UNC13D encodes Munc13-4, a critical regulator of cytotoxic granule exocytosis in immune cells, particularly cytotoxic T lymphocytes and natural killer (NK) cells 1. The protein plays essential roles in multiple steps of vesicle secretion, including granule biogenesis, tethering, and priming of cytotoxic vesicles at immunological synapses 1. UNC13D is required for the rapid and regulated secretion of secretory lysosomes, enabling immune cells to eliminate target cells through cytotoxic mechanisms 2. Pathogenic mutations in UNC13D cause familial hemophagocytic lymphohistiocytosis type 3 (FHL3), accounting for 30-40% of FHL cases 3. FHL3 patients present with defective cytotoxic function leading to antigen accumulation, resulting in severe systemic hyperinflammation characterized by fever, hepatosplenomegaly, cytopenias, and hemophagocytosis 34. UNC13D mutations are also associated with macrophage activation syndrome, where heterozygous variants contribute to defective lymphocyte cytolytic activity 5. The protein's dysfunction can manifest as isolated neuroinflammatory disease before systemic symptoms appear 6. Collectively, mutations in degranulation-related genes including UNC13D represent over 50% of genetic HLH cases, highlighting the critical importance of proper cytotoxic granule function in immune homeostasis 7.