When to suspect inborn errors of immunity in Epstein–Barr virus–related lymphoproliferative disorders

More than 95% of humans have been infected with Epstein-Barr virus (EBV) and develop anti-EBV IgG antibodies, conferring immunity. However, among specific populations, EBV may induce a range of B-cell lymphoproliferative disorders (LPDs). EBV may also contribute to T-cell and natural killer (NK)-cell lymphoproliferation. The immune system is essential to prevent infection and development of cancer. Inborn errors of immunity (IEIs) are a heterogenous group of more than 450 genetic disorders predisposing to severe and/or recurrent infection, autoimmunity, autoinflammation, or early-onset/severe neoplasia or lymphoproliferation. Monogenic disorders of T-cell and B-cell signalling are classic IEIs that predispose to EBV-associated LPDs.We aimed to outline the various clinical manifestations of EBV-associated LPDs and the underlying IEIs associated with such presentations and discuss the recommended management and therapeutic options pertaining to these disorders.We searched PubMed, Embase, and Web of Science Core Collection on 30 September 2021. Clinical studies, systematic reviews, narrative reviews, and case reports were identified through search strategy and cross reference from primary literature.Effective T-cell and NK-cell cytotoxicity towards EBV-infected B cells relies on intact MAGT1-dependent NKG2D pathways and signalling lymphocyte activation molecular-associated protein-dependent signalling lymphocyte activation molecular receptors. The interaction between CD27 and CD70 is also critical to drive the expansion of EBV-specific T cells. IEIs due to T-cell and B-cell signalling defects and/or impaired T-cell and NK-cell cytotoxicity predispose to EBV-related lymphoproliferation. This includes classic disorders such as X-linked lymphoproliferative disease 1 (due to SH2D1A mutations), X-linked lymphoproliferative disease 2 (XIAP), and other genetic diseases, such as ITK, MAGT1, CD27, CD70, CTPS1, RASGRP1, and CORO1A deficiencies. EBV-driven lymphoproliferation may manifest to a lesser degree in MST1/STK4, DOCK8, STIM1, CORO1A, IL21R, PIK3CD gain-of-function, and PI3KR1 deficiencies.Early screening for IEIs is indicated in cases of EBV-related lymphoproliferation because different forms of IEIs have specific prognostic and therapeutic implications.