Primary immunodeficiencies and the control of Epstein-Barr virus infection

Human primary immunodeficiency (PID) states, where mutations in single immune system genes predispose individuals to certain infectious agents and not others, are experiments of nature that hold important lessons for the immunologist. The number of genetically defined PIDs is rising rapidly, as is the opportunity to learn from them. Epstein-Barr virus (EBV), a human herpesvirus, has long been of interest because of its complex interaction with the immune system. Thus, it causes both infectious mononucleosis (IM), an immunopathologic disease associated with exaggerated host responses, and at least one malignancy, EBV-positive lymphoproliferative disease, when those responses are impaired. Here, we describe the full range of PIDs currently linked with an increased risk of EBV-associated disease. These provide examples where IM-like immunopathology is fatally exaggerated, and others where responses impaired at the stage of induction, expansion, or effector function predispose to malignancy. Current evidence from this rapidly moving field supports the view that lesions in both natural killer cell and T cell function can lead to EBV pathology.