Hemophagocytic lymphohistiocytosis: review of etiologies and management

George, Melissa R

An understanding of the defective function of several types of immune cells in HLH has greatly enhanced our knowledge of normal physiology of cytotoxic cells. Several cell types are involved in the pathophysiology of HLH, including macrophages, NK-cells, and cytotoxic T-lymphocytes. Macrophages typically serve as antigen presenting cells to present foreign antigens to lymphocytes for either direct destruction or antibody development. In various forms of HLH, macrophages become activated and secrete cytokines. Cytokines, in turn, can cause organ damage when excreted in excessive amounts. NK-cells directly destroy damaged or infected cells, independent of the major histocompatibility complex (MHC). Cytotoxic T-lymphocytes, while similar to NK-cells, kill autologous cells carrying foreign antigens associated with MHC Class I. An alternate theory proposes ineffective antigen removal, which results in ongoing immune stimulation and inappropriate hemophagocytosis. 202 Defects in NK-cell function may vary within the various types of HLH, indicating that several aspects of cell signaling are likely involved in NK-cell dysfunction seen in the disease. [203] [204] [205] In particular, patients with type 3 NK-cell deficiency with completely absent NK-cell function are likely to need hematopoietic cell transplant. 203, 204 Patients with CHS, which is associated with a high frequency of HLH, often have defects in CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4), such that secretory lysosomes cannot move to the cell membrane. 206 Deficient apoptosis appears to be the underlying mechanism behind at least some forms of FHL, a theory further supported by the success of etoposide, a drug used to trigger apoptosis. 207 Genetics FHL syndromes are sub-classified into FHL-1 through FHL-5, based upon functional protein anomalies and the prerequisite