Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

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Science  11 Sep 2014:
DOI: 10.1126/science.1255904

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Cytotoxic T lymphocyte antigen-4 (CTLA-4, CD152, OMIM: 123890) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects from four unrelated families suffering from severe immune dysregulation. While Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3+ regulatory T (Treg) cells, hyperactivation of effector T cells and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21lo B cells and accumulation of B cells in non-lymphoid organs. Inherited human CTLA-4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.

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