Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0751781 (NOD)
 6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A role for heat shock proteins (HSPs) in autoimmunity has recently been suggested by several authors. Autoantibodies against HSPs have been associated with such autoimmune diseases as systemic lupus erythematosus, polymyositis, and the NOD mouse model of diabetes. Moreover, genes for the major 70,000-M(r) HSP (HSP70) are located within the MHC. To investigate a potential association of an HSP70-2 gene polymorphism with insulin-dependent diabetes mellitus (IDDM), we analyzed restriction-fragment-length polymorphism (RFLP) of this gene in 29 families with one or more member affected by IDDM. With the enzyme PstI, as reported previously, two HSP70-2 alleles of 8.5- and 9.0-kb were found. The 8.5-kb allele was found more frequently on diabetic haplotypes compared with control haplotypes (41 of 66 [62%] vs. 20 of 46 [43%], P = 0.03). This association was due to the conservation of alleles on extended haplotypes we previously reported to be associated with diabetes on initial analysis of families. Twenty-three of 26 diabetic DR3 haplotypes and 3 of 3 normal DR3 haplotypes and all instances of [HLA-B8, SC01, DR3] and [HLA-B18, F1C30, DR3] had the 8.5-kb allele, whereas 0 of 9 normal DR2 haplotypes and 0 of 2 diabetic DR2 haplotypes had the 8.5-kb allele (P = 8 x 10(-7) DR3 vs. DR2 haplotypes). The alleles were equally distributed among DR4 haplotypes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:No independent association between HSP70 gene polymorphism and IDDM. 135 54

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

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

Insulin-dependent diabetes is the direct consequence of an autoimmune reaction causing the destruction of the beta cells of the islets of Langerhans in the pancreas. The frequent association of diabetes with other diseases involving the immune system, the detection of circulating antibodies aimed at the islet cells, the occurrence of the disease in subjects with peculiar HLA antigens are as many arguments supporting the immunological hypothesis. The study of animal models of insulin-dependent diabetes (BB rats, NOD mice) now allows demonstrating the autoimmune process. The transient effectiveness of cyclosporin demonstrated in the human disease confirms these data. The prospects of transplantation of the pancreas, of islets or of islet cells in diabetic subjects to compensate for the insulin deficiency therefore raises the double immunological problem of allogenic rejection and of the risk of recurrence of the anti-islet autoimmune disease.
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PMID:[Diabetes mellitus and autoimmunity]. 229 24

During the last 25 years the concept of a chronic autoimmune process leading to the development of insulin dependent diabetes (IDD) has emerged. The presence of two animal models for IDD, the BB rat and the NOD mouse, has improved our ability to understand the process leading to beta cell destruction. The hallmark of an autoimmune disease is the characteristic pathologic lesion of mononuclear infiltration of the pancreatic islets. Further histologic studies of the diabetic pancreas have identified the type of cells infiltrating the islets and led to the concept of pancreatic beta cells capable of presenting antigen. The initial description of linkage disequilibrium of HLA DR3 and DR4 alleles with IDD has now progressed to the molecular level with the identification of residue 57 of the HLA DQ beta chain as crucial to the genetic predisposition to IDD. Autoantibodies to cytoplasmic antigens (ICA), surface antigens, or a membrane protein of 64 kDa identified by immunoprecipitation, autoantibodies to secreted products such as insulin and proinsulin, and autoantibodies that are cytotoxic to cultured beta cells are islet specific autoantibodies that have been described. Some are probably only markers of immunologic activity; others might participate in the destruction itself. The use of ICA as a screening tool has been successful in identifying individuals prior to the onset of IDD. Widespread cellular immunological defects have been identified both in animal models and in man. In the BB rat, a seeming paradox of severe immunodeficiency occurs in an animal with autoaggressive destruction of beta cells. More subtle defects in immunoregulation have been described in the NOD mouse and in human IDD. The response of IDD in both animal models and in man to immunomodulation and to immunosuppression offers further evidence of an immunologically mediated disease. However, some therapies in the animal models, not typically considered immunologic, such as protein restriction and insulin therapy, have prevented IDD. The possibility of intervening prior to the onset of clinical disease at the level either of the initial process of recognition of the pancreatic beta cell as a target organ or of the effector mechanism is approaching a reality in human IDD.
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PMID:Insulin dependent diabetes mellitus, an autoimmune disorder? 267 79

