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 new viral sequence (IDDMK(1,2)22) similar to the human endogenous retrovirus (HERV)-K10/K18 subfamilies has recently been isolated from the culture supernatants of leukocyte-infiltrated islets from two patients who died at the onset of type 1 diabetes. It was claimed that this endogenous retrovirus is expressed in patients with type 1 diabetes but not in healthy control subjects, suggesting an important role of the retrovirus in beta-cell-specific autoimmunity that results in type 1 diabetes. However, despite exhaustive attempts involving identical and expanded methods of detection, we did not observe the IDDMK(1,2)22 viral sequence in genomic DNA, lymphocyte, or plasma RNA in any subject. Therefore, we believe that the viral sequence is not derived from an endogenous retrovirus and that a role for the retrovirus in the pathogenesis of type 1 diabetes must be reconsidered.
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PMID:The IDDMK(1,2)22 retrovirus is not detectable in either mRNA or genomic DNA from patients with type 1 diabetes. 989 48

To investigate the possible involvement of IDDMK1,2 22/HERV-K18 in childhood type I diabetes mellitus, we identified two nonsynonymous A/G polymorphisms in the superantigen-coding region of IDDMK1,2 22 at the 290- and 461-nucleotide (nt) positions from the initial methionine codon and compared their frequencies in 74 Japanese patients with type 1 diabetes and in 54 nondiabetic controls. Although the G substitution was observed more frequently at either site in the patients than it was in the controls (7% vs. 4% at 290 nt, and 29% vs. 20% at 461 nt), the differences were not statistically significant. A weak significance of difference in the frequency of 461G was obtained only in an early-onset group of patients manifesting the disease at 5 years of age or less (n = 24) when compared with controls (38% vs. 20%; P = 0.03). However, in addition to the common absence of a particular allele among the expected four alleles, remarkable differences in allele frequencies were present between Japanese and European populations. This first trial investigating the association of IDDMK1,12 22 with type 1 diabetes presents intriguing suggestions for the role of this region in the etiology of autoimmune and infectious diseases.
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PMID:Identification of nonsynonymous polymorphisms in the superantigen-coding region of IDDMK1,2 22 and a pilot study on the association between IDDMK1,2 22 and type 1 diabetes. 1177 84

Recently, a newly identified human HERV-K18 like endogenous retrovirus (IDDMK(1,2)22) has been associated to the etiology of type I diabetes (IDDM). Although the exact mechanism remains unclear, it was postulated that the 3' end ORF product of the env gene of IDDMK(1,2)22 would trigger a V beta 7-specific human T cell expansion leading to their infiltration in the pancreas of afflicted patients and to the autoimmune destruction of the insulin-producing beta cells. Since then, such superantigen (SAg)-like activity as well as the association between the IDDMK(1,2)22 virus and IDDM pathogenesis have been challenged. To further characterize functionally the putative IDDMK(1,2)22-encoded SAg, we have cloned from human DNA the identical 462bp ORF sequence originally described. The IDDMK(1,2)22 ORF fragment was transfected in the same human B cell line (Raji) originally used as APC to demonstrate the V beta 7 specificity. The immunostimulatory potential of IDDM ORF was tested on murine T cell hybridomas and compared to the well-characterized mouse mammary tumor virus Mtv7 SAg transfected in the same conditions. A panel of 16 T cell hybridomas encompassing 14 different V betas was analyzed. We have failed to detect IDDMK(1,2)22-induced IL-2 production from any of these hybridomas, even those bearing the murine V beta 1 mV beta 1, V beta 4 or V beta 10 TcR beta chains which are most closely related to the human V beta 7 (hV beta 7). Our results suggest that IDDMK(1,2)22 ORF is devoid of superantigenic activity as defined by classical criteria.
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PMID:Human endogenous retrovirus IDDMK(1,2)22 and mouse mammary tumor virus superantigens differ in their ability to stimulate murine T cell hybridomas. 1184 50

Several lines of evidence suggest the involvement of the human endogenous retrovirus (HERV)-K18 in the etiology of type 1 diabetes. HERV-K18 encodes for a T-cell superantigen (SAg). T-cells with T-cell receptor Vbeta7 chains reactive to the SAg and HERV-K18 mRNA were enriched in the tissues at the onset of the disease. HERV-K18 transcription and SAg function in cells capable of efficient presentation are induced by proinflammatory stimuli such as viruses and interferon-alpha and may trigger progression of disease to insulitis or from insulitis to overt diabetes. Allelic variation of HERV-K18 or the DNA flanking it, the CD48 gene, could modulate genetic susceptibility. Analysis of 14 polymorphisms in the locus using 754 diabetic families provided positive evidence of association of three variants belonging to a single haplotype (P = 0.0026), present at 21.8% frequency in the population. Genotype analysis suggested a dominantly protective effect of this haplotype (P = 0.0061). Further genetic and functional analyses are required to confirm these findings.
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PMID:Association of human endogenous retrovirus K-18 polymorphisms with type 1 diabetes. 1498 74

An experimental system to explore central tolerance in humans is unavailable. However, the human endogenous retrovirus K-18 (HERV-K18) region on chromosome 1 provides an excellent model: HERV-K18 encodes a superantigen (SAg) stimulating Vbeta7CD4 T cells that is implicated in type 1 diabetes and Epstein-Barr virus persistence. In this study, we have addressed thymic HERV-K18 SAg expression, the capacity of SAg to induce negative selection, and the consequences of this for peripheral tolerance compared with SAg reactivity. We demonstrate that thymic HERV-K18 SAg expression is constitutive and is restricted in time and space such that it can induce negative selection. We developed an in vitro assay capable of detecting negative human thymocyte selection by bacterial SAgs presented on extrathymic antigen-presenting cells (APCs). Using this assay, the HERV-K18 SAg is necessary and sufficient for negative selection of immature or semimature Vbeta7CD4 thymocytes. Decreases of SAg reactive Vbeta7CD4 T cells generated in the thymus predict low or absent SAg reactivity. Therefore, these results indicate that negative thymic selection to HERV-K18 SAgs constitutes a first checkpoint controlling peripheral tolerance compared with SAg reactivity. This study now offers a framework to dissect negative selection and its interplay with viral persistence and autoimmunity in humans.
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PMID:Negative thymocyte selection to HERV-K18 superantigens in humans. 1564 16

Type 1 diabetes is an autoimmune heterogeneous disease that is determined by environmental and genetic factors. A possible retroviral etiology has been inferred from the observation that human endogenous retrovirus (HERV)-K18 encoding a superantigen (SAg) has a polymorphism associated with this disease. Type 1 diabetes families from Germany and Belgium were genotyped for the novel HERV-8914 (303 families) and for the known HERV-8594 (284 families) polymorphisms within the SAg-coding region on the HERV-K18. Case-control analysis was performed for the HERV-8914 polymorphism (506 patients) and for the HERV-8594 polymorphism (370 patients) and compared with 350 German controls. Haplotypes were constructed. Additionally, a microsatellite within the CD48 gene was analyzed in German type 1 diabetes families (n=125) as well as in patients (n=375) and in healthy controls (n=350). No association was found for HERV-K18 polymorphisms or the CA repeat within the CD48 gene with type 1 diabetes mellitus either in families or by comparing patients and controls. In conclusion, we cannot confirm a role of HERV-K18 polymorphisms -HERV-8914 and HERV-8594- or of the CD48 CA repeat for type 1 diabetes susceptibility.
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PMID:Neither an intronic CA repeat within the CD48 gene nor the HERV-K18 polymorphisms are associated with type 1 diabetes. 1686 84