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)

A variable number of tandem repeats (VNTR) polymorphism upstream of the insulin promoter is strongly associated with type 1 diabetes. The short class I alleles are predisposing and the long class III alleles are protective. As a possible mechanism for this effect, we previously reported a two- to threefold higher insulin transcription from class III than from class I chromosomes in thymus where insulin is expressed at low levels, presumably for the purpose of self-tolerance. In this article, we confirm this finding with independent methodology and report studies testing the hypothesis that class III alleles are associated with T-cell tolerance to (pro)insulin. Cytokine release in vitro after stimulation with 21 overlapping preproinsulin epitopes was assessed in blood mononuclear cells as well as naive and memory CD4+ T-cell subsets from 33 individuals with the high-risk DRB1*04, DQ8 haplotype (12 type 1 diabetic patients, 11 healthy control subjects, and 10 autoantibody-positive subjects). No significant differences between genotypes (24 I/I subjects versus 10 I/III or III/III subjects) were observed for gamma-interferon, tumor necrosis factor-alpha, or interleukin (IL)-4. By contrast, the I/III + III/III group showed a significant threefold higher IL-10 release in memory T-cells for whole proinsulin and the immunodominant region. Given that IL-10 is a marker of regulatory function, our data are consistent with the hypothesis that higher insulin levels in the thymus promote the formation of regulatory T-cells, a proposed explanation for the protective effect of the class III alleles.
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PMID:Class III alleles at the insulin VNTR polymorphism are associated with regulatory T-cell responses to proinsulin epitopes in HLA-DR4, DQ8 individuals. 1630 35

Spontaneous type 1 diabetes occurs when the autoimmune destruction of pancreatic beta-islet cells prevents production of the hormone insulin. This causes an inability to regulate glucose metabolism, which results in dangerously raised blood glucose concentrations. It is generally accepted that thymus-derived lymphocytes (T cells) are critically involved in the onset and progression of type 1 diabetes, but the antigens that initiate and drive this destructive process remain poorly characterized--although several candidates have been considered. Nakayama et al. and Kent et al. claim that insulin itself is the primary autoantigen that initiates spontaneous type 1 diabetes in mice and humans, respectively, a result that could have implications for more effective prevention and therapy. However, I believe that this proposed immunological role of insulin may be undermined by the atypical responses of T cells to the human insulin fragment that are described by Kent et al..
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PMID:Immunology: Insulin auto-antigenicity in type 1 diabetes. 1588 96

Autoreactive T cells that escape negative selection in the thymus do not normally cause productive immune responses to self-antigens because of a number of regulatory mechanisms. Studies with anti-CD3 monoclonal antibodies (mAbs) have suggested that immune regulatory mechanisms are induced by drug treatments that are able to stop on-going unwanted immune responses, such as type 1 diabetes, involving induction of regulatory T cells. TGF-beta dependent and independent mechanisms have been described involving CD4(+) as well as CD8(+) T cells. The challenge is now to apply these mechanisms in an antigen-specific manner and so that lasting tolerance to the autoimmune responses can be maintained. We discuss recent data concerning the mechanisms of anti-CD3 mAb treatment and the ways in which our understanding of these mechanisms can be used to develop adoptive immune therapy with regulatory T cells to treat patients with type 1 diabetes or other autoimmune diseases.
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PMID:Achieving antigen-specific tolerance in diabetes: regulating specifically. 1631 83

Regulatory T cells ensure a balanced immune response that is competent both to fight pathogens, at the same time, to recognize self-antigens and commensals as harmless. Regulatory mechanisms are essential in preventing autoimmune disorders but may also facilitate the progression of malignant diseases and the establishment of latent infections via suppression of the host immune response. Regulatory T cells arise in the thymus, and regulatory T cell function can be induced in the periphery, so-called infectious tolerance. An absolute or relative defect in regulatory T cell function may contribute to the development of autoimmune disorders such as rheumatoid arthritis, type 1 diabetes mellitus, multiple sclerosis and chronic inflammatory bowel disease. Regulatory T cell therapy is a tempting strategy for reestablishing the immune balance and thus preventing or reversing these disorders. Reestablishment of the immune balance may be accomplished by adoptive transfer of ex vivo-propagated regulatory T cells or by induction of regulatory functions locally in the organs, although such strategies are in their infancy in human research.
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PMID:[CD4 + CD25 + regulatory T cells and their importance to human illnesses]. 1639 60

