Primary Immunodeficiencies Associated with EBV Disease

Abstract

Epstein-Barr virus (EBV) infects nearly all humans and usually is asymptomatic, or in the case of adolescents and young adults, it can result in infectious mononucleosis. EBV-infected B cells are controlled primarily by NK cells, iNKT cells, CD4 T cells, and CD8 T cells. While mutations in proteins important for B cell function can affect EBV infection of these cells, these mutations do not result in severe EBV infection. Some genetic disorders affecting T and NK cell function result in failure to control EBV infection, but do not result in increased susceptibility to other virus infections. These include mutations in SH2D1A, BIRC4, ITK, CD27, MAGT1, CORO1A, and LRBA. Since EBV is the only virus that induces proliferation of B cells, the study of these diseases has helped to identify proteins critical for interactions of T and/or NK cells with B cells. Mutations in three genes associated with hemophagocytic lymphohistocytosis, PRF1, STXBP2, and UNC13D, can also predispose to severe chronic active EBV disease. Severe EBV infection can be associated with immunodeficiencies that also predispose to other viral infections and in some cases other bacterial and fungal infections. These include diseases due to mutations in PIK3CD, PIK3R1, CTPS1, STK4, GATA2, MCM4, FCGR3A, CARD11, ATM, and WAS. In addition, patients with severe combined immunodeficiency, which can be due to mutations in a number of different genes, are at high risk for various infections as well as EBV B cell lymphomas. Identification of proteins important for control of EBV may help to identify new targets for immunosuppressive therapies.

The Immune Response to Epstein Barr Virus and Implications for Posttransplant Lymphoproliferative Disorder

“…Indeed, the importance of immunosuppression in PTLD has been documented extensively, particularly the impact of the cumulative amount and duration of immunosuppression (4, 5). Similar EBV+ B cell lymphomas have been described in individuals with AIDS (6), the elderly (7), and in patients with primary immunodeficiences (8). The common theme in each of these scenarios is impaired T cell function, either intentional because of immunosuppression in transplant recipients, or acquired as in patients with HIV, genetic deficiencies, or aging immune systems.…”

Th17 immune microenvironment in Epstein-Barr virus–negative Hodgkin lymphoma: implications for immunotherapy

“…For instance, both genetic lesions affecting immune response and certain immunosuppressants are associated with increased risk of EBV lymphoproliferative disease. [4][5][6] These EBV-associated hematolymphoid tumors often respond to immune interventions such as adoptive cellular therapy with EBV-specific T cells or withdrawal of immunosuppressive pharmacologic agents. 7 Immune dysfunction as a predisposing factor is poorly defined in EBV 1 tumors not associated with overt systemic immunosuppression, including CHL, nasopharyngeal carcinoma, and gastric carcinoma.…”

Herpesviridae Seropositivity in Patients with Multiple Sclerosis: First Polish Study

“…EBV infects the majority of humans and persists latently in the B cells of the host [6]. Epidemiological studies strongly support the probable role of EBV infection in MS.…”