2. Academic Validation
  3. Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency

Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency

  • J Exp Med. 2017 Jan;214(1):91-106. doi: 10.1084/jem.20160849.
Hassan Abolhassani 1 2,  Emily S J Edwards 3 4,  Aydan Ikinciogullari 5,  Huie Jing 6 7,  Stephan Borte 8,  Marcus Buggert 9 10,  Likun Du 1,  Mami Matsuda-Lennikov 7 11,  Rosa Romano 1,  Rozina Caridha 1,  Sangeeta Bade 6 7,  Yu Zhang 6 7,  Juliet Frederiksen 12,  Mingyan Fang 1,  Sevgi Kostel Bal 5,  Sule Haskologlu 5,  Figen Dogu 5,  Nurdan Tacyildiz 13,  Helen F Matthews 6 7 11,  Joshua J McElwee 14,  Emma Gostick 15,  David A Price 16 15,  Umaimainthan Palendira 17,  Asghar Aghamohammadi 2 18,  Bertrand Boisson 19 20 21,  Nima Rezaei 2 18,  Annika C Karlsson 9,  Michael J Lenardo 7 11,  Jean-Laurent Casanova 19 20 22 21 23,  Lennart Hammarström 1,  Stuart G Tangye 24 4,  Helen C Su 25 7,  Qiang Pan-Hammarström 26
Affiliations

Affiliations

  • 1 Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, SE1418 Stockholm, Sweden.
  • 2 Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, 14149 Tehran, Iran.
  • 3 Immunology Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
  • 4 St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst NSW 2010, Australia.
  • 5 Department of Pediatric Immunology and Allergy, Ankara University Medical School, 06100 Dikimevi-Ankara, Turkey.
  • 6 Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
  • 7 Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
  • 8 ImmunoDeficiency Center Leipzig, Hospital St. Georg Leipzig, D-04129 Leipzig, Germany.
  • 9 Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, SE1418 Stockholm, Sweden.
  • 10 Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104.
  • 11 Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
  • 12 Department of Systems Biology, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.
  • 13 Department of Pediatric Hematology and Oncology, Ankara University Medical School, 06100 Dikimevi-Ankara, Turkey.
  • 14 Merck Research Laboratories, Merck & Co., Boston, MA 02115.
  • 15 Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, UK.
  • 16 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
  • 17 Centenary Institute, University of Sydney, Newtown NSW 2042, Australia.
  • 18 Primary Immunodeficiency Diseases Network, Universal Scientific Education and Research Network, 14149 Tehran, Iran.
  • 19 St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065.
  • 20 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.
  • 21 Paris Descartes University, Imagine Institute, 75015 Paris, France.
  • 22 Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France.
  • 23 Howard Hughes Medical Institute, New York, NY 10065.
  • 24 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.
  • 25 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.
  • 26 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.
PMID: 28011864 DOI: 10.1084/jem.20160849
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.

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