Genetic analysis of susceptibility to Type 1 diabetes

Todd, John A.

doi:10.1007/bf00197131

Cited by 13 publications

(7 citation statements)

References 127 publications

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“…T he nonobese diabetic (NOD) 1 mouse spontaneously develops autoimmune diabetes (1)(2)(3)(4), and is considered an appropriate model for examining the etiology of human type I diabetes. As in human diabetes, the murine disease is associated with lymphocytic infiltration of pancreatic islets (insulitis) (1,5), the appearance of autoantibodies directed against 3 cell proteins (6)(7)(8)(9)(10)(11)(12)(13), the T cell-mediated destruction of 3 cells (14)(15)(16)(17), and the presence of both MHC-linked (18)(19)(20)(21)(22)(23)(24) and non-MHC-linked (25-30) disease susceptibility genes.…”

Section: Discussionmentioning

confidence: 99%

I-E+ nonobese diabetic mice develop insulitis and diabetes.

Podolin

Pressey

DeLarato

et al. 1993

The Journal of Experimental Medicine

118

106

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SummaryThe development of type I diabetes in the nonobese diabetic (NOD) mouse is under the control of multiple genes, one or more of which is linked to the major histocompatibility complex (MHC). The MHC class II region has been implicated in disease development, with expression of an I-E transgene in NOD mice shown to provide protection from insulitis and diabetes. To examine the effect of expressing an I-E + or I-E-non-NOD MHC on the NOD background, three I-E + and three I-E-NOD MHC congenic strains (NOD.H-2/s, NOD.H-2 k, and NOD.H-2 h2, and NOD.H-2 h4, NOD.H-2/7, and NOD.H-2 b, respectively) were developed. Of these strains, both I-E + NOD.H-2 h2 and I-E-NOD.H-2 h4 mice developed insulitis, but not diabetes. The remaining four congenic strains were free of insulitis and diabetes. These results indicate that in the absence of the NOD MHC, diabetes fails to develop. Each NOD MHC congenic strain was crossed with the NOD strain to produce I-E + and I-E-F1 mice; these mice thus expressed one dose of the NOD MHC and one dose of a non-NOD MHC on the NOD background. While a single dose of a non-NOD MHC provided a large degree of disease protection to all of the F1 strains, a proportion of I-E + and I-E-F1 mice aged 5-12 mo developed insulitis and cyclophosphamide-induced diabetes. When I-E + F1 mice were aged 9-17 mo, spontaneous diabetes developed as well. These data are the first to demonstrate that I-E + NOD mice develop diabetes, indicating that expression of I-E in NOD mice is not in itself sufficient to prevent insulitis or diabetes. In fact, I-E-F1 strains were no more protected from diabetes than I-E + F1 strains, suggesting that other non-NOD MHC-linked genes are important in protection from disease. Finally, transfer of NOD bone marrow into irradiated I-E + F1 recipients resulted in high incidences of diabetes, indicating that expression of non-NOD MHC products in the thymus, in the absence of expression in bone marrow-derived ceils, is not sufficient to provide protection from diabetes.T he nonobese diabetic (NOD) 1 mouse spontaneously develops autoimmune diabetes (1-4), and is considered an appropriate model for examining the etiology of human type I diabetes. As in human diabetes, the murine disease is associated with lymphocytic infiltration of pancreatic islets (insulitis) (1, 5), the appearance of autoantibodies directed against 3 cell proteins (6-13), the T cell-mediated destruction of 3 cells (14-17), and the presence of both MHC-linked (18-24) and non-MHC-linked (25-30) disease susceptibility genes.As analyzed in an outcross with the C57BL/10SnJ strain, the development of diabetes in the NOD mouse is under poly-1 Abbreviation used in this paper: NOD, nonobese diabetic. genic control (20). At least three non-MHC-linked genes, located on chromosomes 1, 3, and 11 (25, 26), as well as one or more genes in the MHC (18,(20)(21)(22) contribute to disease progression and onset. The MHC class II region has been implicated in disease susceptibility, with the NOD strain expressing a unique I-A B chain (22) a...

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Section: Discussionmentioning

confidence: 99%

I-E+ nonobese diabetic mice develop insulitis and diabetes.

