title: Graded defects in cytotoxicity determine severity of hemophagocytic lymphohistiocytosis in humans and mice.
abstract: Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease of hyperinflammation resulting from immune dysregulation due to inherited defects in the cytolytic machinery of natural killer and T cells. In humans, mutations in seven genes encoding proteins involved in cytolytic effector functions have so far been identified that predispose to HLH. However, although most affected patients develop HLH eventually, disease onset and severity are highly variable. Due to the genetic heterogeneity and variable time and nature of disease triggers, the immunological basis of these variations in HLH progression is incompletely understood. Several murine models of primary HLH have been established allowing to study HLH pathogenesis under more defined conditions. Here we directly compare the clinical HLH phenotype in six HLH-prone mouse strains with defects in the granule-dependent cytotoxic pathway. A severity gradient of HLH manifestations could be identified that is defined by the genetically determined residual lytic activity of cytotoxic T lymphocytes (CTL) and their ability to control lymphocytic choriomeningitis virus, which was used as a trigger for disease induction. Importantly, analysis of cohorts of HLH patients with severe bi-allelic mutations in the corresponding genes yielded a similar severity gradient in human HLH as reflected by the age at disease onset. Our findings define HLH as a threshold disease determined by subtle differences in the residual lytic activity of CTL.
authors.affiliation: Centre of Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg , Freiburg , Germany.
authors.forename: Birthe
authors.initials: B
authors.lastname: Jessen
authors.affiliation: Department for Medical Microbiology and Hygiene, Institute of Immunology, University Medical Center Freiburg, University of Freiburg , Freiburg , Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Kögl
authors.affiliation: U768, INSERM , Paris , France ; Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité , Paris , France.
authors.forename: Fernando E
authors.initials: FE
authors.lastname: Sepulveda
authors.affiliation: U768, INSERM , Paris , France ; Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité , Paris , France ; Centre d'Etudes des Déficits Immunitaires, Assistance Publique-Hôpitaux de Paris, Hôpital Necker , Paris , France.
authors.forename: Genevieve
authors.initials: G
authors.lastname: de Saint Basile
authors.affiliation: Department for Medical Microbiology and Hygiene, Institute of Immunology, University Medical Center Freiburg, University of Freiburg , Freiburg , Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Aichele
authors.affiliation: Centre of Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg , Freiburg , Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
keywords: CTL; antigen persistence; cytotoxicity; hemophagocytic lymphohistiocytosis; inflammation; virus persistence