Inherited defects causing hemophagocytic lymphohistiocytic syndrome

G de Saint Basile, G Ménasché… - Annals of the New York …, 2011 - Wiley Online Library
G de Saint Basile, G Ménasché, S Latour
Annals of the New York Academy of Sciences, 2011Wiley Online Library
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 …
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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