Coeliac disease frequency increases by obscure reasons and affects in some Western countries as much as 1% of the populations. The second one of monozygotic twins does not develop the disease in 100% but only in 20-50%. To unravel these mysteries, literature was searched to determine the disease background and find suggestions for research and prevention. The causal antigen of coeliac disease is gluten of wheat that is neutralised in the intestine by secretory immune globulin A (sIgA). SIgA is secreted by the secondary (lymphoid) immune system that develops in a newborn infant after the primary (central) immune organs thymus and bone marrow have been primed with antigens of the intestine. Predisposed infants are sensitive for development of coeliac disease during the time without sIgA secretion into the intestine. The risk of the disease diminishes when sIgA cycles of gluten neutralisation develop. Peyer's patches (PP) of the secondary immune system play a central role in the cycles and possibly do not function well in the case of coeliac disease. Coeliac disease in predisposed infants may be prevented by delay of bread consumption till the time of normal sIgA secretion and by application of a challenge period with gluten (see Discussion). It is concluded that sIgA secretion into body cavities and malfunction of immune cells in PP should be included in the future research of coeliac disease as well as in more allergic diseases (type 1 diabetes, Crohn disease, asthma, hay fever).
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PMID:Most probable origin of coeliac disease is low immune globulin A in the intestine caused by malfunction of Peyer's patches. 1640 1

Autoimmune diseases such as type 1 diabetes and multiple sclerosis pose a significant health burden on our society. As a whole, autoimmune diseases affect approximately 6% of the population and are the third largest disease burden after heart disease and cancer. Such pathologic manifestations arise by way of damaging reactions of B-cell derived antibodies and/or T-cells to self-antigens and are triggered by genetic and environmental factors. Currently there is no known cure, with treatment restricted to toxic, long-term immunosuppressive regimes, replacement therapy and in intractable cases, transplantation of autologous or allogeneic haematopoietic stem cells. In experimental models of autoimmunity, gene therapeutic approaches have demonstrated promise in treating the autoimmune diseases. These include delivery of anti-inflammatory cytokines and exploitation of regulatory T cells. However, none of these approaches provide lasting, long-term benefit. We hypothesise that therapeutically transduced haematopoietic stem cells followed by transplantation is an alternative strategy to establish permanent immune tolerance that can not only prevent autoimmunity but also cure these diseases. Our approach is focused on directing autoimmune disease-specific autoantigen expression in the thymus by genetic manipulation of haematopoietic stem cells to establish molecular chimeras. Our hypothesis originates from experimental studies with a mouse model of experimental autoimmune gastritis (EAG) and more recently with the non-obese diabetic (NOD) mouse model for type 1 diabetes (T1D).
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PMID:Gene therapy strategies towards immune tolerance to treat the autoimmune diseases. 1647 45

Mutations in the autoimmune regulator (AIRE) gene cause a recessive Mendelian disorder autoimmune polyendocrinopathy syndrome type 1 (APS-1 or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy). APS-1 patients develop multiorgan autoimmune diseases including type 1 diabetes (prevalence 12%). The AIRE protein controls the central tolerance induction in the thymus by regulating the expression levels of tissue-specific peripheral antigens, such as insulin. We hypothesized that the insulin gene (INS) polymorphisms together with the AIRE variations may predispose individuals to diabetes. The role of the AIRE gene was tested both independently and on the condition of the INS risk genotype in the Finnish type 1 diabetes sample. A total of 733 type 1 diabetic cases and 735 age- and sex-matched healthy controls were used in the analysis. Five common single nucleotide polymorphisms (SNPs) in the AIRE gene were selected from the public database (dbSNP). The -23HphI polymorphism was used as a surrogate marker for the INS gene promoter repeat. The five genotyped SNPs in the AIRE gene showed no evidence of association with type 1 diabetes. As expected, the INS gene polymorphism -23HphI was significantly associated with susceptibility to type 1 diabetes (P=6.8 x 10(-12), chi(2) test). When the subclass of patients carrying the homozygote genotype of the INS gene was used in the analysis, the AIRE polymorphisms showed no association with the disease. In conclusion, the AIRE gene does not seem to contribute to disease susceptibility in Finnish type 1 diabetic patients, whereas the insulin gene represents a notable risk factor for disease in this population.
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PMID:Association analysis of the AIRE and insulin genes in Finnish type 1 diabetic patients. 1655 13

