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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.

Type Journal
ISBN 1540-9538 (Electronic) 0022-1007 (Linking)
Authors Abolhassani, H.; Edwards, E. S.; Ikinciogullari, A.; Jing, H.; Borte, S.; Buggert, M.; Du, L.; Matsuda-Lennikov, M.; Romano, R.; Caridha, R.; Bade, S.; Zhang, Y.; Frederiksen, J.; Fang, M.; Bal, S. K.; Haskologlu, S.; Dogu, F.; Tacyildiz, N.; Matthews, H. F.; McElwee, J. J.; Gostick, E.; Price, D. A.; Palendira, U.; Aghamohammadi, A.; Boisson, B.; Rezaei, N.; Karlsson, A. C.; Lenardo, M. J.; Casanova, J. L.; Hammarstrom, L.; Tangye, S. G.; Su, H. C.; Pan-Hammarstrom, Q.
Responsible Garvan Author Dr Emily Edwards
Publisher Name JOURNAL OF EXPERIMENTAL MEDICINE
Published Date 2017-01-31
Published Volume 214
Published Issue 1
Published Pages 91-106
Status Published in-print
DOI 10.1084/jem.20160849
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/28011864
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/14171