Immune dysregulation in human subjects with heterozygous germline mutations in <i>CTLA4</i>

Hye Sun Kuehn(National Institutes of Health Clinical Center), Weiming Ouyang(Center for Biologics Evaluation and Research), Bernice Lo(National Institute of Allergy and Infectious Diseases), Elissa K. Deenick(Garvan Institute of Medical Research), Julie E. Niemela(National Institutes of Health Clinical Center), Danielle T. Avery(Garvan Institute of Medical Research), Jean-Nicolas Schickel(Yale University), Dat Q. Tran(The University of Texas at Austin), Jennifer Stoddard(National Institutes of Health Clinical Center), Yu Zhang(National Institute of Allergy and Infectious Diseases), David M. Frucht(Center for Biologics Evaluation and Research), Bogdan Dumitriu(National Heart Lung and Blood Institute), Phillip Scheinberg(National Heart Lung and Blood Institute), Les Folio(National Institutes of Health Clinical Center), Cathleen Frein(Leidos (United States)), Susan Price(National Institute of Allergy and Infectious Diseases), Christopher Koh(National Institute of Diabetes and Digestive and Kidney Diseases), Theo Heller(National Institute of Diabetes and Digestive and Kidney Diseases), Christine M. Seroogy(University of Wisconsin–Madison), Anna Huttenlocher(University of Wisconsin–Madison), V. Koneti Rao(National Institute of Allergy and Infectious Diseases), Helen C. Su(National Institute of Allergy and Infectious Diseases), David E. Kleiner(National Cancer Institute), Luigi D. Notarangelo(Boston Children's Hospital), Yajesh Rampertaap(National Institute of Allergy and Infectious Diseases), Kenneth N. Olivier(National Institute of Allergy and Infectious Diseases), Joshua McElwee(Merck & Co., Inc., Rahway, NJ, USA (United States)), Jason D. Hughes(Merck & Co., Inc., Rahway, NJ, USA (United States)), Stefania Pittaluga(National Cancer Institute), João Bosco Oliveira(Instituto de Medicina Integral Professor Fernando Figueira), Eric Meffre(Yale University), Thomas A. Fleisher(National Institutes of Health Clinical Center), Steven M. Holland(National Institute of Allergy and Infectious Diseases), Michael J. Lenardo(National Institute of Allergy and Infectious Diseases), Stuart G. Tangye(Garvan Institute of Medical Research), Gülbû Uzel(National Institute of Allergy and Infectious Diseases)
Science
September 12, 2014
10.1126/science.1255904
Cited by 842

Abstract

Cytotoxic T lymphocyte antigen-4 (CTLA-4) 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 with severe immune dysregulation from four unrelated families. Whereas 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 CD21(lo) B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.

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