ArticleThe Journal of clinical investigation2001
The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model.
Article in The Journal of clinical investigation, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 71 citations in OpenAlex.
- Preclinical Models to Evaluate the Human Response to Autoantigen and Antigen-Specific Immunotherapy in Human Type 1 Diabetes.Frontiers in endocrinology · 2022Review
- A Humanized Mouse Strain That Develops Spontaneously Immune-Mediated Diabetes.Frontiers in immunology · 2021Article
- Proinsulin-mediated induction of type 1 diabetes in HLA-DR4-transgenic mice.Scientific reports · 2018Article
- Modulation of the immune system by the gut microbiota in the development of type 1 diabetes.Human vaccines & immunotherapeutics · 2018Article
- The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model.Clinical and experimental immunology · 2016Article
- The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes.Journal of autoimmunity · 2016Review
- A novel "humanized mouse" model for autoimmune hepatitis and the association of gut microbiota with liver inflammation.Hepatology (Baltimore, Md.) · 2015Article
- T cell epitope mapping of JC polyoma virus-encoded proteome reveals reduced T cell responses in HLA-DRB1*04:01+ donors.Journal of virology · 2013Article
- Rodent models for investigating the dysregulation of immune responses in type 1 diabetes.Journal of diabetes research · 2013Article
- Article
- A model for personalized in vivo analysis of human immune responsiveness.Science translational medicine · 2012Article
- New insights into the functional role of the rheumatoid arthritis shared epitope.FEBS letters · 2011Review
- Differences in self-peptide binding between T1D-related susceptible and protective DR4 subtypes.Journal of autoimmunity · 2011Article
- MHC molecules in health and disease: At the cusp of a paradigm shift.Self/nonself · 2011Article
- A role for calreticulin in the pathogenesis of rheumatoid arthritis.Annals of the New York Academy of Sciences · 2010Review
- Human risk allele HLA-DRB1*0405 predisposes class II transgenic Ab0 NOD mice to autoimmune pancreatitis.Gastroenterology · 2010Article
- The rheumatoid arthritis HLA-DRB1 shared epitope.Current opinion in rheumatology · 2010Review
- Humanized mice for the study of type 1 diabetes and beta cell function.Annals of the New York Academy of Sciences · 2008Review
- Autoreactive human T-cell receptor initiates insulitis and impaired glucose tolerance in HLA DR4 transgenic mice.Journal of autoimmunity · 2008Article
- Age-dependent loss of tolerance to an immunodominant epitope of glutamic acid decarboxylase in diabetic-prone RIP-B7/DR4 mice.Clinical immunology (Orlando, Fla.) · 2006Article
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5 authors at 2 institutions in 2 countries.
Funding
Abstract
MHC class II molecules are critical determinants of genetic susceptibility to human type 1 diabetes. In patients, the most common haplotype contains the DRA1*0101-DRB1*0401 (DR4) and DQA1*0301-DQB1*0302 (DQ8) loci. To assess directly the relative roles of HLA-DQ8 and DR4 for diabetes development in vivo, we generated C57BL/6 transgenic mice that lack endogenous mouse MHC class II molecules but express HLA-DQ8 and/or DR4. Neither HLA-DQ nor HLA-DR transgenic mice developed insulitis or spontaneous diabetes. However, when they were crossed to transgenic mice (C57BL/6) expressing the B7.1 costimulatory molecules on pancreatic beta cells that do not normally develop diabetes, T cells from these double transgenic mice were no longer tolerant to islet autoantigens. The majority of DQ8/RIP-B7 mice developed spontaneous diabetes, whereas only 25% of DR4/RIP-B7 mice did so. Interestingly, when DQ8 and DR4 were coexpressed (DQ8DR4/RIP-B7), only 23% of these mice developed diabetes, an incidence indistinguishable from the DR4/RIP-B7 mice. T cells from both DR4/RIP-B7 and DQ8DR4/RIP-B7 mice, unlike those from DQ8/RIP-B7 mice, exhibited a Th2-like phenotype. Thus, the expression of DR4 appeared to downregulate DQ8-restricted autoreactive T cells in DQ8DR4/RIP-B7 mice. Our data suggest that although both DQ8 and DR4 can promote spontaneous diabetes in mice with a non-autoimmune-prone genetic background, the diabetogenic effect of the DQ8 allele is much greater, whereas DR4 expression downregulates the diabetogenic effect of DQ8, perhaps by enhancing Th2-like immune responses.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.