TY - JOUR
T1 - Combined immunodeficiency and Epstein-Barr virus- induced B cell malignancy in humans with inherited CD70 deficiency
AU - Abolhassani, Hassan
AU - Edwards, Emily S.J.
AU - Ikinciogullari, Aydan
AU - Jing, Huie
AU - Borte, Stephan
AU - Buggert, Marcus
AU - Du, Likun
AU - Matsuda-Lennikov, Mami
AU - Romano, Rosa
AU - Caridha, Rozina
AU - Bade, Sangeeta
AU - Zhang, Yu
AU - Frederiksen, Juliet
AU - Fang, Mingyan
AU - Bal, Sevgi Kostel
AU - Haskologlu, Sule
AU - Dogu, Figen
AU - Tacyildiz, Nurdan
AU - Matthews, Helen F.
AU - McElwee, Joshua J.
AU - Gostick, Emma
AU - Price, David A.
AU - Palendira, Umaimainthan
AU - Aghamohammadi, Asghar
AU - Boisson, Bertrand
AU - Rezaei, Nima
AU - Karlsson, Annika C.
AU - Lenardo, Michael J.
AU - Casanova, Jean-Laurent
AU - Hammarström, Lennart
AU - Tangye, Stuart G.
AU - Su, Helen C.
AU - Pan-Hammarström, Qiang
N1 - This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/).
After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2017/1
Y1 - 2017/1
N2 - 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 EBVassociated 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.
AB - 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 EBVassociated 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.
UR - http://www.scopus.com/inward/record.url?scp=85008512074&partnerID=8YFLogxK
U2 - 10.1084/jem.20160849
DO - 10.1084/jem.20160849
M3 - Article
C2 - 28011864
AN - SCOPUS:85008512074
SN - 0022-1007
VL - 214
SP - 91
EP - 106
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
ER -