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' disease.
abstract: 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 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.
authors.affiliation: Thyroid Study Unit, Department of Medicine, University of Chicago, Chicago, IL 60637. Fujita Health University, Aichi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kouki
authors.forename: Y
authors.initials: Y
authors.lastname: Sawai
authors.forename: C A
authors.initials: CA
authors.lastname: Gardine
authors.forename: M E
authors.initials: ME
authors.lastname: Fisfalen
authors.forename: M L
authors.initials: ML
authors.lastname: Alegre
authors.forename: L J
authors.initials: LJ
authors.lastname: DeGroot
mesh_terms: D000069594:Abatacept; D000225:Adenine; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000483:Alleles; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000235:genetics* / Q000276:immunology*; D005091:Exons / Q000235:genetics / Q000276:immunology*; D006111:Graves Disease / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D006147:Guanine; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011110:Polymorphism, Genetic / Q000276:immunology*; D012995:Solubility
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D006147:Guanine; D000069594:Abatacept; D000225:Adenine