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)

Three groups of thymectomized patients with myasthenia gravis (MG) were selected for study, 16 with thymoma, 16 with thymic atrophy and 32 with follicular hyperplasia of the thymus. All 16 patients with thymoma, 15/16 with thymus atrophy and 30/32 with follicular hyperplasia had AChR antibodies. Non-receptor muscle (CA) antibodies were found in sera of 15/16 patients with thymoma, 3/16 with thymus atrophy and in none of the sera from patients with follicular hyperplasia. There were 2 patients with thymoma and polymyositis, but none of the thymoma patients had rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or other autoimmune disorders. Among the 32 patients with follicular hyperplasia of the thymus were 2 with SLE, 2 with RA and 1 with juvenile diabetes mellitus. In this study, there was an increased incidence of non-muscle autoimmune disorders among MG patients with follicular hyperplasia of the thymus but not among MG patients with thymoma.
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PMID:Myasthenia gravis with thymoma is not associated with an increased incidence of non-muscle autoimmune disorders. 157 78

Diabetes-prone BB rats spontaneously develop type 1 diabetes due to a T-cell-dependent destruction of insulin-producing beta-islet cells. A number of T-cell abnormalities including lymphopenia, poor cell-mediated responsiveness to alloantigen, and an absence of an RT6+ T-cell subset are associated with disease susceptibility. Our previous studies have implicated the thymic antigen-presenting cell in influencing disease potential and responsiveness to alloantigen. Since this cell type is also known to influence T-cell receptor expression in developing thymocytes, we examined the thymic and peripheral T-cell receptor beta chain variable region repertoire in diabetes-prone and diabetes-resistant rats. Our findings indicate that animals susceptible to diabetes induction have a characteristic and limited peripheral beta chain variable region repertoire that differs markedly from that expressed in the thymus.
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PMID:Identification of a limited T-cell receptor beta chain variable region repertoire associated with diabetes in the BB rat. 165 91

Insulin-dependent diabetes mellitus (IDDM) is viewed as a thymus-dependent autoimmune disease, although the specific beta-cell autoantigen or autoantigens remain unknown. The recent identification of the beta-cell 64K antigen as the enzyme glutamic acid decarboxylase (GAD) permits investigation of GAD as a candidate for the autoantigen associated with beta-cell destruction, mediated by T-lymphocytes, in susceptible individuals. In this study, we describe the isolation of GAD-specific T-lymphocyte lines from BB rats, an animal model of IDDM. GAD (Escherichia coli) was inoculated into the footpads of diabetes-resistant BB rats, and after 10 days, a popliteal lymph node cell culture suspension was prepared. GAD-specific T lymphocytes were obtained by culture with interleukin 2 and repeated stimulation with GAD in the presence of BB rat thymic antigen-presenting cells. Four stable, CD4+, MHC (RT1u)-restricted T-lymphocyte lines were isolated. They proliferate selectively in the presence of GAD and secrete interleukin 2 and interferon-gamma. T-lymphocyte lines such as these could be important in the definition of pathogenetic epitopes associated with GAD.
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PMID:T-lymphocyte lines specific for glutamic acid decarboxylase (GAD) the 64K beta-cell antigen of IDDM. 172 31

Transplantation of bone marrow cells from nonobese diabetic (NOD) mice, a model for type 1 diabetes mellitus, to C3H/HeN mice, which express I-E alpha molecules and have aspartic acid at residue 57 of the I-A beta chain, induced insulitis followed by overt diabetes in the recipient C3H/HeN mice more than 40 weeks after bone marrow transplantation. When cyclosporin A, which perturbs T-cell functions, was injected intraperitoneally into [NOD----C3H/HeN] chimeric mice daily for 1 month, the chimeric mice developed insulitis and overt diabetes within 20 weeks following bone marrow transplantation. Transplantation of bone marrow cells from (NZW x BXSB)F1 mice, which develop lupus nephritis, myocardial infarction, and idiopathic thrombocytopenic purpura, into C3H/HeN or C57BL/6J mice induced in the recipient strains both lupus nephritis and idiopathic thrombocytopenic purpura more than 3 months after transplantation. Transplantation of a stem-cell-enriched population from (NZW x BXSB)F1 mice into normal mice also induced autoimmune disease in the recipients. These results indicate that both systemic autoimmune disease and organ-specific autoimmune disease originate from defects that reside within the stem cells; the thymus and environmental factors such as sex hormones appear to act only as accelerating factors.
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PMID:Organ-specific and systemic autoimmune diseases originate from defects in hematopoietic stem cells. 223 44

