Finding a Balance between Protection and Pathology: The Dual Role of Perforin in Human Disease.

Perforin is critical for controlling viral infection and tumor surveillance. Clinically, mutations in perforin are viewed as unfavorable, as lack of this pore-forming protein results in lethal, childhood disease, familial hemophagocytic lymphohistiocytosis type 2 (FHL 2). However, many mutations in the coding region of are not yet associated with disease. Animal models of viral-associated blood-brain barrier (BBB) disruption and experimental cerebral malaria (ECM) have identified perforin as critical for inducing pathologic central nervous system CNS vascular permeability. This review focuses on the role of perforin in both protecting and promoting human disease. It concludes with a novel hypothesis that diversity observed in the gene may be an example of selective advantage that protects an individual from perforin-mediated pathology, such as BBB disruption.