Analysis of the functioning of natural killer (NK) cells and NK cell stimulating cytokines in disorders associated with secondary hemophagocytic lymphohistiocytosis.

Secundary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) is a life-threatening complication of several diseases, including systemic juvenile idiopathic arthritis (sJIA), characterized by systemic inflammation with cytokine storm, overactivation of immune cells and organ failure. A defect cytotoxic function of natural killer (NK) cells is a central component of the pathogenesis of HLH. These cells of the innate immune system perform cytotoxic killing of target cells and are important cytokine producers. Lower numbers and/or defective function of NK cells have been described in different autoimmune and autoinflammatory diseases as well as infections associated with HLH. These defects could explain the development of HLH as a complication. Nevertheless, it remains unclear what underlies these NK cell defects in the different pathologies. The changing inflammatory environment is one of the possible explanations for the development of a defective NK cell function, leading to uncontrolled immune activation and resulting in a higher chance of developing HLH in the underlying diseases. However, the effect of long-term stimulation with cytokines and other immune mediators on the activation of NK cells remains unclear. This project aims to clarify the role of NK cells in relation to NK-stimulating cytokines in inflammatory diseases associated with HLH.