Molecular bases and pathophysiology of hemophagocytic syndromes – HLH-cytotox

Rare syndromes offer unique opportunities to gain insight into central physiological processes. The characterization and understanding of the molecular and functional bases leading to the occurrence of Hemophagocytic Lymphohistiocytic (HLH) syndromes provide a way to approach critical mechanisms controlling T lymphocyte homeostasis and cytotoxic activity. Through the study of human natural mutants of these conditions, critical effectors of the granule dependent cytotoxic activity have been previously identified. The goal of our research project is now to further dissect the precise molecular mechanisms tightly regulating the cytotoxic function of lymphocytes as well as the cellular bases of the development of the primary and “acquired” forms of HLH.
Three major objectives will be developed:
. The search of new components of the cytotoxic machinery through the identification of proteins interacting with the effectors already characterized and through the identification of the causes leading to inherited forms that are yet uncharacterized. The role of the additive effects of partial deficiencies along the granule dependent cytotoxic pathway will be evaluated as a potential mechanism leading to “acquired” forms of HLH, by using relevant murine models.
. The study of the cellular dynamics and the molecular events leading to the development of HLH. This will include the contribution of the NK cells and of the Monocytes/Macrophages population as well as the interactions established between antigen presenting cells and lymphocytes in the course of HLH, using various available murine models.
. The study of the specific role of Munc18-2 in the mechanism of cytotoxic granule exocytosis and gut epithelial cell function, by using a newly generated Munc18-2 deficient mouse.