Abnormal functional lymphoid tolerance and enhanced myeloid exocytosis are characteristics of resting and stimulated PBMCs in cystic fibrosis patients.

Autor:	Gaudin C; Laboratoire d'Excellence Inflamex, Institut National de la Santé et de la Recherche Medicale, Physiopathologie et Épidémiologie des Maladies Respiratoires, Université Paris-Cité, Paris, France., Ghinnagow R; Laboratoire d'Excellence Inflamex, Institut National de la Santé et de la Recherche Medicale, Physiopathologie et Épidémiologie des Maladies Respiratoires, Université Paris-Cité, Paris, France., Lemaire F; Laboratoire d'Excellence Inflamex, Institut National de la Santé et de la Recherche Medicale, Physiopathologie et Épidémiologie des Maladies Respiratoires, Université Paris-Cité, Paris, France., Villeret B; Laboratoire d'Excellence Inflamex, Institut National de la Santé et de la Recherche Medicale, Physiopathologie et Épidémiologie des Maladies Respiratoires, Université Paris-Cité, Paris, France., Sermet-Gaudelus I; INSERM, CNRS, Institut Necker Enfants Malades, Paris, France.; Université Paris-Cité, Paris, France.; ERN-LUNG CF Network, Frankfurt, Germany.; Centre de Ressources et de Compétence de la Mucoviscidose Pédiatrique, Hôpital Mignot, Paris, France., Sallenave JM; Laboratoire d'Excellence Inflamex, Institut National de la Santé et de la Recherche Medicale, Physiopathologie et Épidémiologie des Maladies Respiratoires, Université Paris-Cité, Paris, France.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Feb 26; Vol. 15, pp. 1360716. Date of Electronic Publication: 2024 Feb 26 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1360716
Abstrakt:	Introduction: Cystic Fibrosis (CF) is the commonest genetically inherited disease (1 in 4,500 newborns) and 70% of people with CF (pwCF) harbour the F508Del mutation, resulting in misfolding and incorrect addressing of the channel CFTR to the epithelial membrane and subsequent dysregulation of fluid homeostasis. Although studies have underscored the importance and over-activation of myeloid cells, and in particular neutrophils in the lungs of people with CF (pwCF), relatively less emphasis has been put on the potential immunological bias in CF blood cells, at homeostasis or following stimulation/infection. Methods: Here, we revisited, in an exhaustive fashion, in pwCF with mild disease (median age of 15, median % FEV1 predicted = 87), whether their PBMCs, unprimed or primed with a 'non specific' stimulus (PMA+ionomycin mix) and a 'specific' one (live P.a =PAO1 strain), were differentially activated, compared to healthy controls (HC) PBMCs. Results: 1) we analysed the lymphocytic and myeloid populations present in CF and Control PBMCs (T cells, NKT, Tgd, ILCs) and their production of the signature cytokines IFN-g, IL-13, IL-17, IL-22. 2) By q-PCR, ELISA and Luminex analysis we showed that CF PBMCs have increased background cytokines and mediators production and a partial functional tolerance phenotype, when restimulated. 3) we showed that CF PBMCs low-density neutrophils release higher levels of granule components (S100A8/A9, lactoferrin, MMP-3, MMP-7, MMP-8, MMP-9, NE), demonstrating enhanced exocytosis of potentially harmful mediators. Discussion: In conclusion, we demonstrated that functional lymphoid tolerance and enhanced myeloid protease activity are key features of cystic fibrosis PBMCs. Competing Interests: Author IS-G reports support for the present manuscript from Vaincre la Mucoviscidose and Mucoviscidose ABCF2. Author IS-G also reports, outside the submitted work, grants from Agence Nationale pour la Recherche, Assistance Publique– Hôpitaux de Paris and Vertex Innovation Award, and consulting fees and travel support from Vertex therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 Gaudin, Ghinnagow, Lemaire, Villeret, Sermet-Gaudelus and Sallenave.)
Databáze:	MEDLINE
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