Fig. 7
From: Deep insight into cytokine storm: from pathogenesis to treatment
Mechanisms and clinical manifestation of HLH-associated CRS. Upon recognition of a target cell, cytolytic T/NK cells polarize preformed, perforin-containing lytic vesicles toward the immunologic synapse, facilitating perforin release to form pores and deliver cytotoxic proteins into the target cell. In primary HLH (pHLH), genetic mutations affecting perforin-mediated cytolysis impair the lytic pathway, resulting in prolonged interactions between cytolytic T/NK cells and target cells. This extended engagement increases the production of inflammatory cytokines (e.g., IFN-γ), leading to hyperactivation of APCs and subsequent hypercytokinemia. In secondary HLH (sHLH), APCs are activated by PAMPs or DAMPs from malignancies and viruses, causing multi-organ dysfunction, including damage to the vascular endothelium, central nervous system, spleen, liver, and bone marrow. Abbreviation: HLH hemophagocytic lymphohistiocytosis, APCs antigen-presenting cells, PAMPs pathogen-associated molecular patterns, DAMPs damage-associated molecular patterns, IFN interferon, TNF tumor necrosis factor, CMV human cytomegalovirus, EBV Epstein-Barr virus. The figure was created with the assistance of Adobe Illustrator
