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

Abolhassani, Hassan, Edwards, Emily S.J., Ikinciogullari, Aydan, Jing, Huie, Borte, Stephan, Buggert, Marcus, Du, Likun, Matsuda-Lennikov, Mami, Romano, Rosa, Caridha, Rozina, Bade, Sangeeta, Zhang, Yu, Frederiksen, Juliet, Fang, Mingyan, Bal, Sevgi Kostel, Haskologlu, Sule, Dogu, Figen, Tacyildiz, Nurdan, Matthews, Helen F., McElwee, Joshua J., Gostick, Emma, Price, David, Palendira, Umaimainthan, Aghamohammadi, Asghar, Boisson, Bertrand, Rezaei, Nima, Karlsson, Annika C., Lenardo, Michael J., Casanova, Jean-Laurent, Hammarström, Lennart, Tangye, Stuart G., Su, Helen C. and Pan-Hammarström, Qiang 2017. Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency. Journal of Experimental Medicine 214 (1) , p. 91. 10.1084/jem.20160849

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Rockefeller University Press
ISSN: 0022-1007
Date of First Compliant Deposit: 31 January 2017
Date of Acceptance: 7 December 2016
Last Modified: 20 Mar 2018 14:22

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