期刊
JOURNAL OF IMMUNOLOGY
卷 165, 期 11, 页码 6606-6611出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.165.11.6606
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- NIDDK NIH HHS [5-F32-DK09612, 2-RO1-DK27384-18A1] Funding Source: Medline
Activation of T cells requires at least two signals transduced by the Ag-specific TCR and a costimulatory ligand such as CD28, CTLA-4, expressed on activated T cells, binds to B7 present on APCs and functions as a negative regulator of T cell activation. Our laboratory previously reported the association 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 investigated the function of CTLA-4 in all subjects. PBMCs and DNA were prepared 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% in 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 mAb was similar in GD and NC (GD, HT, NC = 156%, 164%, 175%, respectively). We related CTLA-4 polymorphism to mAb augmentation of T cell proliferation in each subgroup (GD, HT, NC), Although PBMC from individuals with the G/G alleles showed 132% augmentation, those,vith the A/A alleles showed 193% augmentation (p = 0.019), CTLA-4 polymorphism affects the inhibitory function of CTLA-4 The G allele is associated,vith reduced control of T cell proliferation and thus contributes to the pathogenesis of GD and presumably of other autoimmune diseases.
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