There is increasing evidence that both DP and DR BB rats fail to clonally delete autoreactive T cells in the thymus that are important in the development of autoimmune IDDM. The DP BB rat also has a defect in its ability to generate a regulatory (RT6+) T-cell population that would prevent the onset of diabetes and, therefore, it becomes spontaneously diabetic. The DR rat develops autoreactive T cells, but does not express diabetes because of the concurrent development of a regulatory (RT6+) T-cell population. We suggest that in the BB rat, the initial immunological lesion is orchestrated by an APC in close proximity to pancreatic islet beta cells, and may be specifically directed to the beta cell itself. The release of cytokines in the vicinity of the beta cell destroys this highly susceptible target, causing the release of beta cell 'autoantigens'. These autoantigens, in turn, target autoreactive T cells to the beta cells, allowing a focal destructive process to spread throughout the pancreas. The ultimate destruction of the islets and the development of diabetes result from a cascading effect of this process, with the recruitment of other non-specific immune mediators. A similar process may also be initiated by APC within the thyroid of the rat, resulting in thyroiditis. The fact that the thyrocyte does not die is unexplained, but it could relate to the relative insensitivity of this cell type to various cytokines.
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PMID:The pathogenesis of autoimmune diabetes mellitus. 270 Sep 3

The aim of the present study was to investigate the possible role of the thymus-dependent immune system in the disease mechanisms underlying type 1 (insulin-dependent) diabetes mellitus. Both animal experiments and human studies were carried out. Firstly, a brief historical review is given of the scientific progress within the aetiology and pathogenesis of diabetes mellitus during the last few decades. Mention is made summarily of some elements of the thymus-dependent immune system, and the athymic nude mouse is presented. Three diabetic animal models are reported, viz. two exogenously provoked diabetes models in mice, virus-induced diabetes and diabetes induced by streptozotocin, besides the spontaneously diabetic BB rat. Insofar as the mouse models are concerned, experiments were carried out on both nude mice and normal thymus-intact mice. Encephalomyocarditis virus was used in the virus model and could after inoculation be isolated in large quantities from nude mice as well as normal thymus-intact mice. Only the latter developed diabetes; the C57 mice in the form of glucose intolerance and the BALB/c/BOM mice in the form of elevation of the mean blood glucose values to about threefold normal level. The nude mice exhibited only a very short-lasting virus antibody formation, while in the thymus-intact mice it was possible, as might be expected, to demonstrate high titres of neutralizing virus antibodies for months after the virus inoculation. In the streptozotocin model, where the streptozotocin was administered by repeated small injections, the nude mice developed considerably milder diabetes than the thymus-intact mice. This survey includes other experiments using various forms of immunosuppression (thymectomy, irradiation, treatment with antilymphocyte serum), which together supply evidence that the thymus-dependent immune system is involved in the pathogenesis of diabetes in the two mouse models mentioned as well as in the spontaneously diabetic BB rat, regardless of the different aetiologies in the models. On this background, clinical immunological studies in patients with type 1 diabetes were carried out. Firstly, studies are reported of subpopulations of the peripheral lymphocytes which, after labelling with monoclonal antibodies, were investigated by means of flow-cytometry. The number of cytotoxic/suppressor T-lymphocytes was found to be reduced at the time of diagnosis of type 1 diabetes, but increasing towards normal levels five months later. The helper T-cells were found to be slightly increased at diagnosis as compared with the values in controls, whereas there were no differences in the total T-lymphocyte counts.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The thymus-dependent immune system in the pathogenesis of type 1 (insulin-dependent) diabetes mellitus. Animal model and human studies. 316 May 50

The BB rat spontaneously develops insulitis followed by impaired glucose tolerance (IGT) or an insulin-dependent diabetic (IDDM) syndrome. Passive transfer of insulitis from newly detected diabetic BB rats to nude mice has been achieved by intraperitoneal or intravenous injection(s) of blood and spleen lymphocytes. After a single injection of cells, 37% of the mice (n = 72) showed insulitis with a mean intensity of 1.9 +/- 0.3 (on a scale of 0 to 3). After three successive injections, 58% of the recipient mice (n = 12) showed insulitis with a mean intensity of 2.5 +/- 0.3. Only one of the control mice (n = 45) demonstrated mild insulitis. The small number of affected islets (13% after a single injection, 17% after three injections) probably explains the absence of random or post IP glucose hyperglycemia in the recipient mice. During this study the yield of lymphocytes in diabetic BB rats was found to be consistently lower than in control normal Wistar rats. This lymphopenia was found not only in the blood and the spleen but also in the thymus and the lymph nodes. Peripheral blood lymphopenia antedated glucoregulatory disturbances. All rats showing either insulitis alone or with IGT or IDDM were lymphopenic. None with normal lymphocyte counts developed any abnormality. Diabetics showed a marked decrease in the proportions of T+ lymphocytes in all tissues whereas the proportion of B(Ia+) lymphocytes was normal in blood, spleen, and thymus but increased in lymph nodes. However, in absolute terms both T+ and Ia+ lymphocytes were decreased. The subset decreased by the greatest proportion in all tissues, except in the thymus was the one that includes helper T lymphocytes. This lymphopenia could be related to the presence of circulating antilymphocyte antibodies. These results strongly support a role for altered immunity in the etiology of the syndrome. If the observed anomalies of lymphocyte numbers and subsets are responsible, then a novel mechanism different from most other "autoimmune" disorders must be implicated.
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PMID:Passive transfer of insulitis and lymphopenia in the BB rat. 634 96

