DOCK2 mutations and hyper-inflammatory syndromes 2159

Abstract Description Background Cytokine storm syndromes (CSS) are frequently fatal hyper-inflammatory states. CSS is associated with defects in cytolytic lymphocyte killing of target cells through the perforin pathway leading to prolonged lymphocyte-target cell interactions yielding excess pro-inflammatory cytokine production. We previously reported a partial dominant-negative missense mutation in a novel CSS gene, DOCK2, in a child with CSS. We have since identified another child with CSS and a child with a recurrent fever syndrome, each with rare unique missense mutations in DOCK2. DOCK2 disruption is known to diminish natural killer (NK) cell lytic function. Methods Patient DOCK2 mutations, or wild-type (WT) controls, were introduced into human NK-92 cells by foamy virus transduction. WT and mutant DOCK2-expressing NK-92 cells were incubated with K562 target cells and compared for cytolysis, degranulation, and cytokine production by flow cytometry. Results Introduction of the 2 newly identified DOCK2 patient-derived missense mutations into NK-92 cells resulted in diminished NK cell cytolysis and degranulation, and increased pro-inflammatory cytokine (tumor necrosis factor & interferon-gamma) production. Conclusion DOCK2 partial dominant-negative missense mutations are present in children with CSS resulting in increased pro-inflammatory cytokine production. DOCK2 partial dominant-negative missense mutations may function as risk alleles for hyper-inflammatory syndromes. Funding Sources Supported by grants from the Rheumatology Research Foundation, the Histiocytosis Association, and the Kaul Pediatric Research Institute (all to RQC). Topic Categories Immune Mechanisms of Human Disease (HUM)