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The importance of CTLA‐4 polymorphism and human leukocyte antigen genotype for the induction of diabetes‐associated cytokine response in healthy school children
Author(s) -
Jonson CarlOscar,
Lernmark Åke,
Ludvigsson Johnny,
Rutledge Elizabeth A,
Hinkkanen Ari,
Faresjö Maria
Publication year - 2007
Publication title -
pediatric diabetes
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.678
H-Index - 75
eISSN - 1399-5448
pISSN - 1399-543X
DOI - 10.1111/j.1399-5448.2007.00245.x
Subject(s) - immunology , human leukocyte antigen , genotype , medicine , type 1 diabetes , antigen , haplotype , cytotoxic t cell , genetic predisposition , ctla 4 , immune system , t cell , disease , diabetes mellitus , biology , gene , endocrinology , genetics , in vitro
Background: Type 1 diabetes (T1D) is an autoimmune disease associated with the destruction of pancreatic β cells and genetically linked to human leukocyte antigen (HLA) class II DR3‐DQ2 and DR4‐DQ8 haplotypes. The +49A/G polymorphism of the immunoregulatory cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) gene is also associated with T1D. Genetic and environmental risk factors precede the onset of T1D, which is characterized by a T helper 1 cell‐dominating cytokine response to diabetes‐related autoantigens. Aim: To investigate immunological differences between healthy children with and without CTLA‐4 +49A/G and HLA genetic susceptibility for T1D. Study design: Young, 7–15 years of age, healthy subjects (n = 58) were investigated to test whether CTLA‐4 +49A/G genotype was associated with enzyme‐linked immunospot assay T‐cell responses to T1D‐related autoantigens. Because T1D is primarily HLA‐DQ associated, we stratified the healthy subjects by HLA genotypes associated with the disease. Results: Peptide of heat shock protein 60 induced a higher interferon‐γ (IFN‐γ) response in subjects with risk‐associated CTLA‐4 polymorphism (GG genotype) (p = 0.02) while glutamic acid decarboxylase 65‐induced interleukin‐4 (IL‐4) secretion was lower in GG genotype subjects (p = 0.02). Conclusion: The increased IFN‐γ response and lower IL‐4 response toward diabetes‐related autoantigens shown in CTLA‐4 +49 GG risk subjects show a possible mechanism for the association between CTLA‐4 and T1D.