IngentaConnect The association of CTLA-4 and HLA class II autoimmune risk genoty...

Authors: Jonson, C.-O.; Hedman, M.¹; Karlsson Faresjö, M.¹; Casas, R.¹; Ilonen, J.²; Ludvigsson, J.¹; Vaarala, O.¹

Source: Clinical & Experimental Immunology, Volume 145, Number 1, July 2006 , pp. 48-55(8)

Abstract:

Summary

Regulatory T cells (T_reg) are involved in the maintenance of peripheral tolerance by suppression of autoreactive lymphocytes that have avoided thymic depletion. The defective function of T_reg cells has recently attracted attention in autoimmune diseases such as type 1 diabetes (T1D), rheumatoid arthritis and multiple sclerosis. Susceptibility to these diseases is associated with specific human leucocyte antigen (HLA) class II and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene polymorphisms. This study aimed to investigate the relationship between HLA class II and CTLA +49 A/G polymorphisms associated with susceptibility to T1D and the number and characteristics of T_reg cells in children. Samples from 47 5-year-old children who participated in the All Babies in South-east Sweden (ABIS) follow-up study were grouped according to the presence of the T1D risk-associated HLA genotype (DQA1*0501-DQB1*0201, DQA1*0301-DQB1*0302) or neutral HLA genotypes. Lower percentages of CD4⁺ T cells (P = 0·03) and CD4⁺ CD25^high cells (P = 0·06) expressing intracellular CTLA-4 were detected in samples from children with CTLA-4 +49GG compared to children with the +49AA genotype. Similarly, lower percentages of CD4⁺ (P = 0·002) and CD4⁺ CD25^high (P = 0·002) cells expressing CTLA-4 were observed in children positive for HLA DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302 (P = 0·04 for CD4⁺ and P = 0·02 for CD4⁺ CD25^high) risk haplotypes when compared to children without these alleles. The percentage of CD25^high cells among CD4⁺ cells was correlated inversely with CTLA-4 mRNA expression in PBMC (r = -0·56, P = 0·03). Decreased levels of CTLA-4 in CD4⁺ and CD4⁺ CD25^high cells in individuals with CTLA-4 and HLA class II alleles associated with T1D may contribute to the initiation and/or progression of autoimmune response.

Keywords: CTLA-4; HLA; regulatory T cells

Document Type: Research article

DOI: 10.1111/j.1365-2249.2006.03106.x

Affiliations: 1: Division of Pediatrics and Diabetes Research Centre, Department of Molecular and Clinical Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden, and 2: JDRF Center for Prevention of Type 1 Diabetes in Finland and Department of Virology, University of Turku, Turku, Finland

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The association of CTLA-4 and HLA class II autoimmune risk genotype with regulatory T cell marker expression in 5-year-old children