To investigate HLA-linked genes controlling the susceptibility and resistance to insulin dependent diabetes mellitus (IDDM), HLA-DQ alleles of 45 Japanese patients with IDDM were analysed, using sequence specific oligonucleotide (SSO). DQA1*0301 and DQB1*04 were positively associated (R.R = 6.6, Pc less than 0.05 and R.R. = 4.7 Pc less than 0.01) and DQA1*0103 and DQB1*0104 were negatively associated (R.R. = 0.2, Pc less than 0.01) with IDDM. DQA1*0103 and DQB1*0104 were in strong linkage disequilibrium to encode for DQw6 molecule. Therefore, in a Japanese population, the DQw6 molecule seems to control the resistance to IDDM. To determine whether or not the DQw6 molecule itself can protect against glycosuria and insulitis in NOD mice, these animals were mated with HLA-DQw6 transgenic-C57BL/6 mice (DQw6-B6) and the F1 progeny expressing the DQw6 molecule were backcrossed with NOD mice. Eighty-five female backcross progenies were classified into four groups, according to the MHC classII phenotype; I-ANOD/I-ANOD DQw6(-), I-ANOD/I-ANOD DQw6(+), I-ANOD/I-Ab DQw6(-) and I-ANOD/I-Ab DQw6(+). At the age of 16 weeks, 9.1% of the DQw6(-) I-Ab(-) mice had a glycosuria whereas none of the DQw6(+) I-Ab(-) mice had a glycosuria. At the age of 30 weeks 13.6% of the DQw6(-) I-Ab(-) mice had a glycosuria and 7.7% of the DQw6(+) I-Ab(-) mice had a glycosuria. Histological examinations of the pancreas were performed in the 30 week old mice or after the development of glycosuria.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glycosuria and insulitis in NOD mice expressing the HLA-DQw6 molecule. 270 41

As a result of advances in technology, genome searches have been carried out for susceptibility genes for type 1 diabetes in humans and in the NOD mouse. These have shown that, in the NOD mouse, diabetes susceptibility is under the control of at least ten separate chromosomal loci. In the human, in addition to HLA and INS, two new susceptibility genes have been localized, IDDM4 on chromosome 11q and IDDM5 on 6q, demonstrating the polygenic nature of type 1 diabetes and the role of HLA as the major locus. Candidate genes at these loci are the subject of current investigation. Genetic and immunological markers of disease may be of value in screening the general population for individuals at risk of developing type 1 diabetes. The predictive power of different screening strategies should be tested in order to work out the potential value to the general population of preventive therapies that are now undergoing clinical trials in high risk 'pre-diabetics'. Type 2 diabetes is genetically heterogeneous, and, since 1992, two distinct genetic subtypes have been identified. The first is defined by mutations in the GCK gene, which cause up to 60% of cases of MODY. The second, designated MIDD (maternally inherited diabetes and deafness), is defined by mutation in the mitochondrial gene for tRNA(Leu(UUR)). MIDD patients are less obese than is usual for typical type 2 diabetes, may present in early adult life or occasionally in childhood and may have been diagnosed as having autoimmune type 1 diabetes, type 2 diabetes or MODY. Typically, patients with MIDD require insulin earlier than do type 2 diabetics without mitochondrial mutations. Genetically complex diseases, such as diabetes, hypertension, cancer and coronary heart disease, are common in most populations. The approaches to the genetic analysis of diabetes outlined in this review are likely to be useful to the genetic analysis of many of these disorders. Progress in this area will have important implications for public health strategies in the next decade and beyond.
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PMID:Molecular genetics of diabetes mellitus. 757 35

