrifugation, Percoll density gradient centrifugation, and immunofluorescence studies confirmed localization of the antigen to mitochondria. Northern blot, Western blot, and 1C6 T cell proliferation assays showed that, although imogen 38 was more highly expressed in beta cell than alpha cell lines, it was also present in other tissues. It is concluded that imogen 38 may be a target for bystander autoimmune attack in diabetes rather than a primary autoantigen.
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PMID:Imogen 38: a novel 38-kD islet mitochondrial autoantigen recognized by T cells from a newly diagnosed type 1 diabetic patient. 856 80

Autoantibodies against several cytoplasmic autoantigens such as glutamic acid decarboxylase, heat shock protein 65, insulin, and carboxypeptidase H have been identified in the sera of patients with IDDM. To investigate whether type II DNA topoisomerase (TopII) is an autoantigen in IDDM patients, we have constructed a series of overlapping DNA TopII fragments that covered the entire length of this enzyme. These fragments were used as antigens to screen sera of IDDM patients. We have examined 195 Chinese IDDM patients (mean age 14.2 +/- 7.5 years, age at onset 9.2 +/- 6.4 years, duration of diabetes 4.6 +/- 3.4 years) and 51 nondiabetic individuals. The results showed that DNA TopII autoantibodies were detected in 49.2 and 47.2% of IDDM patients using purified TopII fragments and full-length TopII as antigens, respectively. The frequency of anti-TopII positivity was relatively stable irrespective of sex and disease duration. The patients were slightly older at onset and the prevalence of anti-thyroglobulin/anti-microsomal autoantibodies was twice that in the IDDM subgroup positive for anti-TopII than in IDDM patients who were negative for anti-TopII. We also characterized the epitopes of DNA TopII that were recognized by IDDM sera. Those epitopes resided mostly in three distinct domains. One resided in amino acid residues 1-147, another in amino acid residues 286-472, and the third in the COOH-terminal one-third of DNA TopII. Intriguingly, we found that these epitopes shared similarity (up to 36% identity and 63.6% homology) to previously identified epitopes of IDDM autoantigens.
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PMID:Characterization of human DNA topoisomerase II as an autoantigen recognized by patients with IDDM. 860 60


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