Find in Library

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome resulting from uncontrolled hyper-inflammation, excessive immune system activation, and elevated levels of inflammatory cytokines. HLH can be caused by the inability to downregulate activated macrophages by natural killer (NK) and CD8 cytotoxic T cells through a process reliant on perforin and granzyme B to initiate apoptosis. Homozygous genetic mutations in this process result in primary HLH (pHLH), a disorder that can lead to multi-system organ failure and death in infancy. Heterozygous, dominant-negative, or monoallelic hypomorphic mutations in these same genes can cause a similar syndrome in the presence of an immune trigger, leading to secondary HLH (sHLH). A genetic mutation in a potential novel HLH-associated gene, dedicator of cytokinesis 2 (<i>DOCK2)</i>, was identified in a patient with recurrent episodes of sHLH and hyperinflammation in the setting of frequent central line infections. He required baseline immune suppression for the prevention of sHLH, with increased anti-cytokine therapies and corticosteroids in response to flares and infections. Using a foamy-virus approach, the patient’s <i>DOCK2</i> mutation and wild-type (WT) control <i>DOCK2</i> cDNA were separately transduced into a human NK-92 cell line. The NK-cell populations were stimulated with NK-sensitive K562 erythroleukemia target cells in vitro and degranulation and cytolysis were measured using CD107a expression and live/dead fixable cell dead reagent, respectively. Compared to WT, the patient’s <i>DOCK2</i> mutation was found to cause significantly decreased NK cell function, degranulation, and cytotoxicity. This study speaks to the importance of <i>DOCK2</i> and similar genes in the pathogenesis of sHLH, with implications for its diagnosis and treatment.