title: Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency.
abstract: In this study, we describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus (EBV)-related diseases. Three patients presented with EBV-associated Hodgkin's lymphoma and hypogammaglobulinemia; one also had severe varicella infection. The fourth had viral encephalitis during infancy. Homozygous frameshift or in-frame deletions in CD70 in these patients abolished either CD70 surface expression or binding to its cognate receptor CD27. Blood lymphocyte numbers were normal, but the proportions of memory B cells and EBV-specific effector memory CD8+T cells were reduced. Furthermore, although T cell proliferation was normal, in vitro-generated EBV-specific cytotoxic T cell activity was reduced because of CD70 deficiency. This reflected impaired activation by, rather than effects during killing of, EBV-transformed B cells. Notably, expression of 2B4 and NKG2D, receptors implicated in controlling EBV infection, on memory CD8+T cells from CD70-deficient individuals was reduced, consistent with their impaired killing of EBV-infected cells. Thus, autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of inherited CD27 deficiency. Overall, human CD70-CD27 interactions therefore play a nonredundant role in T and B cell-mediated immunity, especially for protection against EBV and humoral immunity.
authors.affiliation: Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, SE1418 Stockholm, Sweden.|Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, 14149 Tehran, Iran.
authors.forename: Hassan
authors.identifier: 0000-0002-4838-0407
authors.initials: H
authors.lastname: Abolhassani
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst NSW 2010, Australia.
authors.forename: Emily S J
authors.identifier: 0000-0002-0240-4370
authors.initials: ES
authors.lastname: Edwards
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University Medical School, 06100 Dikimevi-Ankara, Turkey.
authors.forename: Aydan
authors.initials: A
authors.lastname: Ikinciogullari
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.|Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Huie
authors.initials: H
authors.lastname: Jing
authors.affiliation: ImmunoDeficiency Center Leipzig, Hospital St. Georg Leipzig, D-04129 Leipzig, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Borte
authors.affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, SE1418 Stockholm, Sweden.|Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Marcus
authors.identifier: 0000-0003-0633-1719
authors.initials: M
authors.lastname: Buggert
authors.affiliation: Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, SE1418 Stockholm, Sweden.
authors.forename: Likun
authors.initials: L
authors.lastname: Du
authors.affiliation: Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.|Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Mami
authors.initials: M
authors.lastname: Matsuda-Lennikov
authors.affiliation: Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, SE1418 Stockholm, Sweden.
authors.forename: Rosa
authors.initials: R
authors.lastname: Romano
authors.affiliation: Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, SE1418 Stockholm, Sweden.
authors.forename: Rozina
authors.identifier: 0000-0002-3663-6575
authors.initials: R
authors.lastname: Caridha
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.|Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Bade
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.|Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.
authors.forename: Juliet
authors.initials: J
authors.lastname: Frederiksen
authors.affiliation: Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, SE1418 Stockholm, Sweden.
authors.forename: Mingyan
authors.identifier: 0000-0001-7185-6445
authors.initials: M
authors.lastname: Fang
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University Medical School, 06100 Dikimevi-Ankara, Turkey.
authors.forename: Sevgi Kostel
authors.identifier: 0000-0002-3718-5323
authors.initials: SK
authors.lastname: Bal
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University Medical School, 06100 Dikimevi-Ankara, Turkey.
authors.forename: Sule
authors.identifier: 0000-0002-2668-0441
authors.initials: S
authors.lastname: Haskologlu
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University Medical School, 06100 Dikimevi-Ankara, Turkey.
authors.forename: Figen
authors.identifier: 0000-0002-7869-4941
authors.initials: F
authors.lastname: Dogu
authors.affiliation: Department of Pediatric Hematology and Oncology, Ankara University Medical School, 06100 Dikimevi-Ankara, Turkey.
authors.forename: Nurdan
authors.initials: N
authors.lastname: Tacyildiz
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.|Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.|Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Helen F
authors.initials: HF
authors.lastname: Matthews
authors.affiliation: Merck Research Laboratories, Merck & Co., Boston, MA 02115.
authors.forename: Joshua J
authors.identifier: 0000-0002-4888-7152
authors.initials: JJ
authors.lastname: McElwee
authors.affiliation: Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.|Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Centenary Institute, University of Sydney, Newtown NSW 2042, Australia.
authors.forename: Umaimainthan
authors.identifier: 0000-0002-1113-3306
authors.initials: U
authors.lastname: Palendira
authors.affiliation: Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, 14149 Tehran, Iran.|Primary Immunodeficiency Diseases Network, Universal Scientific Education and Research Network, 14149 Tehran, Iran.
authors.forename: Asghar
authors.initials: A
authors.lastname: Aghamohammadi
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065.|Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale U.1163, Necker Hospital for Sick Children, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.affiliation: Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, 14149 Tehran, Iran.|Primary Immunodeficiency Diseases Network, Universal Scientific Education and Research Network, 14149 Tehran, Iran.
authors.forename: Nima
authors.identifier: 0000-0002-3836-1827
authors.initials: N
authors.lastname: Rezaei
authors.affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, SE1418 Stockholm, Sweden.
authors.forename: Annika C
authors.initials: AC
authors.lastname: Karlsson
authors.affiliation: Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.|Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065.|Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale U.1163, Necker Hospital for Sick Children, 75015 Paris, France.|Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.|Howard Hughes Medical Institute, New York, NY 10065.
authors.forename: Jean-Laurent
authors.identifier: 0000-0002-7782-4169
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, SE1418 Stockholm, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia Qiang.Pan-Hammarstrom@ki.se s.tangye@garvan.org.au hsu@niaid.nih.gov.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst NSW 2010, Australia.
authors.forename: Stuart G
authors.identifier: 0000-0002-5360-5180
authors.initials: SG
authors.lastname: Tangye
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Qiang.Pan-Hammarstrom@ki.se s.tangye@garvan.org.au hsu@niaid.nih.gov.|Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Helen C
authors.identifier: 0000-0002-5582-9110
authors.initials: HC
authors.lastname: Su
authors.affiliation: Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, SE1418 Stockholm, Sweden Qiang.Pan-Hammarstrom@ki.se s.tangye@garvan.org.au hsu@niaid.nih.gov.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pan-Hammarström
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology*; D053282:CD27 Ligand / Q000172:deficiency* / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002648:Child; D003602:Cytotoxicity, Immunologic; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology; D006689:Hodgkin Disease / Q000209:etiology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications*; D007156:Immunologic Memory; D008297:Male; D009154:Mutation; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology
chemical_list: D053282:CD27 Ligand; C505771:CD70 protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7