Genetics and pathogenesis of hemophagocytic lymphohistiocytosis

Abstract

Haemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by excessive T cell activation and severe hyperinflammation. It can be subdivided into primary, inherited, forms and secondary forms as a complication of various infections, malignancies and autoinflammatory/autoimmune disorders. In the last decade, it has been shown that most of the primary forms of HLH result from genetic defects that impair the cytotoxic function of natural killer cells and cytotoxic T cells (mutations in the perforin gene or in genes whose products are essential for the exocytosis of the cytotoxic granule contents). Studies of cytotoxicity-deficient mice have helped to define primary HLH as a syndrome in which T cell over-activation by a viral infection leads to excessive, uncontrolled macrophage activation and inflammation-associated cytopenia. The recent identification of late-onset HLH, sometimes associated with hypomorphic and/or monoallelic mutations in genes encoding effectors of the lymphocyte cytotoxicity, has changed our view of HLH’s pathophysiology, in which the disease develops after the progressive accumulation of genetic and environmental factors exceeds a critical threshold.