CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves' disease

Activation of T cells requires at least two signals transduced by the Ag-sp ecific TCR and a costimulatory ligand such as CD28, CTLA-4, expressed on ac tivated T cells, binds to B7 present on APCs and functions as a negative re gulator of T cell activation. Our laboratory previously reported the associ ation of Graves' disease (GD) with a specific CTLA-4 gene polymorphism. In theory, reduced expression or function of CTLA-4 might augment autoimmunity , In the present study, we categorized autoimmune thyroid disease patients and normal controls (NC) by genotyping a CTLA-4 exon 1 polymorphism and inv estigated the function of CTLA-4 in all subjects. PBMCs and DNA were prepar ed from GD (n = 45), Hashimoto's thyroiditis (HT) (n = 18), and NC (n = 43) , There were more GD patients with the G/G or A/G alleles (82.2% vs 65.1% i n NC), and significantly fewer patients with the A/A allele (17.8% vs 31.9% in NC). In the presence of soluble blocking anti-human CTLA-4 mAb, T cell proliferation following incubation with allogeneic EBV-transformed B cells was augmented in a dose dependent manner. Augmentation induced by CTLA-4 mA b was similar in GD and NC (GD, HT, NC = 156%, 164%, 175%, respectively). W e related CTLA-4 polymorphism to mAb augmentation of T cell proliferation i n each subgroup (GD, HT, NC), Although PBMC from individuals with the G/G a lleles showed 132% augmentation, those,vith the A/A alleles showed 193% aug mentation (p = 0.019), CTLA-4 polymorphism affects the inhibitory function of CTLA-4 The G allele is associated,vith reduced control of T cell prolife ration and thus contributes to the pathogenesis of GD and presumably of oth er autoimmune diseases.