Format

Send to

Choose Destination
J Allergy Clin Immunol. 2017 May;139(5):1641-1649.e6. doi: 10.1016/j.jaci.2016.08.033. Epub 2016 Oct 1.

Mammalian target of rapamycin inhibition counterbalances the inflammatory status of immune cells in patients with chronic granulomatous disease.

Author information

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.

KEYWORDS:

Chronic granulomatous disease; IL-17A; IL-1β; autophagy; inflammasome; inflammatory manifestations; mammalian target of rapamycin inhibition

PMID:
27702670
DOI:
10.1016/j.jaci.2016.08.033
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center