Editor's ChoiceIMMUNODEFICIENCY

It’s all in the family

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Science Immunology  03 Mar 2017:
Vol. 2, Issue 9, eaan0291
DOI: 10.1126/sciimmunol.aan0291

Abstract

CD70-deficiency causes primary immunodeficiency and susceptibility to EBV-driven lymphoma.

Understanding the genetic basis of primary immunodeficiency has provided great insights into fundamental mechanisms of human immune regulation. Although often associated with broad deficits in immune function, some primary immunodeficiencies can also be characterized by specific immune deficits, as exemplified by the susceptibility to Epstein-Barr virus (EBV) infection in patients with X-linked lymphoproliferative syndrome.

Abolhassani et al. report findings from four patients in two unrelated consanguineous families who presented at a young age with susceptibility to recurrent viral infections, including severe varicella pneumonia, viral encephalitis, and EBV infection, with one patient developing a Behҫet-like syndrome. Remarkably, three of the four affected patients developed EBV-positive classical Hodgkin lymphoma (mixed cellularity type).

Upon immunologic evaluation, all four patients had evidence of hypogammaglobulinemia and/or impaired antibody responses to vaccination. Although overt abnormalities in total lymphocyte counts were not seen, affected patients had evidence of impaired immune memory, including decreased numbers of memory T and B cells, reduced expression of the activating receptors CD244 and NKG2D on CD8-positive T effector memory (TEM) cells, decreased numbers of EBV-specific CD8-positive TEM, and decreased cytotoxicity against EBV-infected B cells.

Using next-generation sequencing, the authors found a homozygous frameshift mutation (c.250delT, p.S84Pfs27X) in exon 3 of CD70 in two affected siblings from one family, which led to complete loss of CD70 protein in the patients' B cells. In the second family, a homozygous in-frame deletion (c.555_557delCTT, p.F186del) in exon 3 of CD70 was detected in both affected siblings. Although this variant did not affect total CD70 protein expression, it did lead to impaired binding with its receptor, CD27.

These findings further implicate the CD27-CD70 costimulatory axis as a critical regulator of human immune function and are particularly timely in light of the growing interest in targeting CD27 and CD70 therapeutically in the context of cancer and autoimmune disease. Although the full spectrum of immunologic effects caused by these therapies remain to be defined, the risk of infection and EBV-driven pathology should be given due consideration when designing appropriate monitoring strategies for clinical trials of novel agents that disrupt CD27-CD70 interactions.

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