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Inherited defects causing hemophagocytic lymphohistiocytic syndrome

Abstract : Hemophagocytic lymphohistiocytosis (HLH) manifests as the uncontrolled activation of T lymphocytes and macrophages infiltrating multiple organs. Molecular studies of individuals with HLH have demonstrated in most of these conditions a critical role of granule-dependent cytotoxic activity in the regulation of lymphocyte homeostasis, and have allowed the characterization of key effectors regulating cytotoxic granule release. The cytolytic process may now be considered a multistep process, including cell activation; the polarization of cytotoxic granules toward the conjugated target cell; the tethering, priming, and fusion of the cytotoxic granules with the plasma membrane; and the release of their contents (perforin and granzymes) into the intercellular cleft, leading to target cell death. Cytolytic cells have a second effector function involving the production of cytokines, principally γ-interferon, which is secreted independently of the exocytosis cytotoxic granule pathway. An analysis of the mechanisms underlying HLH has identified γ-interferon as a key cytokine inducing uncontrolled macrophage activation, and thus represents a potential therapeutic target.
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Geneviève de Saint Basile, Gaël Ménasché, Sylvain Latour. Inherited defects causing hemophagocytic lymphohistiocytic syndrome. Annals of the New York Academy of Sciences, Wiley, 2011, 1246 (1), pp.64-76. ⟨10.1111/j.1749-6632.2011.06307.x⟩. ⟨inserm-02440299⟩



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