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)

Autoimmune polyglandular syndrome type 1 (APS1) is characterized by a variable combination of disease components: (1) mucocutaneous candidiasis; (2) autoimmune tissue destruction; (3) ectodermal dystrophy. The disease is caused by mutations in a single gene called APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy) or AIRE (autoimmune regulator) coding for a putative transcription factor featuring two zinc-finger (PHD-finger) motifs. APS1 shows a penetrance of 100%, lack of female preponderance and lack of association with HLA-DR. Typically, onset of APS1 occurs in childhood and multiple autoimmune manifestations evolve throughout lifetime. Organ-specific autoantibodies associated with hypoparathyroidism, adrenal and gonadal failures, IDDM, hepatitis and vitiligo are discussed, and autoantibody patterns in APS1 patients are compared with autoantibodies in APS type 2 (APS2). APS2 is characterized by adult onset adrenal failure associated with IDDM and/or hyperthyroidism. APS2 is believed to be polygenic, characterized by dominant inheritance and association with HLA DR3.
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PMID:Autoimmune polyglandular syndromes. 989 74

The most compelling case for autoimmune mediated hypogonadism occurs when ovarian failure is part of an autoimmune polyglandular syndrome (APS). In patients with the rare, recessively inherited type 1 APS (APS-1), characterized by the triad of chronic mucocutaneous moniliasis, hypoparathyroidism, and Addison's disease, primary amenorrhea (elevated pituitary gonadotropins) or oligomenorrhea and infertility are constant features. Ovarian failure is associated with autoantibodies to steroid hormone secreting cells in the adrenal cortex, Leydig cells of the testes, granulosa/thecal cells of the Graffian follicles, corpus luteum, and the syncytiotrophoblast of the placenta. These autoantibodies react with 3 P450 enzymes involved with steroidogenesis, namely, 21-hydroxylase (adrenal specific), 17 alpha-hydroxylase, and the side chain cleavage enzyme. Recently the 14 exon, APS-1 (autoimmune regulator or AIRE) gene has been cloned (chr. 21p22.3), and multiple mutants discovered. Parents who are obligatory heterozygotes for a single mutant gene lack clinical features of APS-1. They also do not develop APS-1 autoantibodies. Thus, hypogonadal patients without features of APS-1 are unlikely to have AIRE gene mutations. In the more common APS-2/3, characterized by combinations of autoimmune thyroid disease, immune mediated type 1 diabetes, vitiligo, pernicious anemia, and Addison's disease (type 2, not type 3), ovarian disease may be seen. In primary hypogonadism outside of the context of an APS, these autoantibodies are rare.
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PMID:Autoimmune hypogonadism as part of an autoimmune polyglandular syndrome. 1122 74

Autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy (APECED) is a rare recessively inherited disorder caused by mutations in the AIRE (autoimmune regulator) gene. APECED is characterized by variable combinations of endocrine autoimmune diseases such as Addison's disease, hypoparathyroidism, and type 1 diabetes. The AIRE protein contains motifs suggestive of a transcription regulator and can activate transcription of a reporter gene when fused to a heterologous DNA biding domain. In this article, mutation analyses of over 200 APECED patients published by several laboratories are summarized. To date 42 different mutations have been identified. These mutations include nonsense and missense mutations, small insertions and deletions leading into frame shifts, and splice site mutations. Although mutations are spread throughout the coding region of the gene some hotspots emerge, including the more common and recurrent mutations R257X and 967-979del13bp. Some of the identified mutations have been shown to affect subcellular localization or transactivation properties of the protein, thus providing insights into the functional properties of the predicted protein motifs.
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PMID:APECED mutations in the autoimmune regulator (AIRE) gene. 1152 31

