The pathogenesis of familial hemophagocytic lymphohistiocytosis (HLH). Patients with familial HLH (F-HLH) often have defects of the perforin cytotoxic pathway. Experimental studies have demonstrated that this pathway provides critical feedback regulating CD8+ T–cell activation. Defects result in excessive antigen presentation by dendritic cells, leading to excessive T-cell activation and overproduction of IFN-gamma, which results pathologic systemic macrophage activation. Thus, clinical HLH results from a primary defect of immune regulation leading to largely IFN-γ driven immunopathology. Created with BioRender.com