The products of the class II-like H2-M genes of the major histocompatibility complex are required for class II antigen processing. We sequenced H2-Ma and Mb from several mouse strains to determine whether these genes are polymorphic like the classical H2-A and E genes, or are oligomorphic, like H2-O. Both Mb loci appear to be transcribed and are distinct from each other. Mb1 and Mb2 differ by about 11% at the nucleotide level and are most dissimilar in their second exons (corresponding to the beta 1 domain). Relative to the published Mb1d haplotype sequence, the products of the b, g7, f, and k2 alleles of Mb1 from Mus musculus domesticus and the separate mouse species Mus spretus differ by only one to four amino acids. The majority of the changes occurred in the second exon of Mb1, in contrast to HLA-DMB, the human orthologue. Little polymorphism was seen for Mb2, and Ma was invariant in all strains tested. The similarity of the g7 allele to those from other haplotypes makes it unlikely that the M class II genes play a role in the autoimmune diabetes of NOD strain mice. The M genes are regulated in a manner similar to classical class II genes, in that they are upregulated by IFN-gamma in macrophages, and to a lesser extent by IL4 in B cells. When modeled on the crystal structure of the HLA-DR1 class II molecule, nearly all of the differences between M beta 1 and M beta 2 affect residues facing away from the putative peptide binding groove.
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PMID:Characterization of polymorphism within the H2-M MHC class II loci. 760 4

IDDM is unquestionably an autoimmune disease, as reflected by the presence of beta-cell-reactive autoantibodies and T cells, T cell-mediated transfer of the disease in nondiabetic mice, rats, and humans, and disease sensitivity to immunosuppressive therapy. T cells are predominantly, if not exclusively, involved in creating the islet lesions that lead to beta-cell atrophy after a stage of reversible inflammation. A full understanding of the disease pathogenesis will require a better definition of the nature of the triggering and target autoantigen(s) and of the effector mechanisms (cytokines, cytotoxic cells?). Much less information is available on the etiology than on the pathogenesis. Genetic factors are mandatory and the involvement of predisposition genes (HLA and non-HLA) is now being unravelled. The modulatory role of environmental factors is demonstrated by the high disease discordance rate in identical twins and by experimental data showing positive and negative modulation of the disease by a number of agents, notably infectious agents and food constituents. It is not clear, however, whether a given environmental factor, e.g. a precise virus or a cow's milk component, plays a real etiological role in a selected genetic background. IDDM thus appears as a multifactorial disease. It is not known, however, whether all factors intervene concomitantly in a given individual or separately in subsets of patients, explaining the clinical heterogeneity of the disease. The mechanisms underlying the loss of tolerance to self beta-cell autoantigen(s) are still unknown. Defective intrathymic negative selection of autoantigen-specific autoreactive T cell clones is unlikely. Breakdown of T cell anergy could occur according to various mechanisms, including aberrant expression of MHC molecules and molecular mimicry. Defective suppressor T cell function, perhaps related to TH1/TH2 imbalance, probably intervenes by amplifying the anti-beta-cell autoimmune response whatever its triggering mechanism. Before putative etiological agents are identified, one must base immunotherapy on nonantigen-specific agents. 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. This double strategy (early intervention, tolerance induction) is the main challenge for immunodiabetologists.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Insulin-dependent diabetes mellitus as an autoimmune disease. 798 84

IDDM is caused by autoimmune destruction of insulin-producing beta cells of the pancreas in genetically susceptible individuals. Although the incidence and prevalence if IDDM in Japan are much lower than those in Caucasian countries, the recurrence risk in siblings of IDDM probands is much higher than the population prevalence, indicating that IDDM is clustered in families even in Japan, where the incidence of the disease is the lowest in the world. The higher concordance rate in monozygotic twins than in dizygotic twins indicates that genetic factors contribute to the familial clustering of IDDM in Japan. Analysis of the HLA region revealed that susceptibility genes (IDDM1) consist of multiple components, those in class II DR and DQ regions and another in the class I region. Analysis in NOD mice, an animal model of IDDM, supports this observation: susceptibility genes (Idd1) are mapped to class II A and E regions, but the incidence of the disease is strongly affected by a gene or genes outside of this segment (Idd16). Studies in both humans and an animal model will clarify the genetic components of IDDM, facilitating prediction of the disease and the development of effective strategies for its prevention.
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PMID:Genetics of insulin-dependent diabetes mellitus. 907 99


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