title: Mammalian target of rapamycin inhibition counterbalances the inflammatory status of immune cells in patients with chronic granulomatous disease.
abstract: BACKGROUND
  Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defective production of reactive oxygen species in phagocytic cells that results in life-threatening infections and severe inflammatory manifestations. The treatment of inflammatory manifestations remains challenging because it can be associated with an increased risk of infections. Previous studies have shown that phagocytes from patients with CGD display a defect in autophagy and a reactive oxygen species-independent activation of the inflammasome.
  
  
  OBJECTIVE
  Because the intersections between autophagy and the inflammasome have been observed in patients with various diseases and microbial infections, we investigated the possible benefit of restoring the autophagy defect through rapamycin, a potent autophagy inducer, in the setting of CGD.
  
  
  METHODS
  We studied 15 patients given a diagnosis of CGD and followed in our institution. All patients were free of any active infection at the time of the study.
  
  
  RESULTS
  We show that patients with CGD present a consistent inflammatory phenotype defined by (1) increased nonclassical and intermediate monocytes, (2) a proinflammatory state of mononuclear phagocytes with increased IL-1β and TNF-α content, (3) a TH17 bias of CD4+T cells, (4) and an increase in IL-17A-secreting neutrophil numbers. We document the reversion of CGD inflammatory status by the mammalian target of rapamycin inhibitor rapamycin on the different immune cell subsets. We also provide evidence for the enhancement of rapamycin's inhibitory effect on IL-1β secretion by the IL-1 receptor antagonist anakinra in phagocytes of patients with CGD.
  
  
  CONCLUSIONS
  Altogether, these data open new therapeutic approaches for CGD-related inflammatory manifestations.
authors.affiliation: Biotherapy Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, AP-HP, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Gabrion
authors.affiliation: Biotherapy Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, AP-HP, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hmitou
authors.affiliation: Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Inserm UMR 1163, Paris, France.
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.affiliation: Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Inserm UMR 1163, Paris, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Neven
authors.affiliation: Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lefèvre-Utile
authors.affiliation: Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Diana
authors.affiliation: University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Inserm UMR 1163, Paris, France; Department of Hematology, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
authors.forename: Félipe
authors.initials: F
authors.lastname: Suarez
authors.affiliation: University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Inserm UMR 1163, Paris, France; Centre d'Etude des Déficits Immunitaires, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
authors.affiliation: Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Inserm UMR 1163, Paris, France; Collège de France, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Biotherapy Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, AP-HP, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Inserm UMR 1163, Paris, France.
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana
authors.affiliation: Biotherapy Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, AP-HP, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Inserm UMR 1163, Paris, France. Electronic address: fabien.touzot@aphp.fr.
authors.forename: Fabien
authors.initials: F
authors.lastname: Touzot
mesh_terms: D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007223:Infant; D007249:Inflammation / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010586:Phagocytes / Q000187:drug effects / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D053590:Interleukin 1 Receptor Antagonist Protein; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Chronic granulomatous disease; IL-17A; IL-1β; autophagy; inflammasome; inflammatory manifestations; mammalian target of rapamycin inhibition