Aurélie Gabrion1, Isabelle Hmitou1, Despina Moshous2, Bénédicte Neven2, Alain Lefèvre-Utile3, Jean-Sébastien Diana3, Félipe Suarez4, Capucine Picard5, Stéphane Blanche6, Alain Fischer7, Marina Cavazzana8, Fabien Touzot9. 1. Biotherapy Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, AP-HP, Paris, France. 2. 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. 3. Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France. 4. 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. 5. 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. 6. 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. 7. 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. 8. 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. 9. 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.
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. CONCLUSION: Altogether, these data open new therapeutic approaches for CGD-related inflammatory manifestations.
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. CONCLUSION: Altogether, these data open new therapeutic approaches for CGD-related inflammatory manifestations.
Authors: Sophie L Gibbings; Kelsey C Haist; Heidi Nick; S Courtney Frasch; Teagan H Glass; Brian Vestal; Thomas Danhorn; Kara J Mould; Peter M Henson; Donna L Bratton Journal: Blood Date: 2022-03-17 Impact factor: 22.113