{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T02:43:56Z","timestamp":1793933036070,"version":"4.8.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2000,12,1]],"date-time":"2000-12-01T00:00:00Z","timestamp":975628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2000,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2019 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\u2019s 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 34.9% 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 with 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 with reduced control of T cell proliferation and thus contributes to the pathogenesis of GD and presumably of other autoimmune diseases.<\/jats:p>","DOI":"10.4049\/jimmunol.165.11.6606","type":"journal-article","created":{"date-parts":[[2014,4,21]],"date-time":"2014-04-21T22:44:50Z","timestamp":1398120290000},"page":"6606-6611","source":"Crossref","is-referenced-by-count":404,"title":["CTLA-4 Gene Polymorphism at Position 49 in Exon 1 Reduces the Inhibitory Function of CTLA-4 and Contributes to the Pathogenesis of Graves\u2019 Disease"],"prefix":"10.1093","volume":"165","author":[{"given":"Tsuyoshi","family":"Kouki","sequence":"first","affiliation":[{"name":"Thyroid Study Unit, Department of Medicine, University of Chicago , Chicago, IL 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshikuni","family":"Sawai","sequence":"additional","affiliation":[{"name":"Fujita Health University , Aichi ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyprian A","family":"Gardine","sequence":"additional","affiliation":[{"name":"Thyroid Study Unit, Department of Medicine, University of Chicago , Chicago, IL 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Elena","family":"Fisfalen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Chicago , Chicago, IL 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Luisa","family":"Alegre","sequence":"additional","affiliation":[{"name":"Committee on Immunology, University of Chicago , Chicago, IL 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie J","family":"DeGroot","sequence":"additional","affiliation":[{"name":"Thyroid Study Unit, Department of Medicine, University of Chicago , Chicago, IL 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2000,12,1]]},"reference":[{"key":"2026020213093303400_R1","first-page":"27","volume-title":"Immunol. 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