Autosomal-dominant immune dysregulation syndrome in humans with CTLA4 mutations
By D. Schubert, C. Bode, R. Kenefeck, T. Hou, J. Wing, A. Kennedy, A. Bulashevska, B. Petersen, Alejandro A. Schäffer, Björn A. Grüning and 30 more. Nature Medicine, 2014
768 citations recorded by the source corpus.
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.
Subfields: Immunology
View Paper: https://www.semanticscholar.org/paper/b3503a5f8822f140f0c0cf29ce4ed1a36fd7d56d
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In Immunology
- Shimon Sakaguchi
- Atsushi Tanaka
- J. Bluestone
- Naganari Ohkura
- J. Wing
- K. Ichiyama
- N. Mikami
- Alexander Y. Rudensky
Citations in the corpus
- Regulatory T Cells and Human Disease. (2020, background): “Autoimmune/inflammatory disease also develops in family groups with heterologous mutations of CTLA-4, which hamper Treg expression of CTLA-4 in resting as well as activated states (117, 118).”
- CD28 costimulation: from mechanism to therapy (2016, background): “Patients with mutations presented with immunodeficiency and autoimmunity, with defects in both effector T cells and Treg cell function (Kuehn et al., 2014; Schubert et al., 2014).”