Biology and treatment of familial hemophagocytic lymphohistiocytosis: importance of perforin in lymphocyte-mediated cytotoxicity and triggering of apoptosis.

Familial hemophagocytic lymphohistiocytosis (FHL) is, without treatment, an invariably fatal disease of infancy and early childhood characterized by fever, hepatosplenomegaly, pancytopenia, and a widespread accumulation of T-lymphocytes and macrophages. During recent years, the diagnosis and the survival as well as the understanding of the disease have improved dramatically. Recent studies suggest that FHL is caused by impaired lymphocyte-mediated cytotoxicity and defective triggering of apoptosis, and that the symptoms are mediated by a pro-inflammatory hypercytokinemia. Moreover, specific genetic alterations, mutations in the perforin gene, have been revealed in FHL patients. Perforin, which normally is secreted from cytotoxic T-lymphocytes and natural killer (NK) cells upon conjugation between effector and target cells, is able to insert into the membrane of the target cell. It there polymerizes to form a cell death-inducing pore through which toxic granzymes may enter the cell and trigger apoptosis. The establishment of perforin deficiency as a cause of the rapidly fatal disease FHL has demonstrated the essential role of perforin in human immune homeostasis.