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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T cells and antibodies against self and non-self hsp are present in both patients and healthy controls. T cells responding to hsp65 can be involved in autoimmune diseases, this was demonstrated for two site-specific animal autoimmune diseases: AA in Lewis rats and diabetes (IDDM) in NOD mice. In human ReA there is evidence for a direct stimulation of joint T cells by antigens of the organisms causing the infection which precedes the joint inflammation. The individual antigens of the triggering bacteria still have to be defined, but hsp65 may be of importance since this is one of the molecules recognized by synovial T cells in ReA patients. In RA there are no clear data implicating an infection in the initiation of joint inflammation, but mycobacteria have been suggested to be involved. We have discussed experimental findings which are in favor of, or in contradiction with, a role of mycobacterial antigens--particularly hsp65--in the etiology of RA. T cells recognizing hsp65 and other mycobacterial antigens are present in the joint, but there is no indication for a specific involvement of one or a limited set of (myco)bacterial antigens in the pathogenesis of RA.
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PMID:Heat-shock proteins and autoimmunity in humans. 177 20

It has been demonstrated, in certain autoimmune disease models, that pathogenic T cells express antigen receptors of limited diversity. It has been suggested that the T cells responsible for the pathogenesis of type I diabetes mellitus might similarly demonstrate restricted T cell receptor (TCR) usage. Recently, attempts have been made to identify the V beta subset(s) that initiates and/or perpetuates the antiislet response in a mouse model of spontaneous autoimmune diabetes (non-obese diabetic [NOD] mice). In studies reported here, we have bred NOD mice to a mouse strain that congenitally lacks approximately one-half of the conventional TCR V beta alleles. Included in this deletion are TCR V beta gene products previously implicated as being involved in the pathogenesis of NOD disease. By studying second backcross-intercross animals, we were able to demonstrate that this deletion of TCR V beta gene segments did not prevent the development of insulitis or diabetes.
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PMID:Genetic dissection of T cell receptor V beta gene requirements for spontaneous murine diabetes. 183 91

In insulin dependent diabetes mellitis (IDDM) beta cell destruction is associated with infiltration of the pancreatic islets by T lymphocytes and macrophages. Cytokine products from the infiltrating immunocytes not only have powerful immunoregulatory actions but also are capable of impairing islet cell functions and have thus been postulated to assume a central role in mediating anti-beta cell immunity and beta cell destruction. In an effort to explore further the role of cytokines in the pathogenesis of IDDM, we examined clinical, metabolic and pathological features of NOD/Wehi mice injected intraperitoneally with multiple doses of IFN-gamma and/or TNF-alpha. Blood glucose profiles were not significantly altered by injection of cytokines alone or in combination. Except for a hypoglycaemic rebound in mice injected with TNF-alpha, arginine stimulation tests revealed no disturbances in islet secretory function in cytokine injected mice. Compared with vehicle and cytokines alone, injection of IFN-gamma + TNF-alpha was associated with a variety of clinical and pathological changes including abdominal distention, piloerection, ascites, oedema, thymic atrophy, splenic enlargement and pancreatic distention. Histological examination of the pancreas in these mice revealed moderate to severe pancreatitis which included focal haemorrhagic necrosis, oedema and polymorphonuclear and mononuclear cell infiltration. The islets in these mice appeared normal morphologically and when stained for insulin. The injection of IFN-gamma + TNF-alpha, and to a lesser extent TNF-alpha alone, was associated with a significant reduction in the severity of insulitis. Examination of pancreatic MHC-class I and class II molecule expression revealed in mice given IFN-gamma + TNF-alpha, as compared with controls, significant and uniform induction of both these molecules on ductal and acinar cells; low level MHC-class II expression was also detectable on beta cells in these mice. MHC-class I molecules which were expressed at high levels by beta cells in control mice did not appear to change following administration of the cytokines alone or in combination. We conclude that despite their immunostimulatory actions in vitro and in other models in vivo, systemic administration of the cytokines IFN-gamma and/or TNF-alpha to NOD/Wehi mice does not activate or enhance, and may actually suppress, anti-beta cell immunity in this model.
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PMID:Reduction in insulitis following administration of IFN-gamma and TNF-alpha in the NOD mouse. 190 36

