Fig. 1.

Convergent pathways of the hyperferritinemic syndromes HLH and MAS. In a typical immune response, infectious (often viral) triggers induce activation and expansion of specific CD8⁺ cytotoxic T Lymphocytes (CTLs). Both CD8+ CTLs and NK cells receive signals from antigen-presenting cells (APCs), leading to enhanced IFNγ production and cytolytic killing (red arrows). Contraction and resolution of the immune response also depend upon NK cell killing of activated lymphocytes. In HLH, impaired CTL function leads an inability to kill target cells and excessive IFNγ production. IFNγ has essential roles in activating macrophages, which produce high levels of inflammatory cytokines and further enhance the CTL response. Absent NK cell cytotoxicity further leads to inability to contract the immune response. During MAS, innate immune activation including excessive IL-18 production, drives activation and expansion of CTLs to overproduce IFNγ, which further stimulating macrophages to produce inflammatory cytokines. Partial genetic or acquired CTL and NK cell defects may augment this IFNγ response and similarly impair resolution of inflammation. In both HLH and MAS, this overwhelming immune activation leads to a systemic cytokine storm.