Journal
THYROID
Volume 13, Issue 12, Pages 1083-1089Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/10507250360731479
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Funding
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK027384] Funding Source: NIH RePORTER
- NIDDK NIH HHS [2-R01-DK27384-18A1] Funding Source: Medline
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Graves' disease (GD) is thought to be an autoimmune disease with a strong genetic component. Candidate genes include human leukocyte antigen (HLA) class 11 genes and CTLA-4. The CTLA-4 gene has a variable length AT-repeat polymorphism in the 3'-untranslated region. We previously found that the AT-repeat of 104 by or longer was associated with GD. In this study, we categorized patients with GD and normal controls (NC) by genotyping the CTLA-4 AT-repeat and investigated the function of CTLA-4. Peripheral blood mononuclear cells (PBMC) and DNA were prepared from adult Caucasians (NC = 34, GD = 37). Genotypes of the AT-repeat polymorphism were divided into three groups according to their alleles. We related the CTLA-4 polymorphism in each genotype to augmentation of T-cell proliferation induced by a soluble anti-CTLA-4 antibody during incubation with irradiated Epstein-Barr virus (EBV)-transformed B cells. Proliferation of T cells from subjects with the 86/86 by (shorter) allele was less than T cells from patients with longer alleles. The length of the AT-repeat allele correlated inversely with augmentation of proliferation after CTLA-4 blockade in subjects with GD. The CTLA-4 AT-repeat polymorphism affects the inhibitory function of CTLA-4. The long AT-repeat allele is associated with reduced control of T-cell proliferation and thus contributes to the pathogenesis of GD.
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