title: CTLA-4 and autoimmunity: new insights into the dual regulator of tolerance.
abstract: Cytotoxic T-Lymphocye Antigen 4 (CTLA-4) or CD152 is an inhibitory molecule that plays a critical role in maintenance of tolerance to self-antigens. CTLA-4 is structurally as well as functionally related to CD28, since it shares 31% of homology and binds the B7 family molecules CD80 and CD86 with higher affinity. Nevertheless, CTLA-4 has opposing effects on T cell activation and current evidence shows that its inhibitory role goes beyond the ligand-binding interaction. CTLA-4 competes with CD28 in binding to B7, interacts within the immunological synapsis elements and with clathrin adaptor proteins and tyrosine phosphatases through its cytoplasmic domain to regulate cell trafficking and to set the activation threshold within T cells. Moreover, we have learned from the knock out model that CTLA-4 plays a key role in regulatory T cells and in central tolerance. Because of its importance in maintenance of peripheral tolerance, CTLA-4 has been implicated in several autoimmune diseases, such as systemic lupus erythematosus. Multiple single-nucleotide polymorphisms have been located to human Ctla-4 gene, and their association with autoimmune disease is still a matter of controversy. Despite the promising results of abatacept or CTLA-4-Ig in rheumatoid arthritis and murine lupus nephritis, more clinical randomized trials and standardization of outcomes are needed to prove its efficacy and safety in human lupus nephritis.
authors.affiliation: Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Tlalpan 14000, Mexico City, Mexico.
authors.forename: Jorge
authors.initials: J
authors.lastname: Romo-Tena
authors.forename: Diana
authors.initials: D
authors.lastname: Gómez-Martín
authors.forename: Jorge
authors.initials: J
authors.lastname: Alcocer-Varela
mesh_terms: D000069594:Abatacept; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D018796:Immunoconjugates / Q000627:therapeutic use; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008213:Lymphocyte Activation
chemical_list: D001324:Autoantigens; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D000069594:Abatacept
keywords: Abatacept; Autoimmunity; CTLA-4; Polymorphisms; Systemic lupus erythematosus