title: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Paris, France. genevieve.de-saint-basile@inserm.fr
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
authors.forename: Gaël
authors.initials: G
authors.lastname: Ménasché
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
mesh_terms: D000818:Animals; D003594:Cytoplasmic Granules / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics* / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051938:Munc18 Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D054353:Perforin / Q000235:genetics / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C105987:FHL2 protein, human; C117563:FHL3 protein, human; C504656:FHL5 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins; D051938:Munc18 Proteins; D009124:Muscle Proteins; D050765:Qa-SNARE Proteins; C541732:STX11 protein, human; C497940:STXBP2 protein, human; D014157:Transcription Factors; C507969:UNC13D protein, human; D054353:Perforin; D007371:Interferon-gamma