Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases

Abstract

Epstein-Barr Virus (EBV) is a gamma-herpes virus that infects 90% of humans without any symptoms in most cases, but has an oncogenic potential, especially in immunocompromised individuals. In the past 30 years, several primary immunodeficiencies (PIDs) associated with a high risk to develop EBV-associated lymphoproliferative disorders (LPDs), essentially consisting of virus-associated hemophagocytic syndrome, non-malignant and malignant B-cell LPDs including non-Hodgkin and Hodgkin's types of B lymphomas have been characterized. Among them are SH2D1A (SAP), XIAP, ITK, MAGT1, CD27, CD70, CTPS1, RASGRP1, and CORO1A deficiencies. Penetrance of EBV infection ranges from 50 to 100% in those PIDs. Description of large cohorts and case reports has refined the specific phenotypes associated with these PIDs helping to the diagnosis. Specific pathways required for protective immunity to EBV have emerged from studies of these PIDs. SLAM-associated protein-dependent SLAM receptors and MAGT1-dependent NKG2D pathways are important for T and NK-cell cytotoxicity toward EBV-infected B-cells, while CD27-CD70 interactions are critical to drive the expansion of EBV-specific T-cells. CTPS1 and RASGRP1 deficiencies further strengthen that T-lymphocyte expansion is a key step in the immune response to EBV. These pathways appear to be also important for the anti-tumoral immune surveillance of abnormal B cells. Monogenic PIDs should be thus considered in case of any EBV-associated LPDs.

Keywords: Epstein–Barr virus; T lymphocyte activation; T lymphocytes; genetic predisposition to disease; immunodeficiencies; lymphoproliferative disorders.

Figure 1

Schematic representation of defective identified pathways in immunodeficiencies predisposing to high susceptility to Epstein–Barr virus (EBV)-driven B-cell lymphoproliferative diseases. Defective components in the pathways are in yellow. Three non-redundant pathways have been shown to be impaired: the SLAMF6/2B4/SLAM-associated protein (SAP) pathway, the CD70/CD27 pathway, and the NKG2D/MICA/MAGT1 pathway. At some point, several of these pathways may converge toward distal effector molecules such as RASGRP1 and CTPS1 that are required for expansion of T cells. The connection of CORO1A to these pathways is not known. Besides the essential role of CD8⁺ T cells, NK and iNKT cells which are often decreased in these primary imunodeficiencies may play a role in the immune response against EBV, particularly during the early phase of the primary infection. Vγ9δ2 T cells are also thought to play an important role in the primary infection by recognition of latently EBV-replicating B cells.