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Cited by 832

The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.

Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations

Open access
Schubert, Desirée, Bode, Claudia, Kenefeck, Rupert, Hou, Tie Zheng, Wing, James B, Kennedy, Alan, Bulashevska, Alla, Petersen, Britt-Sabina, Schäffer, Alejandro A, Grüning, Björn A, Unger, Susanne, Frede, Natalie, Baumann, Ulrich, Witte, Torsten, Schmidt, Reinhold E, Dueckers, Gregor, Niehues, Tim, Seneviratne, Suranjith, Kanariou, Maria, Speckmann, Carsten, Ehl, Stephan, Rensing-Ehl, Anne, Warnatz, Klaus, Rakhmanov, Mirzokhid, Thimme, Robert, Hasselblatt, Peter, Emmerich, Florian, Cathomen, Toni, Backofen, Rolf, Fisch, Paul, Seidl, Maximilian, May, Annette, Schmitt-Graeff, Annette, Ikemizu, Shinji, Salzer, Ulrich, Franke, Andre, Sakaguchi, Shimon, Walker, Lucy S K, Sansom, David M, Grimbacher, Bodo·2014·Nature Medicine
DOI 10.1038/nm.3746
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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.

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Authors
Schubert, D., Bode, C., Kenefeck, R., Hou, T. Z., Wing, J. B., Kennedy, A., Bulashevska, A., Petersen, B.-S., Schäffer, A. A., Grüning, B. A., Unger, S., Frede, N., Baumann, U., Witte, T., Schmidt, R. E., Dueckers, G., Niehues, T., Seneviratne, S., Kanariou, M., Speckmann, C., Ehl, S., Rensing-Ehl, A., Warnatz, K., Rakhmanov, M., Thimme, R., Hasselblatt, P., Emmerich, F., Cathomen, T., Backofen, R., Fisch, P., Seidl, M., May, A., Schmitt-Graeff, A., Ikemizu, S., Salzer, U., Franke, A., Sakaguchi, S., Walker, L. S. K., Sansom, D. M., & Grimbacher, B.
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2014-10-20
Volume
20
Issue
12
Pages
1410-1416
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.3746
OpenAlex
W1967067685
Cited by
832
References
10
FWCI
28.53
Type
journal article
Language
en
Open access
green

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