The pathophysiology of hemophagocytic lympho-histiocytosis (HLH) syndrome and insights from animal models.

This article reviews the pathophysiology of hemophagocytic lymphohistiocytosis (HLH), a severe hyperinflammatory syndrome caused by impaired cytotoxic function of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, leading to excessive CD8+ T-cell expansion, interferon-gamma (IFN-γ) release, macrophage activation, and a resultant cytokine storm. Both primary (genetic) and secondary (triggered by infections, malignancies, autoimmune diseases, or therapies) HLH share common immune dysregulation pathways involving hypercytokinemia, hemophagocytosis, and organ damage. The review highlights key biomarkers such as IL-18, ferritin, and soluble IL-2 receptor alpha, and discusses insights gained from various animal models that elucidate the roles of immune cells, cytokines, and signaling pathways in HLH and macrophage activation syndrome (MAS). These models have advanced understanding of disease mechanisms, trigger-specific differences, and therapeutic targets, emphasizing the importance of timely diagnosis and tailored immunomodulatory treatments.