High-dimensional single-cell analysis reveals the immune signature of narcolepsy.
Narcolepsy type 1 is a devastating neurological sleep disorder resulting from the destruction of orexin-producing neurons in the central nervous system (CNS). Despite its striking association with the HLA-DQB1*06:02 allele, the autoimmune etiology of narcolepsy has remained largely hypothetical. Here, we compared peripheral mononucleated cells from narcolepsy patients with HLA-DQB1*06:02-matched healthy controls using high-dimensional mass cytometry in combination with algorithm-guided data analysis. Narcolepsy patients displayed multifaceted immune activation in CD4+and CD8+T cells dominated by elevated levels of B cell-supporting cytokines. Additionally, T cells from narcolepsy patients showed increased production of the proinflammatory cytokines IL-2 and TNF. Although it remains to be established whether these changes are primary to an autoimmune process in narcolepsy or secondary to orexin deficiency, these findings are indicative of inflammatory processes in the pathogenesis of this enigmatic disease.
Institute of Experimental Immunology, University of Zurich, CH-8057 Zurich, Switzerland.
Felix J
0000-0002-4174-2276
FJ
Hartmann
Centre de Physiopathologie Toulouse-Purpan, Université de Toulouse, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, UPS, 31024 Toulouse, France.
Raphaël
0000-0001-7447-344X
R
Bernard-Valnet
Centre de Physiopathologie Toulouse-Purpan, Université de Toulouse, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, UPS, 31024 Toulouse, France.
Clémence
C
Quériault
Institute of Experimental Immunology, University of Zurich, CH-8057 Zurich, Switzerland.
Dunja
0000-0001-9269-2806
D
Mrdjen
Institute of Molecular Life Sciences, University of Zurich, CH-8057 Zurich, Switzerland.|SIB Swiss Institute of Bioinformatics, University of Zurich, CH-8057 Zurich, Switzerland.
Lukas M
0000-0002-3282-1730
LM
Weber
Institute of Experimental Immunology, University of Zurich, CH-8057 Zurich, Switzerland.
Edoardo
0000-0002-9760-2643
E
Galli
Institute of Experimental Immunology, University of Zurich, CH-8057 Zurich, Switzerland.
Carsten
C
Krieg
Institute of Molecular Life Sciences, University of Zurich, CH-8057 Zurich, Switzerland.|SIB Swiss Institute of Bioinformatics, University of Zurich, CH-8057 Zurich, Switzerland.
Mark D
0000-0002-3048-5518
MD
Robinson
Centre de Physiopathologie Toulouse-Purpan, Université de Toulouse, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, UPS, 31024 Toulouse, France.
Xuan-Hung
XH
Nguyen
National Reference Center for Orphan Diseases, Narcolepsy, Idiopathic hypersomnia and Kleine-Levin Syndrome, Department of Neurology, Gui-de-Chauliac Hospital, CHU de Montpellier, Institut National de la Santé et de la Recherche Médicale U1061, 34090 Montpellier, France.
Yves
0000-0003-0683-6506
Y
Dauvilliers
Centre de Physiopathologie Toulouse-Purpan, Université de Toulouse, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, UPS, 31024 Toulouse, France roland.liblau@inserm.fr becher@immunology.uzh.ch.
Roland S
0000-0002-8710-4587
RS
Liblau
Institute of Experimental Immunology, University of Zurich, CH-8057 Zurich, Switzerland roland.liblau@inserm.fr becher@immunology.uzh.ch.
Burkhard
0000-0002-1541-7867
B
Becher
D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007109:Immunity; D016130:Immunophenotyping; D007252:Influenza Vaccines / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009290:Narcolepsy / Q000276:immunology*; D010641:Phenotype; D059010:Single-Cell Analysis / Q000379:methods*; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014611:Vaccination
D016207:Cytokines; D007252:Influenza Vaccines; D014409:Tumor Necrosis Factor-alpha; C556153:pandemrix