The analysis of HLA class II sequence variation in IDDM patients and controls, made possible by the PCR, has revealed that specific alleles are associated with IDDM. The HLA-DQ beta chain appears to play a role in determining genetic susceptibility and resistance, although polymorphisms in the DRB1, the DQ alpha, and the DP beta chain may also contribute. Although there is a correlation between susceptibility and the charge of DQ beta residue 57, the complex genetic epidemiology of IDDM cannot be accounted for by polymorphism at this position. As we have discussed previously (Horn et al, 1988a, 1988b; Erlich et al, 1990b), there are no unique class II sequences associated with IDDM, consistent with the view that 'normal' class II alleles confer susceptibility. Given the estimates of concordance of under 50% for monozygotic twins and approximately 15% (Tattersall and Pyke, 1972; Thomson, 1988) for HLA-identical sibs--it is not surprising that some unaffected individuals contain putative susceptibility alleles. Perhaps some environmental 'triggering' agent, such as viral infection, is required for the disease to develop in susceptible individuals. Other non-MHC-linked genes which contribute to susceptibility may account for the difference in concordance rates for monozygotic twins and for HLA-identical sibs. In the NOD (non-obese diabetic) mouse and the BB rat models for IDDM, non-MHC susceptibility loci have been identified and mapped (Colle et al, 1981; Hattori et al, 1986) but, in humans, the analysis of non-MHC candidate loci (i.e. the T cell receptor) has, thus far, failed to reveal any other susceptibility loci. In general, the HLA-linked genetic susceptibility to IDDM, as well as to other autoimmune diseases, appears to be associated with specific combinations of class II epitopes (e.g. alleles, haplotypes or genotypes) rather than with specific individual residues or epitopes. Understanding the role of these predisposing sequences will require structural analysis of the class II molecules as well as in vitro and in vivo functional studies of interactions with putative autoantigens and T cell receptors. In the meantime, DNA typing offers the potential for identifying individuals at high risk. These susceptible individuals could be monitored by immunological (e.g. anti-islet cell antibody) or by metabolic tests to detect the preclinical phase of IDDM.
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PMID:HLA class II sequences and genetic susceptibility to insulin dependent diabetes mellitus. 190 60

Transplantation of the islets of Langerhans could be the most promising approach to the clinical treatment of insulin-dependent (type I) diabetes mellitus. In this study, we report on a modified encapsulation technique that produces small alginate-polylysine capsules (0.25-0.35 mm diam). In an in vitro study, both encapsulated and unencapsulated islets showed comparable responses to glucose challenge in terms of insulin secretion. With the new capsules, 16 spontaneously diabetic NOD mice received transplants of 800 encapsulated rat islets/animal. Nonfasting blood glucose concentration decreased from 24.4 +/- 1.4 to 4.0 +/- 1.3 mM. At 4 and 5 mo posttransplantation, the capsules were removed from 2 recipients. Both animals regressed to a hyperglycemic state after capsule removal. However, after another islet transplantation, normoglycemia was again restored in these 2 animals. In control mice, which received unencapsulated islets, the xenografts remained functional for less than 10 days. A high mortality rate was observed among these animals within 2 mo of the recurrence of the hyperglycemic state. Our results clearly indicate that encapsulation of pancreatic islets in the improved capsules can effectively prolong xenograft survival without immunosuppression in an animal model that mimics human type I diabetes mellitus.
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PMID:Prolonged reversal of diabetic state in NOD mice by xenografts of microencapsulated rat islets. 193 9

The aim of this study was to investigate whether neonatal glucose treatment influences the incidence of diabetes in NOD mice. Thirty-nine NOD mice (19 males, 20 females) were treated with 8 g glucose/kg BW/day administered by subcutaneous injections twice a day for the first six days of life. Thirty-six untreated NOD mice (20 males, 16 females) served as a control group. In the glucose-treated group, 33% became diabetic compared with 58% in the control group (X2 = 5.3, p = 0.021). Among the glucose-treated males, 16% became diabetic compared with 50% of the untreated males (X2 = 5.5, p = 0.019), whereas 50% of the glucose-treated females became diabetic compared with 69% of the untreated females (X2 = 1.1, NS). We conclude that neonatal glucose treatment can reduce the diabetes incidence in NOD mice. These results could have implications for the prevention of type 1 diabetes mellitus in humans.
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PMID:Reduction of diabetes incidence in NOD mice by neonatal glucose treatment. 195 55

Type 1 (insulin-dependent) diabetes mellitus results from an autoimmune disease which is directed to insulin-secreting islet cells. In man, it is closely associated to definite major histocompatibility complex alleles. The islets are infiltrated by inflammatory cells (insulitis). Anti-islet cell autoantibodies are present in most patients and represent a valuable marker for the autoimmune reaction. The major role of autoreactive T lymphocytes has been demonstrated in animal models of spontaneous insulin-dependent diabetes (the BB rat and the NOD mouse). Such pathophysiological concepts already have clinical applications. The presence of anti-islet cell antibodies identifies patients with type 1 diabetes of slow onset who initially present with non-insulin dependent diabetes. In the same respect it is now feasible to predict the possible occurrence of diabetes in 'at risk' subjects (such as siblings of a diabetic patient) on the basis of HLA typing and the presence of markers of anti-beta cell immunity. Lastly, both in animal models and in human diabetes, it has been demonstrated that immune intervention can alter the course of anti-islet autoimmunity. From these results one may hope in the future to get preventive treatment of type 1 diabetes before the onset of metabolic disturbances.
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PMID:[Type 1 diabetes mellitus, autoimmune disease: physiopathologic aspects and practical applications]. 206 84

