HLH is a hyperinflammatory disease triggered by activating stimuli, including malignancy, infection, or autoimmunity, that leads to CD8⁺ T-cell activation, IFN-γ production, and activation of immune effector cells that produce additional cytokines. Due to inherited or acquired defects in cytolytic granule release, termination of the immune response does not occur. Continuous cytokine production ensues (green arrows), leading to a cytokine storm with continued immune effector cell activation and downstream tissue damage. The work by Albeituni et al implicates neutrophils as an additional effector of this tissue damage. IFN-γ blockade (yellow X) specifically blocks the driving cytokine in this process.⁹  The JAK inhibitor ruxolitinib (red Xs) blocks IFN-γ, but also has more pleiotropic effects impacting additional cytokine-mediated signals, including those that impact deleterious neutrophil activity. MΦ, macrophage; PMN, polymorphonuclear neutrophil.