CTLA-4 AT-repeat polymorphism reduces the inhibitory function of CTLA-4 in Graves' disease.
Graves' disease (GD) is thought to be an autoimmune disease with a strong genetic component. Candidate genes include human leukocyte antigen (HLA) class II 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 bp 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 bp (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.
Takara
Masaki
M
Thyroid Study Unit/MC3090, Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
Kouki
Tsuyoshi
T
DeGroot
Leslie J
LJ
D000225:Adenine; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D002455:Cell Division; D002472:Cell Transformation, Viral; D006111:Graves Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006147:Guanine; D004854:Herpesvirus 4, Human; D006801:Humans; D009000:Monocytes / Q000473:pathology; D011110:Polymorphism, Genetic; D012091:Repetitive Sequences, Nucleic Acid; D013601:T-Lymphocytes / Q000473:pathology; D013941:Thymine
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006147:Guanine; D000225:Adenine; D013941:Thymine