Acquired NK cell dysfunction and role of IL-18 in inflammatory diseases associated with secondary hemophagocytic lymphohistiocytosis

Secondary hemophagocytic lymphohistiocytosis (sHLH), a hyperinflammatory syndrome with severe morbidity and potential mortality, can develop as a complication of a variety of autoimmune and autoinflammatory diseases. The reason patients develop sHLH is unknown, hampering timely diagnosis and treatment. We aim to provide evidence for the hypothesis that sHLH results from acquired defects in natural killer (NK) cell activities, impairing their ability to remove activated immune cells, leading to hyperinflammation. Experiments will be performed on blood cells from different patient groups and in mice. Innovative approaches, including NK cell killing assays on autologous target cells, advanced cytometry, CyTOF technology and single cell RNA sequencing, will be applied for identification of acquired NK cell abnormalities, paving the way towards new tools for predicting sHLH. We will focus on IL-18 and aim to demonstrate its key role in acquiring NK cell anergy and NK cell defects. The use of novel mouse strains overexpressing IL-18 represent a unique opportunity to validate our findings. Using antagonists for IL-18 in appropriate mouse models of sHLH and associated diseases will improve our understanding of the pathogenesis, and may identify novel treatment targets.