title: Polygenic mutations in the cytotoxicity pathway increase susceptibility to develop HLH immunopathology in mice.
abstract: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disease. Inherited forms of HLH are caused by biallelic mutations in several effectors of granule-dependent lymphocyte-mediated cytotoxicity. A small proportion of patients with a so-called "secondary" form of HLH, which develops in the aftermath of infection, autoimmunity, or cancer, carry a monoallelic mutation in one or more HLH-associated genes. Although this observation suggests that HLH may have a polygenic mode of inheritance, the latter is very difficult to prove in humans. In order to determine whether the accumulation of partial genetic defects in lymphocyte-mediated cytotoxicity can contribute to the development of HLH, we generated mice that were doubly or triply heterozygous for mutations in HLH-associated genes, those coding for perforin, Rab27a, and syntaxin-11. We found that the accumulation of monoallelic mutations did indeed increase the risk of developing HLH immunopathology after lymphocytic choriomeningitis virus infection. In mechanistic terms, the accumulation of heterozygous mutations in the two degranulation genes Rab27a and syntaxin-11, impaired the dynamics and secretion of cytotoxic granules at the immune synapse of T lymphocytes. In addition, the accumulation of heterozygous mutations within the three genes impaired natural killer lymphocyte cytotoxicity in vivo. The genetic defects can be ranked in terms of the severity of the resulting HLH manifestations. Our results form the basis of a polygenic model of the occurrence of secondary HLH.
authors: INSERM Unité Mixte de Recherche 1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France;
authors: Fernando E
authors: FE
authors: Sepulveda
authors: INSERM Unité Mixte de Recherche 1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France;
authors: Alexandrine
authors: A
authors: Garrigue
authors: INSERM Unité Mixte de Recherche 1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France;
authors: Sophia
authors: S
authors: Maschalidi
authors: Cell Imaging Platform, INSERM US24 Centre National de la Recherche Scientifique Unité Mixte de Service 3633, Structure Fédérative de Recherche Necker, Paris Descartes Sorbonne Paris Cité University, Paris, France;
authors: Meriem
authors: M
authors: Garfa-Traore
authors: INSERM Unité Mixte de Recherche 1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France;
authors: Gaël
authors: G
authors: Ménasché
authors: INSERM Unité Mixte de Recherche 1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France; Immunology and Pediatric Hematology Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Collège de France, Paris, France; and.
authors: Alain
authors: A
authors: Fischer
authors: INSERM Unité Mixte de Recherche 1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France; Centre d'Etudes des Déficits Immunitaires, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France.
authors: Geneviève
authors: G
authors: de Saint Basile
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000235:genetics; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D054992:Immunological Synapses / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D020412:Multifactorial Inheritance; D009154:Mutation; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics* / Q000502:physiology; D050765:Qa-SNARE Proteins / Q000235:genetics* / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000502:physiology; D000075745:rab27 GTP-Binding Proteins
chemical_list: D052899:Pore Forming Cytotoxic Proteins; D050765:Qa-SNARE Proteins; C483886:perforin, mouse; D000075745:rab27 GTP-Binding Proteins; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins