Proposed pathophysiology contributing to MAS/HLH and associated cytokine storm. (a) MAS and (b) HLH result from the inability of a CD8 T cell to lyse an APC due to cytolytic pathway defects resulting in sustained immune cell activation and a cytokine storm of pro-inflammatory cytokines, including IFNγ. Blockade of IL-1 (with IL-1RA, anakinra) can help control the cytokine storm, and IL-10 expression can help prevent hemophagocytosis in a model of MAS. CsA can also help prevent the cytokine storm in models of MAS/HLH. CD8, CD8 T cells; DC, dendritic cell; MHC-Ag, major histocompatibility complex coupled to antigen; NK, natural killer cell; TCR, T-cell receptor; TLR, Toll-like receptor.