1. Netherton syndrome subtypes share IL-17/IL-36 signature with distinct IFN-α and allergic responses
- Author
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Barbieux, Claire, Bonnet Des Claustres, Mathilde, Fahrner, Matthias, Petrova, Evgeniya, Tsoi, Lam, Gouin, Olivier, Leturcq, Florent, Nicaise-Roland, Pascale, Bole, Christine, Béziat, Vivien, Bourrat, Emmanuelle, Schilling, Oliver, Gudjonsson, Johann, Hovnanian, Alain, Genetic skin diseases : from disease mechanism to therapies (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Freiburg [Freiburg], Department of Biology [Fribourg], Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Fonctionnelles d′Immunologie [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Service de Dermatologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Michigan [Ann Arbor], University of Michigan System, Université Paris Cité (UPCité), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], This project was funded by the French National Research Agency ANR-17-CE14-0025 Tfh Atopy (A.H.), ANR-19-CE17-0017 Target-NS (A.H.), the Imagine Institute with Cross-Lab program, and Association Ichtyose France (A.H.). A.H. and O.S. were supported by the European Union’s Horizon 2020 research and innovation program under the ERA-NET Cofund action 643578 (KLKIN project), J.E.G. and L.C.T. are supported by NIH P30-AR075043 and AI130025., ANR-17-CE14-0025,Tfh-Atopy,Différentiation et rôle pathogénique des lymphocytes T auxiliaires folliculaires dans la marche atopique(2017), ANR-19-CE17-0017,TARGET-NS,Développement d'une nouvelle biothérapie ciblant les mécanismes inflammatoires du syndrome de Netherton(2019), European Project: 643578,H2020,H2020-HCO-2014,E-Rare-3(2014), Université Paris Cité, Equipe HAL, Différentiation et rôle pathogénique des lymphocytes T auxiliaires folliculaires dans la marche atopique - - Tfh-Atopy2017 - ANR-17-CE14-0025 - AAPG2017 - VALID, Développement d'une nouvelle biothérapie ciblant les mécanismes inflammatoires du syndrome de Netherton - - TARGET-NS2019 - ANR-19-CE17-0017 - AAPG2019 - VALID, and ERA-NET rare disease research implementing IRDiRC objectives - E-Rare-3 - - H20202014-12-01 - 2019-11-30 - 643578 - VALID
- Subjects
TH2 ,IL-36 ,scaly erythroderma ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,integumentary system ,ichthyosis linearis circumflexa ,TH9 ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Netherton syndrome ,type I IFN - Abstract
International audience; Background: Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in SPINK5 encoding the protease inhibitor LEKTI (lymphoepithelial Kazal-type–related inhibitor). NS patients experience severe skin barrier defects, display inflammatory skin lesions, and have superficial scaling with atopic manifestations. They present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE). Objective: We used a combination of several molecular profiling methods to comprehensively characterize the skin, immune cells, and allergic phenotypes of NS-ILC and NS-SE patients. Methods: We studied a cohort of 13 patients comprising 9 NS-ILC and 4 NS-SE. Results: Integrated multiomics revealed abnormal epidermal proliferation and differentiation and IL-17/IL-36 signatures in lesion skin and in blood in both NS endotypes. Although the molecular profiles of NS-ILC and NS-SE lesion skin were very similar, nonlesion skin of each disease subtype displayed distinctive molecular features. Nonlesion and lesion NS-SE epidermis showed activation of the type I IFN signaling pathway, while lesion NS-ILC skin differed from nonlesion NS-ILC skin by increased complement activation and neutrophil infiltration. Serum cytokine profiling and immunophenotyping of circulating lymphocytes showed a TH2-driven allergic response in NS-ILC, whereas NS-SE patients displayed mainly a TH9 axis with increased CCL22/MDC and CCL17/TARC serum levels. Conclusions: This study confirms IL-17/IL-36 as the predominant signaling axes in both NS endotypes and unveils molecular features distinguishing NS-ILC and NS-SE. These results identify new therapeutic targets and could pave the way for precision medicine of NS.
- Published
- 2021
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