期刊
NATURE MEDICINE
卷 20, 期 12, 页码 1410-1416出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3746
关键词
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资金
- Bundesministerium fur Bildung und Forschung, grant: Integriertes Forschungs und Behandlungszentrum/Center for Chronic Immunodeficiencies [01EO1303]
- Bildung und Forschung, grant Systems Biology E:med/SysInflame [012X1306F]
- Deutsches Zentrum fur Infelctionsforschung [8000805-3]
- Excellence Initiative of the German Research Foundation [GSC-4]
- Intramural Research Program of the US National Institutes of Health, National Library of Medicine
- DFG [CRC 992]
- UK Medical Research Council
- Wellcome Trust
- Diabetes UK
- Japan Society for the Promotion of ScienceYoung Scientist B grant
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Science and Technology Agency
- Biotechnology and Biological Sciences Research Council [BB/H013598/1, BB/H013598/2] Funding Source: researchfish
- Diabetes UK [12/0004477] Funding Source: researchfish
- Medical Research Council [G0802382] Funding Source: researchfish
- BBSRC [BB/H013598/2, BB/H013598/1] Funding Source: UKRI
- MRC [G0802382] Funding Source: UKRI
- Grants-in-Aid for Scientific Research [25440031, 25860356] Funding Source: KAKEN
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 (T-reg cells) in both patients and carriers with CTLA4 mutations. Whereas T-reg 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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