Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.

Desirée Schubert, Claudia Bode, Rupert Kenefeck, Tie Zheng Hou, James B Wing, Alan Kennedy, Alla Bulashevska, Britt-Sabina Petersen, Alejandro A Schäffer, Björn A Grüning, Susanne Unger, Natalie Frede, Ulrich Baumann, Torsten Witte, Reinhold E Schmidt, Gregor Dueckers, Tim Niehues, Suranjith Seneviratne, Maria Kanariou, Carsten Speckmann, Stephan Ehl, Anne Rensing-Ehl, Klaus Warnatz, Mirzokhid Rakhmanov, Robert Thimme, Peter Hasselblatt, Florian Emmerich, Toni Cathomen, Rolf Backofen, Paul Fisch, Maximilian Seidl, Annette May, Annette Schmitt-Graeff, Shinji Ikemizu, Ulrich Salzer, Andre Franke, Shimon Sakaguchi, Lucy S K Walker, David M Sansom, Bodo Grimbacher
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Nature medicine
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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.