Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency PMID: 28011864

Target-related Cytokines

2026-09-23

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

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 [email protected] [email protected] [email protected].
25. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 [email protected] [email protected] [email protected].
26. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, SE1418 Stockholm, Sweden [email protected] [email protected] [email protected].

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.