The Emerging Role of CTLA-4 as an Immune Attenuator

Based on the striking phenotype of CTLA-4–deficient animals, the role of CTLA-4 in various human autoimmune diseases has been investigated using a candidate gene approach. Initial linkage between CTLA-4 and autoimmune disease was made in a case/control study involving patients with Grave's disease. By analyzing CTLA-4 alleles identified through variations in an AT repeat in the 3′ untranslated region, Yanagawa et al. 1995xCTLA-4 gene polymorphism associated with Graves' disease in a caucasian population. Yanagawa, T, Hidaka, Y, Guimaraes, V, Soliman, M, and DeGroot, L.J. J. Clin. Endocrinol. Metab. 1995; 80: 41–45Crossref | PubMedSee all ReferencesYanagawa et al. 1995 demonstrated that CTLA-4 or a closely linked gene could be associated with an increased risk of Grave's disease. Subsequent studies have verified and extended these observations. Using an A/G polymorphism within CTLA-4 exon 1, Donner et al. 1997xCTLA-4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus. Donner, H, Rau, H, Walfish, P.G, Braun, J, Siegmund, T, Finke, R, Herwig, J, Usadel, K.H, and Badenhoop, K. J. Clin. Endocrinol. Metab. 1997; 82: 143–146Crossref | PubMed | Scopus (385)See all ReferencesDonner et al. 1997 were able to confirm a statistical association between Grave's disease and the CTLA-4 polymorphism. Furthermore, these studies demonstrated that CTLA-4 contributes to the risk of Grave's disease independently of human leukocyte antigen status or sex.An association between CTLA-4 and autoimmune diabetes mellitus has also been reported (26xThe CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Nistic, L, Buzzetti, R, Pritchard, L.E, Van der Auwera, B, Giovannini, C, Bosi, E, Larrad, M.T.M, Rios, M.S, Chow, C.C, Cockram, C.S et al. Hum. Mol. Genet. 1996; 5: 1075–1080Crossref | PubMed | Scopus (584)See all References, 32xPanning for gold (genome-wide scanning for linkage in type 1 diabetes) . Todd, J.A and Farrall, M. Hum. Mol. Genet. 1996; 5: 1443–1448PubMedSee all References, 7xCTLA-4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus. Donner, H, Rau, H, Walfish, P.G, Braun, J, Siegmund, T, Finke, R, Herwig, J, Usadel, K.H, and Badenhoop, K. J. Clin. Endocrinol. Metab. 1997; 82: 143–146Crossref | PubMed | Scopus (385)See all References). The same polymorphisms found in Grave's disease were found to be associated with diabetes. Although it remains possible that the involved gene may be a CTLA-4–linked gene such as CD28, the number of independent confirmations that the CTLA-4 gene is associated with these two autoimmune diseases makes it likely that certain CTLA-4 alleles may be risk factors for this disease. Consistent with this hypothesis, the linkage of autoimmune diseases to a CTLA-4 allele with a long AT repeat in the 3′ untranslated region is intriguing. Previous studies have demonstrated that such AT-rich tracks contribute to mRNA instability. If the size of the CTLA-4 AT tract limited the accumulation of CTLA-4 mRNA, the resulting decrease in CTLA-4 expression might account for the observed increase in the risk of autoimmune disease.Based on the strong association with Grave's disease and diabetes mellitus, the linkage of CTLA-4 to additional autoimmune diseases should be explored. However, no matter how extensive the involvement of CTLA-4 in the pathogenesis of human autoimmune diseases, it is clear from the present data that CTLA-4 can play a regulatory role in terminating peripheral immune responses. Disruption of the normal physiologic control provided by the CTLA-4 receptor can contribute to the pathogenesis of autoimmune disease, as demonstrated both by gene knockout studies in mice and by genetic linkage analysis in human autoimmune disorders.‡To whom correspondence should be addressed (e-mail: craig@knapp.uchicago.edu).