In some primary immunodeficiencies, there is unique susceptibility to a single pathogen. Such is the case for two rare Xlinked immunodeficiencies with a similar lymphoproliferative defect that results from vulnerability to a herpes family virus, the Epstein–Barr virus (EBV), albeit via independent mechanisms. EBV specifically infects B cells and typically causes a selflimiting infection in normal individuals due to active control of the virus by the actions of NK cells, NKT cells, and cytotoxic T cells with specificity for B cells expressing EBV antigens. Following the development of immunity to EBV, the virus is not completely cleared, but is maintained in a latent state in infected B cells (see Section 1324). In the presence of certain types of immunodeficiency, however, this control can break down, resulting in overwhelming EBV infection (severe infectious mononucleosis) that is accompanied by unrestrained proliferation of EBVinfected B cells and cytotoxic T cells, hypogammaglobulinemia (low levels of circulating immunoglobulins), and the potential for the development of lethal, nonHodgkin’s Bcell lymphomas. These occur in the rare immunodeficiency Xlinked lymphoproliferative (XLP) syndrome. XLP syndrome results from mutations in one of two Xlinked genes: the SH2 domaincontaining gene 1A (SH2D1A), which encodes SAP [signaling lymphocyte activation molecule (SLAM)associated protein], or the Xlinked inhibitor of apoptosis gene (XIAP).
In XLP1, which accounts for approximately 80% of patients with this syndrome, the defect in SAP results in defective coupling of immunecell receptors of the SLAM family with the Srcfamily tyrosine kinase Fyn in T cells, NKT cells, and NK cells (Fig. 13.10). SLAM family members interact through homotypic or heterotypic binding to modulate the outcome of interactions between T cells and antigenpresenting cells and between NK cells and their target cells. In the absence of SAP, ineffective EBVspecific cytotoxic Tcell and NKcell responses are made, and there is severe deficiency of NKT cells, indicating that SAP has a nonredundant role in the control of EBV infection and the development of NKT cells. There is unchecked proliferation of EBVreactive cytotoxic T cells and NK cells that results in systemic macrophage activation, inflammation, and hemophagocytic features similar to those that occur in immunodeficiencies caused by defects in the cytolytic pathway (see