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Nat Med. 2014 Dec;20(12):1410-1416. doi: 10.1038/nm.3746. Epub 2014 Oct 20.

Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.

Author information

1
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
2
Spemann Graduate School of Biology and Medicine and Faculty of Biology, Freiburg University, Freiburg, Germany.
3
UCL Institute of Immunity and Transplantation, Royal Free Campus, London, UK.
4
WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
5
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
6
National Library of Medicine, National Institutes of Health, Bethesda, USA.
7
Department of Computer Science, University of Freiburg, Freiburg, Germany.
8
Department of Pediatric Pulmonology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
9
Children's Hospital Krefeld, Germany.
10
Department of Immunology and Histocompatibility, "Aghia Sophia" Children's Hospital, Athens, Greece.
11
Clinic for Internal Medicine 2, University Medical Center Freiburg, Freiburg, Germany.
12
Institute for Cell and Gene Therapy, University Medical Center Freiburg, Freiburg, Germany.
13
Department of Pathology, University Medical Center Freiburg, Freiburg, Germany.
14
Division of structural biology, Kumamoto University, Kumamoto, Japan.
#
Contributed equally

Abstract

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.

PMID:
25329329
PMCID:
PMC4668597
DOI:
10.1038/nm.3746
[Indexed for MEDLINE]
Free PMC Article

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