Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis

HLH encompasses several entities, including the primary or familial form and the secondary forms associated with infections or malignancies. 1, 2 In all forms, HLH is believed to be a reactive process resulting from hyperactivation, proliferation, and migration of macrophages and type 1 T cells. 3 Cytotoxic chemotherapy and/or immune suppressive therapy are usually effective in achieving symptomatic remission of HLH. 4, 5 The proven curative potential of haematopoietic stem cell transplantation underscores the premise that all forms of HLH result from genetic defects intrinsic to the immune system. 5- 7 Abnormalities in the function (but rarely the quantity) of cytotoxic immune cells, principally natural killer (NK) cells, but also cytotoxic T cells, have been observed in patients with HLH for nearly 20 years. 8- 11 Several genetic changes are thought to contribute to the development of HLH. All of the patients with PRF1 mutations demonstrated absent or decreased perforin expression in NK cells by flow cytometry, in the proportion of perforin expressing cells and/or intensity of staining (table 1), and all but one (P35) demonstrated absent or markedly decreased NK cell function, suggesting that a single amino acid substitution can drastically affect the expression and/or function of the protein.