Introduction

Farquhar and Claireaux published a report in 1952 of a disease characterized by progressive erythropaenia, neutropaenia and thrombocytopaenia, despite a reactive bone marrow, and named it familial hemophagocytic reticulosis (Farquhar and Claireaux, 1952). In the 50 years since their seminal report, the knowledge and understanding of this condition, now termed hemophagocytic lymphohistiocytosis (HLH), has increased rapidly. It is now well established that familial HLH (FHL) is a primary immunodeficiency, characterized by hypercytokinemia (elevated serum levels of inflammatory cytokines) and a concomitant defect in natural killer (NK) cell cytotoxicity (Perez et al., 1984; Arico et al., 1988; Eife et al., 1989; Henter et al., 1998; Sullivan et al., 1998; Kogawa et al., 2002). Recent genetic studies have revealed underlying molecular defects in FHL patients, greatly improving our understanding of the basic pathogenesis of this disease. Deciphering the underlying molecular mechanism of immunodeficiency in FHL patients may also teach us more about the role of cellular cytotoxicity in immune homoeostasis under normal conditions.

Pathogenesis of HLH

Cytotoxic T lymphocytes- and NK cell-mediated apoptosis

Lymphocyte-mediated cytotoxicity is the main pathway for tumour surveillance and for eradicating virus-infected cells and intracellular pathogens. The effector lymphocytes are the cytotoxic T lymphocytes (CTLs) and NK cells, which act by killing their cellular targets through induction of apoptosis. CTLs and NK cells utilize either of two mechanisms for killing, both of which require direct contact between effector and target cells.