Pathogenesis of primary HLH and MAS. Genetic variants associated with primary HLH result in defective lymphocyte cytotoxicity (left pathway) or inflammasome degranulation, liberating IL-18 (right). Either mechanism culminates in uncontrolled activation of cytotoxic lymphocytes. The pathogenesis of MAS also involves IL-18-mediated activation of lymphocytes (all HLH patients may have elevated IL-18 levels; however, the increase may be particularly profound among those with MAS). Activated lymphocytes secrete inflammatory cytokines such as IFN-γ, activating macrophages. Activated macrophages in turn secrete additional inflammatory cytokines.