The development of IDDM results from the destruction of pancreatic beta cells. Genetic factors, various immune system alterations, and environmental factors have been studied as the possible causes of IDDM. The concordance rate for developing IDDM between monozygotic twins approaches 50%, suggesting that genetic factors are necessary, but nongenetic factors such as various immune system alterations and environmental factors also influence the clinical expression of genetic susceptibility. Environmental factors (e.g., viruses, chemicals, and diet) affecting the induction of diabetes may act as primary injurious agents which damage pancreatic beta cells or as triggering agents of autoimmunity. Certain viruses including EMC-D and Mengo virus 2T can directly infect pancreatic beta cells and replicate in the cells. The replication of viruses in the beta cells results in the destruction of the cells within 3 days, and the infected mice develop a diabeteslike syndrome in 3-4 days without the involvement of autoimmunity. In contrast, rubella virus appears to be somewhat weakly associated with autoimmune IDDM in hamsters. In addition, endogenous retrovirus expressed in pancreatic beta cells is clearly associated with the development of insulitis and diabetes in NOD mice. In man, there appears to be no correlation between the detection of islet cell autoantibodies and anti-Coxsackie B viral antibodies in newly diagnosed IDDM. In contrast, persistent infection of CMV and rubella virus appears to be associated with the presence of autoantibodies in newly diagnosed IDDM patients. It is particularly noteworthy that human CMV can induce islet cell autoantibodies that react specifically with a 38 kDa islet cell protein which may represent islet cell-specific antigens in a proportion of CMV-associated IDDM cases. These observations suggest that the association of diabetes with Coxsackie B viruses might be due to cytolytic infection of the beta cells with no link to autoimmunity, while both rubella virus and CMV are probably associated with autoimmune IDDM. A number of structurally diverse chemicals including alloxan, streptozotocin, chlorozotocin, Vacor, and cyproheptadine are diabetogenic mainly in rodents and sometimes in man. Possible mechanisms for beta cell destruction by these chemicals include (a) generation of oxygen free radicals and alteration of endogenous scavengers of these reactive species; (b) breakage of DNA and a consequent increase in the activity of poly-ADP-ribose synthetase, an enzyme depleting nicotinamide adenine dinucleotide in beta cells; and (c) inhibition of active calcium transport and calmodulin-activated protein kinase activity. (ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of viruses and environmental factors in the induction of diabetes. 207 86

The MSZ diabetic male mouse represents one of the most useful tools available to researchers interested in analyzing the consequences of insulin dependent diabetes in male mice. In contrast to the high mortality induced by single high doses of SZ, protracted administration of smaller SZ dosages yields a more stable diabetic condition. Moreover, in insulitis prone strains such as BKs, the model allows "synchronization" of beta cell destruction such that the inflammatory events occur on a predictable timescale. The MSZ-diabetic mouse represents a diabetic condition in which the primary etiopathologic effect is produced by an environmental toxin, and not by a genetically programmed loss of tolerance to beta cell specific antigens. In this regard, etiopathogenesis in the MSZ model is quite distinct from that underlying autoimmune type I diabetes in humans, NOD mice, and BB rats, and it is probably not appropriate to refer to pathogenesis in the MSZ model as one of "autoimmune insulitis" as has sometimes been done. The fact that insulitis in the MSZ model may not be "autoimmune," but may actually be a normal response to either tissue damage or to beta cells that have been structurally modified by a chemical, makes the model of special interest. Clearly, there is no single cause of insulin dependent diabetes, with disease induction representing a genetic susceptibility interacting with environmental triggers, such as toxins in the diet (including nitrosamines and fungal metabolites) as well as pathogenic viruses. The MSZ model will continue to be actively investigated because of insights it will afford regarding the genetic bases for susceptibility and resistance to diabetogenic environmental toxins. The model will be of further value by contributing to knowledge of the complicated interactions between pancreatic islet cells, other endocrine cells, and leukocytes in maintenance of glucose homeostasis.
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PMID:Streptozotocin interactions with pancreatic beta cells and the induction of insulin-dependent diabetes. 214 32

Very little is known about the genes involved in the pathogenesis of IDDM. One component is known to be linked to the major histocompatibility complex, but the other components are unknown. We know from the major animals models of IDDM, both the NOD mouse and the BB rat, that the disease is under multigenic control. However, due to the size and complexity of the mammalian genome as well as to the lack of useful clues, the location and identity of the other genes remains a mystery. This is compounded by the fact that well-characterized genetic markers are not available for all regions of the mammalian genome, and it is likely that at least some of the genes of interest are located in these regions. The testing of pedigrees for the linkage of RFLP with the genetic factors involved in IDDM promises to be the most effective means of mapping, and ultimately identifying, these genes. However, the number of genes which are theoretically necessary to test for linkage makes even this approach impractical. Here, we have described here how the amount of work and time can be significantly reduced by utilizing repetitive DNA sequences as probes for the linkage of random RFLPs to diabetes. With each screening, one can simultaneously test multiple unlinked loci in the genome. Preliminary results which show promising linkage to two of the genetic components have been presented, thereby supporting the usefulness of this approach.
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PMID:The genetics of insulin-dependent diabetes in the BB rat. 219 68


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