The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.
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We thank the patients and their relatives for their participation in this study. We thank F. Atschekzei, S. Kock, A. Gaa, S. Glatzel and M. Stenzel for technical assistance, and D. Comtesse, R. Weinert, R. Wieland, M. Schüler and N. Verma for their excellent and dedicated patient care. This research was funded by the Bundesministerium für Bildung und Forschung with the following grants: Integriertes Forschungs und Behandlungszentrum/Center for Chronic Immunodeficiencies 01EO1303, Systems Biology E:med/SysInflame: 012X1306F; the Deutsches Zentrum für Infektionsforschung #8000805-3 and in part by the Excellence Initiative of the German Research Foundation (GSC-4, Spemann Graduate School) and by the Intramural Research Program of the US National Institutes of Health, National Library of Medicine. We also thank the German Crohn's and Colitis Foundation for support of the exome sequencing and the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence “Inflammation at Interfaces.” B.A.G. is funded by the DFG CRC 992 Medical Epigenetics, L.S.K.W. by a UK Medical Research Council Senior Fellowship, T.Z.H. by the Wellcome Trust, R.K. by Diabetes UK, J.B.W. by a Japan Society for the Promotion of ScienceYoung Scientist B grant and S.S. by the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Japan Science and Technology Agency.
The authors declare no competing financial interests.
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Schubert, D., Bode, C., Kenefeck, R. et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med 20, 1410–1416 (2014). https://doi.org/10.1038/nm.3746
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