title: Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.
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.
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.|Spemann Graduate School of Biology and Medicine and Faculty of Biology, Freiburg University, Freiburg, Germany.
authors.forename: Desirée
authors.initials: D
authors.lastname: Schubert
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bode
authors.affiliation: UCL Institute of Immunity and Transplantation, Royal Free Campus, London, UK.
authors.forename: Rupert
authors.initials: R
authors.lastname: Kenefeck
authors.affiliation: UCL Institute of Immunity and Transplantation, Royal Free Campus, London, UK.
authors.forename: Tie Zheng
authors.initials: TZ
authors.lastname: Hou
authors.affiliation: WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: James B
authors.initials: JB
authors.lastname: Wing
authors.affiliation: UCL Institute of Immunity and Transplantation, Royal Free Campus, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Kennedy
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Alla
authors.initials: A
authors.lastname: Bulashevska
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Britt-Sabina
authors.initials: BS
authors.lastname: Petersen
authors.affiliation: National Library of Medicine, National Institutes of Health, Bethesda, USA.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: Department of Computer Science, University of Freiburg, Freiburg, Germany.
authors.forename: Björn A
authors.initials: BA
authors.lastname: Grüning
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Unger
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Frede
authors.affiliation: Department of Pediatric Pulmonology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baumann
authors.affiliation: Department of Pediatric Pulmonology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Witte
authors.affiliation: Department of Pediatric Pulmonology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Reinhold E
authors.initials: RE
authors.lastname: Schmidt
authors.affiliation: Children's Hospital Krefeld, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Dueckers
authors.affiliation: Children's Hospital Krefeld, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Niehues
authors.affiliation: UCL Institute of Immunity and Transplantation, Royal Free Campus, London, UK.
authors.forename: Suranjith
authors.initials: S
authors.lastname: Seneviratne
authors.affiliation: Department of Immunology and Histocompatibility, "Aghia Sophia" Children's Hospital, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Kanariou
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Speckmann
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Rensing-Ehl
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Mirzokhid
authors.initials: M
authors.lastname: Rakhmanov
authors.affiliation: Clinic for Internal Medicine 2, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.affiliation: Clinic for Internal Medicine 2, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hasselblatt
authors.affiliation: Institute for Cell and Gene Therapy, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Emmerich
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.|Institute for Cell and Gene Therapy, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Toni
authors.initials: T
authors.lastname: Cathomen
authors.affiliation: Department of Computer Science, University of Freiburg, Freiburg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Backofen
authors.affiliation: Department of Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Fisch
authors.affiliation: Department of Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Seidl
authors.affiliation: Department of Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: May
authors.affiliation: Department of Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Schmitt-Graeff
authors.affiliation: Division of structural biology, Kumamoto University, Kumamoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Ikemizu
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.affiliation: UCL Institute of Immunity and Transplantation, Royal Free Campus, London, UK.
authors.forename: Lucy S K
authors.initials: LSK
authors.lastname: Walker
authors.affiliation: UCL Institute of Immunity and Transplantation, Royal Free Campus, London, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Sansom
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
mesh_terms: D000293:Adolescent; D000328:Adult; D000361:Agammaglobulinemia / Q000235:genetics* / Q000276:immunology; D000744:Anemia, Hemolytic, Autoimmune / Q000235:genetics / Q000276:immunology; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D018122:B7-1 Antigen / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000276:immunology; D002648:Child; D018389:Codon, Nonsense; D004705:Endocytosis / Q000235:genetics / Q000276:immunology; D005091:Exons; D005260:Female; D006099:Granuloma / Q000235:genetics / Q000276:immunology; D006579:Heterozygote; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics; D017563:Lung Diseases, Interstitial / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000276:immunology; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000235:genetics / Q000276:immunology; D012008:Recurrence; D012141:Respiratory Tract Infections / Q000235:genetics / Q000276:immunology; D013577:Syndrome; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D055815:Young Adult
chemical_list: D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018389:Codon, Nonsense