As a complement to basic research, thorough clinical investigation of rare diseases may provide fundamental elements which improve our understanding of still obscure pathophysiologic mechanisms. This is the case with immunoendocrinopathy syndromes. Since Addison's pioneer observations in the 19th century, physicians have known that some individuals and their families may be affected by several spontaneous endocrine insufficiencies that are associated with autoimmune extra-endocrine processes. APS-I or APECED syndrome appears in children firstly affected by recurrent muco-cutaneous candidiasis and hypoparathyroidism, followed by adrenocortical insufficiency and by other autoimmune processes. APS-I is a monogenic disorder resulting from one mutation in the AIRE gene. The protein encoded by AIRE is a nuclear transcription factor the precise target of which is still not known. AIRE is mainly expressed by cells playing a crucial role in the establishment of central T cell self-tolerance (medullary epithelium, macrophages and dendritic cells of the thymus). APS-I must be considered in children affected with recurrent candidiasis without any sign of primary immune deficiency. Scientific investigation of the biological nuclear events controlled by AIRE has to be pursued. Undoubtedly, their deciphering will increase our knowledge of the mechanisms responsible for the establishment of central T cell self-tolerance and will open novel strategies for managing many autoimmune diseases. APS-II is a more common syndrome characterized by adrenocortical insufficiency spontaneously occurring in non tuberculous adults and associated with autoimmune thyroiditis and/or type 1 diabetes. Contrary to APS-I, APS-II is linked to genetic loci of the major histocompatibility complex. There is no adrenal insufficiency in APS-III which includes autoimmune thyroiditis, type 1 diabetes, and other autoimmune extra-endocrine processes (like pernicious anemia and vitiligo).
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PMID:[Autoimmune polyendocrine syndrome (APS)]. 1256 2

Autoimmune Polyendocrine Syndromes (APS) were initially defined as a multiple endocrine gland insufficiency associated to an autoimmune disease in a patient. Neufeld & Blizzard (1980) suggested a classification of APS, based on clinical criteria only, describing four main types. APS-1 is characterized by presence of chronic candidiasis, chronic hypoparathyroidism, Addison's disease. It is a very rare syndrome interesting young subjects correlating to different mutations of AIRE (AutoImmuneRegulator) gene on chromosome 21. APS-2 is characterized by presence of Addison's disease (always present), autoimmune thyroid diseases and/or type 1 diabetes mellitus. It is a rare syndrome interesting particularly adult females and associated to a genetic pattern of HLA DR3/DR4. Autoimmune thyroid diseases associated to other autoimmune diseases (excluding Addison's disease and/or hypoparathyroidism), are the main characteristics of APS-3. The different clinical combinations of autoimmune diseases not included in the previous groups are characteristics of APS-4. In this paper criteria for defining a disease as autoimmune are presented. Furthermore, the classification, epidemiology, pathogenesis, genetic, animal models, clinical features, laboratory's tests, imaging, therapy, recent progresses in understanding the APS and a detailed analysis of large group of our patients affected by different types of APS are proposed and discussed.
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PMID:Update on autoimmune polyendocrine syndromes (APS). 1281 89

Type 1 diabetes is an autoimmune disease with a complex polygenic inheritance. Until recently, only three susceptibility genes had been reproducibly identified, namely HLA, INS-VNTR, and CTLA4. During the past 7 years, a number of new putative susceptibility genes have been isolated from both human and animal models of the disease. We present eight genes implicated in type 1 diabetes etiology and discuss them in relation to the pathogenesis of the disease: VDR, IL6, IL12B, AIRE, FOXP3, B2m, Cblb, and Lyp/Ian4l1.
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PMID:New autoimmune genes and the pathogenesis of type 1 diabetes. 1503 74

It is well established that the polymorphisms at the 5' of the insulin gene (IDDM2) confers susceptibility to type 1 diabetes, probably by modifying the level of insulin expression in the thymus that in turn influences immunological tolerance to insulin as self-antigen. AIRE is a transcription regulator which controls the expression of many peripheral antigens within the thymus, among them insulin. Results presented here confirm that insulin gene copies from both parental chromosomes are expressed in human thymus and that IDDM2 class III protective alleles are indeed associated with a higher level of insulin message expression. However, differences in insulin mRNA expression among different thymi were far wider than those determined by the class I and class III insulin gene alleles and maintained a clear correlation with AIRE expression. These results confirm the effect of IDDM2 alleles on insulin expression in the thymus, but suggest that the levels of AIRE may exert a stronger influence than IDDM2 alleles themselves.
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PMID:Insulin alleles and autoimmune regulator (AIRE) gene expression both influence insulin expression in the thymus. 1624 24

This presentation is an overview of mechanisms for developing and maintaining self-tolerance in mammalian organisms. Because this meeting is focused on type 1 diabetes and its mechanisms, the discussion deals primarily with mechanisms of T-cell tolerance, since type 1 diabetes in both effector and initiator phases is primarily a T-cell-mediated autoimmune disease. Emphasis is placed on more recently discovered mechanisms of maintaining self-tolerance (autoimmune regulator [AIRE]) and a new defect in T-cell negative selection. The emerging picture is that of a polygenic disease with various combinations of different alleles of many genes with important roles in the normal immune response or normal immune responses.
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PMID:Characteristics of autoimmunity in type 1 diabetes and type 1.5 overlap with type 2 diabetes. 1630 38

Progress has been made in investigating the genetic factors involved in type 1 diabetes (T1D) development for the past few years. While Linkage disequilibrium (LD) mapping has been useful for both the confirmation and fine-mapping of susceptibility intervals, as well as identification of etiological mutations, identification of specific disease genes has been a challenge and limited to known candidate genes. The overall risk for T1D from the HLA DR and DQ molecules (IDDM1) is determined by combinations of polymorphic alleles. Functional studies indicate that the susceptible and protective HLA-DR and -DQ bind and present non-overlapping peptides. Although consistent linkage evidence was reported for the susceptibility intervals IDDM2, IDDM5 and IDDM12, evidence for most other intervals varies in different data sets. The variable number of tandem repeats at the 5' end of the insulin gene (IDDM2) regulates insulin expression in the thymus. Studies on IDDM5 have led to the discovery of a novel polymorphism 163 A-->G (M55V) in SUMO4 gene, which was found to be associated with T1D patients with Asian origin. Functionally SUMO4 conjugates to IkBalpha and negatively regulates NFkB transcriptional pathway. The M55V substitution reduces the sumoylation activity of the V55 variant, which resulted in higher NFkB dependent transcriptional activity. The polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4, IDDM12) encoding a regulatory molecule in the immune system associate with T1D and autoimmune thyroid diseases (ATD). The 3' untranslated region of this gene determines the level of soluble CTLA-4. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as evidenced by quantitative alterations of candidate genes contributing to autoimmune tissue destruction. Moreover, the identification of two transcription factors that, when mutated, are responsible for severe autoimmune disease is leading to a better understanding of T cell tolerance. Both AIRE and Foxp3, identified initially via their association with genetically manipulated mice, are involved in tolerance induction in humans. Although mutations in these genes may cause rare but serious diseases, it is likely that other transcription factors will contribute to the genetic load that predisposes certain individuals to disease.
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PMID:Functional evaluation of the type 1 diabetes (T1D) susceptibility candidate genes. 1744 64

Beneficial effects of angiotensin converting enzyme inhibitors (ACEI) and angiotensin type 1 receptor (AT1) blockers in patients with cardiovascular and renal diseases have been clearly demonstrated in numerous large outcomes studies. In patients with heart failure (HF), ACEI have been shown to reduce overall mortality, mortality from cardiovascular causes, to increase life expectancy, as well as to preserve the renal function (CONSENSUS, SAVE, TRACE, AIRE, AIREX, CATS trials). In addition, in the PROGRESS study ACEI substantially decreased the risk of stroke and transient ischemic attacks in patients with cerebrovascular disorders. The HOPE and EUROPA studies confirmed that long term therapy with ACEI provides significant survival benefit in patients with broad range of atherosclerotic cardiovascular diseases. After these large and well designed clinical studies, ACEI have become standard therapy for routine secondary prevention in all patients with cardiovascular diseases, unless contraindicated. AT1 receptor blockers have been recently added to the cardiovascular therapeutic armamentarium. They are believed to provide additional protection by inhibition of locally synthesized angiotensin II on the level of AT1 receptor. The ELITE II, ValHeFT and CHARM studies have shown that AT1 receptor blockers are equally effective as ACEI in reduction of mortality and morbidity in patients with HF. Importantly, they may be used together with ACEI, or as alternative treatment in ACEI intolerant patients. Renal protection is another important effect of both ACEI and AT1 blockers that has been confirmed in several large clinical trials. The North American Microalbuminemia Study group and EUCLID group demonstrated significant reduction in progression of diabetic nephropathy in patients with insulin dependent diabetes mellitus (IDDM) treated with ACEI. AT1 receptor blockers are mainly studied in the non-insulin dependent diabetes mellitus (NIDDM) nephropathy. Four recent clinical trials (IRMA-2, DETAIL, RENAAL and IDNT) examined the effect of AT1 receptor blockers in patients with NIDDM nephropathy. These studies confirmed the beneficial effect of AT1 receptor blockers in patients with NIDDM nephropathy that was extended beyond the blood pressure reduction. Ongoing studies (ONTARGET, TRANSCEND and PROTECTION) should provide us with additional insights about cardiovascular, renal and other end-organ protective effects of these therapeutics.
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PMID:Role of renin angiotensin system inhibitors in cardiovascular and renal protection: a lesson from clinical trials. 1750 19


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