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 ORCID: https://orcid.org/0000-0001-9416-2737, 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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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.

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:	05 May 2023 18:12
URI:	https://orca.cardiff.ac.uk/id/eprint/97895

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