The HLA system in congenital rubella patients with and without diabetes

Rubinstein, Pablo; Walker, M. E.; Fedun, Barbara; Witt, M. E.; Cooper, Louis Z.; Ginsberg‐Fellner, Fredda

doi:10.2337/diabetes.31.12.1088

Cited by 65 publications

(28 citation statements)

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“…Nor has it proved possible to retrieve sera for further analysis, although there is some faint hope that these may still exist (L. Z. Cooper, personal communication). The absence of HLA DR2 and excess of HLA DR3 in the small sample of 21 cases is, however, consistent with a diagnosis of type 1 diabetes [32].…”

Section: Discussionsupporting

confidence: 53%

“…The striking exception is the New York study, which contains almost half the cases reported in the literature: 21 of 173 (16 on insulin) at a mean age of 14 years [32], and 30 of 242 (15 on continuous insulin) at a mean age of 17 years [33]. Ascertainment bias may have contributed to this very high rate, which is otherwise unexplained.…”

Section: Discussionmentioning

confidence: 99%

“…Comparison between 21 affected individuals who also had diabetes and 152 with no diabetes showed HLA DR2 to be present in 25% of those without, but in none of those with diabetes. HLA DR3 was significantly more frequent in those with diabetes, and the authors propose that exposure to the rubella virus may increase the penetrance of diabetes susceptibility alleles [32].…”

Section: Hla Associationsmentioning

confidence: 99%

“…Three studies in different populations have suggested that susceptibility is HLA-linked, but the findings are inconsistent [37][38][39]. In contrast, Rubinstein et al observed no difference between individuals with congenital rubella and controls [32]. Comparison between 21 affected individuals who also had diabetes and 152 with no diabetes showed HLA DR2 to be present in 25% of those without, but in none of those with diabetes.…”

Section: Hla Associationsmentioning

confidence: 99%

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Congenital rubella: citation virus or viral cause of type 1 diabetes?

Gale

2008

Diabetologia

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Hla Associationsmentioning

confidence: 99%

Section: Hla Associationsmentioning

confidence: 99%

See 2 more Smart Citations

Congenital rubella: citation virus or viral cause of type 1 diabetes?

Gale

2008

Diabetologia

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“…Rubella virus can infect cultured human fetal pancreatic islet cells and such infection could lead to significant reductions in concentrations of secreted insulin [28]. Patients with Type I diabetes associated with CRS show the same immunogenetic (DR3 or DR4 or both) associations as conventional Type I diabetic patients [29]. Thus, CRS-associated Type I diabetes serves as an excellent human model in which to study viral influences in the pathogenesis of diabetes [7].…”

mentioning

confidence: 99%

Cross-reactive rubella virus and glutamic acid decarboxylase (65 and 67) protein determinants recognised by T cells of patients with Type I diabetes mellitus

Mitchell

Metzger

et al. 2000

Diabetologia

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Type I (insulin-dependent diabetes) mellitus, is caused by the progressive loss of insulin-producing pancreatic beta cells and is generally believed to result from T-cell-mediated autoimmune destruction [1,2]. Type I diabetes has long been known as a hereditary disease whose aetiology seems to be polygenic and multifactorial. The role of HLA genes in susceptibility to Type I diabetes is important, as indicated by high disease concordance in HLA-identical siblings (15±17 % in DR3/4 heterozygotes, compared with approximately 1 % for HLA-discordant siblings). Although a genetic predisposition to Type I di- Abstract Aims/hypothesis. To examine the cross-reaction between viral and beta-cell protein determinants and to further understand the potential role of this mechanism in Type I (insulind-dependent) diabetes mellitus. Methods. Immune responses to a panel of 28 viral and beta-cell protein peptides representing selected sequences of rubella virus (RV), Coxsackie virus, human 38 KDa31G and glutamic acid decarboxylase (GAD 65 and 67) proteins in proliferation or cytotoxicity assays have been studied using uncloned and cloned T-cell cohorts from a group of 60 Type I diabetic patients. Results. Peptide GAD65(252±266) induced the responses of patients with recent onset diabetes in proliferation assays at the highest frequency (77 %), whereas GAD67(212±226) stimulated the cellular responses at the highest rate (61 %) in patients with late-onset diabetes. RVE1(157±176) was recognised by all groups of patients at the highest frequency and the largest amplitude among the viral peptides tested. T-cell clones specific to GAD65(252±266), GAD65(274±286) or GAD67(212±226) were tested in cytotoxicity assays for their responses to rubella virus peptides. Each of these T-cell clones cross-reacted with two to four rubella virus peptides, including RVE1(157±176) and RVE2(87±107). Analysis of the sequences of cross-reactive viral and glutamic acid decarboxylase antigens showed that these epitopes shared similar peptide binding motifs to HLA DR3/ DR4. There is a statistically significant correlation between the response amplitude of patient's peripheral blood mononuclear cells to RVE1(157±176), RVE2(87±107) and GAD65(274±286) in patients with recent onset diabetes, and to RVE1(157±176) and GAD67(212±226) in patients with late onset diabetes. Conclusion/interpretation. Cross-reactive glutamic acid decarboxylase and rubella virus determinants identified by T-cell clones were also recognised at high frequencies by general T-cell populations of Type I diabetic patients. [Diabetologia (2000) 43: 750±762]

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Impact of genetic and non‐genetic factors in type 1 diabetes

Hawa¹,

Beyan²,

Buckley

et al. 2002

Am. J. Med. Genet.

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Type 1 insulin-dependent diabetes is due to destruction of the insulin secreting cells of the islets of Langerhans. The disease is caused by non-genetic, probably environmental, factors operating in a genetically susceptible host to initiate a destructive immune process. These unknown environmental factors may operate over a limited period either in early or later and to a variable degree, playing a particularly substantial role in adults. The environment then induces an immune process associated with destruction of the islet beta cell that can be detected in early life and persists up to disease onset. Apart from an association with the insulin gene there is no evidence that genes associated with type 1 diabetes, including HLA and CTLA4 influence the targeting of the immune response to the insulin-secreting cells. The critical period of immune activation is probably short and the process leading to diabetes probably has a long prodrome but of variable duration that determines the age at presentation with clinical disease. The amplification both of this immune response and the destructive process is in part genetically determined, involving HLA genes. The clinical spectrum of the disease process associated with type 1 diabetes is wide, encompassing insulin-dependence, non-insulin dependence and even transient impaired glucose tolerance. Type 1 diabetes presenting in adults, in contrast to children, is predominantly determined by non-genetic factors with a reduced role for protective and susceptibility HLA alleles. Thus, the evidence is that genes involved in genetic susceptibility to type 1 diabetes operate predominantly in children not adults and in both amplify the immune response and the rate of disease progression.

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The HLA system in congenital rubella patients with and without diabetes

Cited by 65 publications

References 0 publications

Congenital rubella: citation virus or viral cause of type 1 diabetes?

Congenital rubella: citation virus or viral cause of type 1 diabetes?

Cross-reactive rubella virus and glutamic acid decarboxylase (65 and 67) protein determinants recognised by T cells of patients with Type I diabetes mellitus

Impact of genetic and non‐genetic factors in type 1 diabetes

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