Abstract
Activated PI3Kδ Syndrome (APDS) is an inherited immune disorder caused by heterozygous, gain-of-function mutations in the genes encoding the phosphoinositide 3-kinase delta (PI3Kδ) subunits p110δ or p85δ. This recently described primary immunodeficiency disease (PID) is characterized by recurrent sinopulmonary infections, lymphoproliferation, and susceptibility to herpesviruses, with Epstein–Barr virus (EBV) infection being most notable. A broad range of PIDs having disparate, molecularly defined genetic etiology can cause susceptibility to EBV, lymphoproliferative disease, and lymphoma. Historically, PID patients with loss-of-function mutations causing defective cell-mediated cytotoxicity or antigen receptor signaling were found to be highly susceptible to pathological EBV infection. By contrast, the gain of function in PI3K signaling observed in APDS patients paradoxically renders these patients susceptible to EBV, though the underlying mechanisms are incompletely understood. At a cellular level, APDS patients exhibit deranged B lymphocyte development and defects in class switch recombination, which generally lead to defective immunoglobulin production. Moreover, APDS patients also demonstrate an abnormal skewing of T cells toward terminal effectors with short telomeres and senescence markers. Here, we review APDS with a particular focus on how the altered lymphocyte biology in these patients may confer EBV susceptibility.
Highlights
Epstein–Barr virus (EBV) is a gammaherpesvirus carried by ~95% of the world population
Inherited gene defects causing primary immunodeficiency diseases (PIDs) are often associated with recurrent or persistent EBV infections and related malignancies, and unraveling the genetic and molecular mechanisms underlying PIDs has led to better knowledge of the cellular and molecular components of the immune system that control herpesviruses
We hypothesize that hemophagocytic lymphohistiocytosis (HLH) does not occur in APDS patients because, as described below, hyperactive PI3K drives polyclonal T-cell senescence, which limits homing, expansion, and survival of EBV-specific T cells and thereby prevents the cytokine storm that causes HLH (Figure 1B)
Summary
Epstein–Barr virus (EBV) is a gammaherpesvirus carried by ~95% of the world population. Gain-of-function (GoF) mutations in the PIK3CD or PIK3R1 gene encoding p110δ or p85α, respectively, have been identified by us and others in PID patients with a disorder known as PASLI Disease (PI3Kδ-Activating mutation causing Senescent T cells, Lymphadenopathy, and Immunodeficiency), or APDS for short. We hypothesize that HLH does not occur in APDS patients because, as described below, hyperactive PI3K drives polyclonal T-cell senescence, which limits homing, expansion, and survival of EBV-specific T cells and thereby prevents the cytokine storm that causes HLH (Figure 1B).
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