The murine model of human insulin dependent diabetes mellitus (IDDM), the non-obese diabetic (NOD) mouse, develops a T cell-dependent destruction of pancreatic islets. While the target antigens are unknown, there is clearly a lack of tolerance to them. Neonatal intrathymic (i.t.) antigen injection has been successfully employed to prevent insulitis in BB rats but previous i.t. islet antigen studies in NOD mice were done on older mice. We have injected syngeneic islets into the thymus of NOD mice at birth and found that diabetes and insulitis can be completely prevented by this procedure. The effect is islet antigen-specific since other T cell responses, including autoimmune salivary infiltration, ard unaffected. Furthermore, contrary to previous studies, cyclophosphamide administration was unable to induce diabetes in treated mice which suggests that deletion or anergy might be the mechanism by which neonatal intrathymic islet injection protects from disease. However, anti-islet antigen antibodies were still present in these mice which suggests that the mechanism of disease protection may be more complex.
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PMID:Prevention of diabetes and insulitis by neonatal intrathymic islet administration in NOD mice. 784 Aug 50

We developed two distinct transgenic mouse models in which virus induced insulin-dependent (type 1) diabetes mellitus (IDDM). In one of these lines, the unique viral transgene was expressed in the islets of Langerhans and also in the thymus, but in the other line, expression was only in the islets. Insertion and expression of the viral (self) gene, per se, did not lead to IDDM, (incidence < 5%). By contrast, induction of an anti-self (anti-viral) CD8+ CTL response to the same virus later in life caused IDDM (incidence < 90%) in both transgenic lines, although the kinetics and requirements for CD4 help, the affinity and avidity of CD8+ CTL differed in each line. Mice not expressing the viral (self) gene in the thymus developed IDDM 10-14 days after infection. CD4+ T cells played no detectable role, since their depletion failed to alter either the kinetics or incidence of IDDM. By contrast, mice that expressed the viral gene in the thymus required significantly more time to develop IDDM. Their anti-self (viral) CD8+ CTL were of lower affinity and avidity than CD8+ CTL generated by nontransgenic controls. Disease was dependent on T cell help, since deletion of CD4+ cells completely circumvented the IDDM.
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PMID:How virus induces a rapid or slow onset insulin-dependent diabetes mellitus in a transgenic model. 788 11

The nonobese diabetic (NOD) mouse is a model for human Type 1 diabetes mellitus. Pancreatic beta-cell destruction in NOD mice is mediated by an autoimmune process which can be accelerated by cyclophosphamide (CP). We studied the phenotype of lymphocytes from central, peripheral and regional lymphoid tissues in prediabetic NOD and C3H mice before and after a single large dose of CP. All lymphoid organs showed a greatly diminished cell number and most alterations appeared early after CP and were transient, but an aggressive insulitis was not seen in NOD mice until 14 d after injection. The pancreatic islets in C3H mice remained intact and were not infiltrated. NOD female mice, which are most prone to spontaneous and CP-induced diabetes, exhibited the most unusual lymphoid kinetics after treatment with CP. Their thymus and spleen showed the least relative drop in total cell number and the most rapid rate of recovery. The thymus of these mice was also found to have an increased proportion of CD3+ thymocytes while CD4/CD8 double positive thymocytes decreased 7 d after CP. At 14 d after CP the number of IL-2R+ thymocytes had surpassed that of normal levels. The most dramatic observation was the rapid recovery and overshoot in the number of pancreatic lymph node cells of female NOD mice which coincided with aggressive insulitis.
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PMID:The effect of cyclophosphamide treatment on lymphocyte subsets in the nonobese diabetic mouse: a comparison of various lymphoid organs. 821 26


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