Podolin

Pressey

DeLarato

et al. 1993

The Journal of Experimental Medicine

118

106

View full text Add to dashboard Cite

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“…The HLA shows association with T1D (locus termed IDDM1; Table 1) [15][16][17][18][19][20][21][22] and accounts for approximately 40% of the familial aggregation of the disease. The predisposing HLA class II haplotypes, HLA-DRB1*04, DQB1*03:02 (identified by serology as DR4) and DRB1*03:01, DQB1*02:01 (DR3) are present in 95% of affected individuals.…”

Section: Familial Risk Of Type 1 Diabetesmentioning

confidence: 99%

From Markers to Molecular Mechanisms: Type 1 Diabetes in the Post-GWAS Era

Baxter

Jordan²

2012

Rev Diabet Stud

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■ AbstractBy the year 2000, a draft of the human genome sequence was completed. Millions of single-nucleotide polymorphisms (SNPs) had been deposited into public databases, and high throughput technologies were under development for SNP genotyping. At that time, it was predicted that large case control association studies would provide far better resolution and power than genome-wide linkage studies. Type 1 diabetes was one of the first phenotypes to be examined by genome-wide association studies (GWAS), and to date over 50 genomic regions have been associated with the disease.In general, the great majority of these loci individually contribute a relatively small degree of risk, and most loci lie outside of coding sequences. The identification of molecular mechanisms from these genomic data therefore remains a significant challenge. Here, we summarize genetic candidate, linkage, and association studies of type 1 diabetes and discuss a potential strategy to identify mechanisms of disease from genomic data.

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“…Although T1D is a complex disorder involving interaction of multiple susceptibility loci with unknown environmental factors, the primary genetic component of susceptibility in humans and NOD mice is provided by particular MHC haplotypes (reviewed in refs. [3][4][5][6]. Within the MHC, specific combinations of HLA-DQ and -DR class II alleles provide a large component of T1D susceptibility in humans by mediating ␤ cell autoreactive CD4 T cell responses (reviewed in refs.…”

mentioning

confidence: 99%

Functional evidence for the mediation of diabetogenic T cell responses by HLA-A2.1 MHC class I molecules through transgenic expression in NOD mice

Marron

Graser

Chapman

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Particular major histocompatibility complex (MHC) class II alleles clearly contribute to T cell-mediated autoimmune type 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice. However, studies in NOD mice indicate MHC class I-restricted T cell responses are also essential to T1D development. In humans, epidemiological studies have suggested that some common class I alleles, including HLA-A2.1 (A*02011), may confer increased susceptibility to T1D when expressed in conjunction with certain class II alleles. We show here that when HLA-A2.1 molecules are transgenically expressed in NOD mice, A2-restricted T cell responses arise against pancreatic ␤ cells, leading to an earlier onset of T1D. The accelerated onset of T1D in the NOD.HLA-A2.1 transgenic mice is not due to nonspecific effects of expressing a third class I molecule, because a stock of NOD mice transgenically expressing HLA-B27 class I molecules showed no such acceleration of T1D, but rather were significantly protected from disease. These findings provide the first functional evidence that certain human MHC class I molecules can contribute to the development of T1D.T ype 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is the result of T cell-mediated autoimmune destruction of insulin-secreting pancreatic ␤ cells. The immunotolerogenic defects underlying the initial development of diabetogenic T cells, as well as the events involved in their subsequent activation, are genetically controlled by multiple susceptibility (Idd) alleles both within and outside of the major histocompatibility complex (MHC) (1, 2). Although T1D is a complex disorder involving interaction of multiple susceptibility loci with unknown environmental factors, the primary genetic component of susceptibility in humans and NOD mice is provided by particular MHC haplotypes (reviewed in refs. 3-6). Within the MHC, specific combinations of HLA-DQ and -DR class II alleles provide a large component of T1D susceptibility in humans by mediating ␤ cell autoreactive CD4 T cell responses (reviewed in refs. 3 and 4). A particularly strong class II contributor to T1D in humans is the DQ8 variant characterized by histidine and serine, rather than the more common proline and aspartic acid residues at positions 56 and 57 of the ␤ chain. Similarly, transgenic analyses (7-11) have demonstrated that T1D development in NOD mice requires that the unusual H2-A g7 MHC class II gene product (homologue of human DQ8) be homozygously expressed in the absence of H2-E MHC class II molecules (homologue of human DR). However, although they represent common variants shared by many strains lacking autoimmune proclivity, the K Several studies have provided evidence that the risk of T1D development in humans is increased when certain MHC class I variants are expressed in conjunction with particular MHC class II susceptibility alleles (17-20, ‡). As in NOD mice, these putative human class I susceptibility variants include some common alleles such as HLA-A2.1 (official designation A*02011) (17,18...

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Genetic analysis of susceptibility to Type 1 diabetes

Cited by 13 publications

References 127 publications

I-E+ nonobese diabetic mice develop insulitis and diabetes.

I-E+ nonobese diabetic mice develop insulitis and diabetes.

From Markers to Molecular Mechanisms: Type 1 Diabetes in the Post-GWAS Era

Functional evidence for the mediation of diabetogenic T cell responses by HLA-A2.1 MHC class I molecules through transgenic expression in NOD mice

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