학술논문
Genetic association of HLA DQB1 with CD4+ [CD25+.sup.high] T-cell apoptosis in type 1 diabetes
Document Type
Clinical report
Author
Source
Genes and Immunity. June 2009, Vol. 10 Issue 4, p334, 7 p.
Subject
Language
English
ISSN
1466-4879
Abstract
Introduction Type 1 diabetes (T1D) is the result of T-cell-mediated destruction of insulin-producing β-cells in the pancreas, leading to a lifelong dependency on exogenous insulin. Susceptibility to this destructive process [...]
Type 1 diabetes (T1 D) has a strong genetic component and the major locus lies in the HLA DOB 1 region. We found earlier an increased apoptosis with decreased viability and function of the CD4+ [CD25+.sup.high] T-cell subset (Treg) in human subjects with recent-onset T1 D and in multiple autoantibody-positive, high of-risk individuals. Tregs normally inhibit or delay onset of T1 D in animal models and increased Treg apoptosis could bring on or accelerate disease from effector T-cell-mediated destruction of insulin-producing beta cells. In this study, we test the hypothesis that HLA DOB1 genotypes are associated with increased CD4+ [CD25+.sup.high] T-cell apoptosis. HLA DO-based genetic risk status was significantly associated with CD4+ [CD25+.sup.high] T-cell apoptosis, after adjustment for age, gender and phenotypic status (n = 83, F = 4.04 (d.f. = 3), P = 0.01). Unaffected, autoantibody-negative high risk HLA DOB1 control subjects showed increased CD4+CD25[+.sup.high] apoptosis levels compared with low risk HLA DOB 1 control subjects (n = 26, P = 0.002), confirming that the association precedes disease. The association of specific HLA DOB1 genotypes with Treg apoptosis was also tested, showing significance for HLA DOB1*0302, DOB1*0201 and HLA DOB1*0602 alleles. Our study shows an association of HLA DOB1 genotypes with CD4+ [CD25+.sup.high] T-cell apoptosis, which implicates CD4+ [CD25+.sup.high] T-cell apoptosis as a new intermediate trait for T1D. doi:10.1038/gene.2009.14; published online 19 March 2009 Keywords: tregs; regulatory T-cells; apoptosis; HLA class II; type 1 diabetes
Type 1 diabetes (T1 D) has a strong genetic component and the major locus lies in the HLA DOB 1 region. We found earlier an increased apoptosis with decreased viability and function of the CD4+ [CD25+.sup.high] T-cell subset (Treg) in human subjects with recent-onset T1 D and in multiple autoantibody-positive, high of-risk individuals. Tregs normally inhibit or delay onset of T1 D in animal models and increased Treg apoptosis could bring on or accelerate disease from effector T-cell-mediated destruction of insulin-producing beta cells. In this study, we test the hypothesis that HLA DOB1 genotypes are associated with increased CD4+ [CD25+.sup.high] T-cell apoptosis. HLA DO-based genetic risk status was significantly associated with CD4+ [CD25+.sup.high] T-cell apoptosis, after adjustment for age, gender and phenotypic status (n = 83, F = 4.04 (d.f. = 3), P = 0.01). Unaffected, autoantibody-negative high risk HLA DOB1 control subjects showed increased CD4+CD25[+.sup.high] apoptosis levels compared with low risk HLA DOB 1 control subjects (n = 26, P = 0.002), confirming that the association precedes disease. The association of specific HLA DOB1 genotypes with Treg apoptosis was also tested, showing significance for HLA DOB1*0302, DOB1*0201 and HLA DOB1*0602 alleles. Our study shows an association of HLA DOB1 genotypes with CD4+ [CD25+.sup.high] T-cell apoptosis, which implicates CD4+ [CD25+.sup.high] T-cell apoptosis as a new intermediate trait for T1D. doi:10.1038/gene.2009.14; published online 19 March 2009 Keywords: tregs; regulatory T-cells; apoptosis; HLA class II; type 1 diabetes