title: Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.
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.
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Kuehn
authors.affiliation: Laboratory of Cell Biology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Ouyang
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.|NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: Bernice
authors.initials: B
authors.lastname: Lo
authors.affiliation: Immunology and Immunodeficiency Group, Immunology Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.|St. Vincent's Clinical School Faculty of Medicine, University of New South Wales, Sydney, NSW 2010, Australia.
authors.forename: Elissa K
authors.initials: EK
authors.lastname: Deenick
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Niemela
authors.affiliation: Immunology and Immunodeficiency Group, Immunology Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: Danielle T
authors.initials: DT
authors.lastname: Avery
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Schickel
authors.affiliation: Department of Pediatrics, University of Texas Medical School, Houston, TX 77030, USA.
authors.forename: Dat Q
authors.initials: DQ
authors.lastname: Tran
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stoddard
authors.affiliation: NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.|Immunological Diseases Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Cell Biology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Frucht
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Dumitriu
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Scheinberg
authors.affiliation: Radiology and Imaging and Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Les R
authors.initials: LR
authors.lastname: Folio
authors.affiliation: Clinical Research Directorate, Clinical Monitoring Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Cathleen A
authors.initials: CA
authors.lastname: Frein
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.|NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Price
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Koh
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA.
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Seroogy
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, WI 53706, USA.|Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Huttenlocher
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.|NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: V Koneti
authors.initials: VK
authors.lastname: Rao
authors.affiliation: NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.|Immunological Diseases Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Su
authors.affiliation: Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kleiner
authors.affiliation: Division of Immunology and Manton Center for Orphan Disease Research, Children's Hospital, Harvard Medical School, Boston, MA 10217, USA.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: Yajesh
authors.initials: Y
authors.lastname: Rampertaap
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Olivier
authors.affiliation: Merck Research Laboratories, Merck & Co., Boston, MA 02130, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: McElwee
authors.affiliation: Merck Research Laboratories, Merck & Co., Boston, MA 02130, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Hughes
authors.affiliation: Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.affiliation: Instituto de Medicina Integral Prof. Fernando Figueira-IMIP, 50070 Recife-PE, Brazil.
authors.forename: Joao B
authors.initials: JB
authors.lastname: Oliveira
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.affiliation: NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.|Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.|NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
authors.affiliation: Immunology and Immunodeficiency Group, Immunology Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.|St. Vincent's Clinical School Faculty of Medicine, University of New South Wales, Sydney, NSW 2010, Australia.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
mesh_terms: D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D018095:Germ-Line Mutation; D057895:Haploinsufficiency; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D007109:Immunity / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010375:Pedigree; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D055815:Young Adult
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors