Genetic and functional basis of familial hemophagocytic lymphohistiocytosis

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Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome of impaired immune regulation. HLH is a key clinical manifestation in a number of genetic diseases, most of which are characterized by mutations in genes relevant for lymphocyte cytotoxicity. Here, we want to further elucidate the genetic and functional basis of inherited diseases predisposing to HLH. Based on a growing, clinically and immunologically well-characterized cohort of patients referred for evaluation for HLH, we will focus on patients with familial or recurrent disease, EBV triggered disease or HLH in the context of an immunodeficiency. Functional screening will identify patients with cytotoxicity and degranulation defects, particular response patterns to EBV and particular T cell differentiation patterns. Based on this phenotypic screen, we will use state of the art genetic tools including whole exome sequencing to identify novel genetic defects and characterize them in-vitro and in-vivo using cell biological and immunological approaches. The study aims to identify unknown components involved in organelle trafficking, lymphocyte cytotoxicity, and immune regulation and to improve the diagnosis and treatment options for patients with HLH.