title: Narcolepsy Type 1 Is Associated with a Systemic Increase and Activation of Regulatory T Cells and with a Systemic Activation of Global T Cells.
abstract: Narcolepsy is a rare neurologic disorder characterized by excessive daytime sleepiness, cataplexy and disturbed nocturnal sleep patterns. Narcolepsy type 1 (NT1) has been shown to result from a selective loss of hypothalamic hypocretin-secreting neurons with patients typically showing low CSF-hypocretin levels (<110 pg/ml). This specific loss of hypocretin and the strong association with the HLA-DQB1*06:02 allele led to the hypothesis that NT1 could be an immune-mediated pathology. Moreover, susceptibility to NT1 has recently been associated with several pathogens, particularly with influenza A H1N1 virus either through infection or vaccination. The goal of this study was to compare peripheral blood immune cell populations in recent onset pediatric NT1 subjects (post or non-post 2009-influenza A H1N1 vaccination) to healthy donors. We demonstrated an increased number of central memory CD4+ T cells (CD62L+ CD45RA-) associated to an activated phenotype (increase in CD69 and CD25 expression) in NT1 patients. Percentage and absolute count of regulatory T cells (Tregs) in NT1 patients were increased associated with an activated phenotype (increase in GITR and LAP expression), and of activated memory phenotype. Cytokine production by CD4+ and CD8+ T cells after activation was not modified in NT1 patients. In H1N1 vaccinated NT1 patients, absolute counts of CD3+, CD8+ T cells, and B cells were increased compared to non-vaccinated NT1 patients. These results support a global T cell activation in NT1 patients and thus support a T cell-mediated autoimmune origin of NT1, but do not demonstrate the pathological role of H1N1 prophylactic vaccination. They should prompt further studies of T cells, particularly of Tregs (such as suppression and proliferation antigen specific assays, and also T-cell receptor sequencing), in NT1.
authors.affiliation: AP-HP, Pediatric Sleep Center and National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia and Kleine-Levin Syndrome (CNR narcolepsie-hypersomnie), CHU Robert-Debré, Paris, France.|Pediatric Sleep Disorders Center, Robert Debré Hospital, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Lecendreux
authors.affiliation: AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), Paris, France.|Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology- Immunotherapy (I3), Paris, France.|INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France.
authors.forename: Guillaume
authors.identifier: http://orcid.org/0000-0003-1343-752X
authors.initials: G
authors.lastname: Churlaud
authors.affiliation: AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), Paris, France.|Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology- Immunotherapy (I3), Paris, France.|INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Pitoiset
authors.affiliation: Aviesan/Institut Multi-Organismes Immunologie, Hématologie et Pneumologie (ITMO IHP), Paris, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Regnault
authors.affiliation: Pediatrics department, Centre hospitalo-universitaire de Nîmes, 30029 Nîmes Cedex 9, France. INSERM U1012, Le Kremlin Bicêtre, France.
authors.forename: Tu Anh
authors.initials: TA
authors.lastname: Tran
authors.affiliation: INSERM UMR1043-CNRS UMR5282-Université Toulouse III, Toulouse, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Liblau
authors.affiliation: AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), Paris, France.|Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology- Immunotherapy (I3), Paris, France.|INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
authors.affiliation: AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), Paris, France.|Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology- Immunotherapy (I3), Paris, France.|INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France.
authors.forename: Michelle
authors.initials: M
authors.lastname: Rosenzwajg
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets; D008297:Male; D009290:Narcolepsy / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D055815:Young Adult
chemical_list: D016207:Cytokines