Glutamate decarboxylase (GAD), which has two isoforms, GAD65, and GAD67, is responsible for synthesis of the major inhibitory neurotransmitter, gamma-aminobutyric acid. GAD is expressed predominantly in the central nervous system; recent reports suggest that GAD is also expressed in non-neuronal organs including the pancreas. In the pancreatic islets, GAD serves as one of the autoantigens in type I diabetes mellitus. Recent flow cytometric analyses have shown that a variety of self-antigens, including GAD, are ectopically transcribed and expressed in particular cell populations of the thymus, although consensus concerning the cellular phenotype has not been obtained. The aim of this study was to clarify the localization and cellular phenotype of GAD67-expressing cells in the thymus at a cellular level with a novel approach using GAD67-green fluorescent protein (GFP) knock-in mice, in which GFP is expressed specifically in GAD67-positive cells. GFP-positive cells were detected in the thymic medulla and were identified as epithelial cells by immunohistochemistry. Almost all GFP-positive cells were positive for major histocompatibility complex (MHC) class II antigen staining and were positive for both cytokeratin and Ulex Europaeus Agglutinin I, markers of medullary thymic epithelial cells, but were negative for CD11c, Gr-1, and CD45, markers of dendritic cells, macrophages, and B-lymphocytes, respectively.
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PMID:Antigen-presenting cells expressing glutamate decarboxylase 67 were identified as epithelial cells in glutamate decarboxylase 67-GFP knock-in mouse thymus. 1657 56

Factors that determine the spectrum of target organs involved in autoimmune destruction are poorly understood. Although loss of function of autoimmune regulator (AIRE) in thymic epithelial cells is responsible for autoimmunity, the pathogenic roles of AIRE in regulating target-organ specificity remain elusive. In order to gain insight into this issue, we have established NOD mice, an animal model of type 1 diabetes caused by autoimmune attack against beta cell islets, in which Aire has been abrogated. Remarkably, acinar cells rather than beta cell islets were the major targets of autoimmune destruction in Aire-deficient NOD mice, and this alteration of intra-pancreatic target-organ specificity was associated with production of autoantibody against pancreas-specific protein disulfide isomerase (PDIp), an antigen expressed predominantly by acinar cells. Consistent with this pathological change, the animals were resistant to the development of diabetes. The results suggest that Aire not only is critical for the control of self-tolerance but is also a strong modifier of target-organ specificity through regulation of T cell repertoire diversification. We also demonstrated that transcriptional expression of PDIp was retained in the Aire-deficient NOD thymus, further supporting the concept that Aire may regulate the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus.
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PMID:Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice. 1662 55

Principles of prevention of infectious diseases have been known for several thousands of years. One of the most significant tools of infection prophylaxis is immunization. Vaccines containing thymus-dependent antigens produce massive and complex immune response and feature immunologic memory. That is why they can successfully protect patients with diabetes. Lately, it has been thought by general public and even experts that application of vaccines within national immunization programmes is one of the etiopathogenetic factors in the development of type 1 diabetes mellitus (DM). However, analysis of extensive studies performed by the experts of the Institute for Vaccine Safety proved that there is no positive or negative impact of immunization on the development of type 1 diabetes mellitus. The basic vaccinations recommended for diabetics include immunizations against influenza, pneumococcal infections, tetanus and viral hepatitis B. Other vaccines are administered only after individual assessment of benefits and risks for the diabetic patient. Most often, these are vaccinations against viral hepatitis A, tick-borne encephalitis, meningococcal infections and other infections that put in risk diabetic patients travelling abroad.
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PMID:[Diabetes mellitus and immunization]. 1677 Oct 85


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