PMID- 27621438 OWN - NLM STAT- MEDLINE DCOM- 20180126 LR - 20181113 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 113 IP - 39 DP - 2016 Sep 27 TI - CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice. PG - 10956-61 LID - 10.1073/pnas.1603325113 [doi] AB - Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin(+) neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin(+) neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin(+) neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin(+) neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin(+) neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy. FAU - Bernard-Valnet, Raphael AU - Bernard-Valnet R AD - Center for Pathophysiology Toulouse Purpan, Universite Toulouse III, INSERM U1043, CNRS UMR 5282, 31024 Toulouse, France; FAU - Yshii, Lidia AU - Yshii L AD - Center for Pathophysiology Toulouse Purpan, Universite Toulouse III, INSERM U1043, CNRS UMR 5282, 31024 Toulouse, France; FAU - Queriault, Clemence AU - Queriault C AD - Center for Pathophysiology Toulouse Purpan, Universite Toulouse III, INSERM U1043, CNRS UMR 5282, 31024 Toulouse, France; FAU - Nguyen, Xuan-Hung AU - Nguyen XH AD - Center for Pathophysiology Toulouse Purpan, Universite Toulouse III, INSERM U1043, CNRS UMR 5282, 31024 Toulouse, France; FAU - Arthaud, Sebastien AU - Arthaud S AD - Center for Research in Neuroscience, INSERM U1028, CNRS UMR 5292, 69675 Bron, France; FAU - Rodrigues, Magda AU - Rodrigues M AD - Center for Pathophysiology Toulouse Purpan, Universite Toulouse III, INSERM U1043, CNRS UMR 5282, 31024 Toulouse, France; FAU - Canivet, Astrid AU - Canivet A AD - Center for Pathophysiology Toulouse Purpan, Universite Toulouse III, INSERM U1043, CNRS UMR 5282, 31024 Toulouse, France; FAU - Morel, Anne-Laure AU - Morel AL AD - Center for Research in Neuroscience, INSERM U1028, CNRS UMR 5292, 69675 Bron, France; FAU - Matthys, Arthur AU - Matthys A AD - Center for Pathophysiology Toulouse Purpan, Universite Toulouse III, INSERM U1043, CNRS UMR 5282, 31024 Toulouse, France; FAU - Bauer, Jan AU - Bauer J AD - Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria; FAU - Pignolet, Beatrice AU - Pignolet B AD - Center for Pathophysiology Toulouse Purpan, Universite Toulouse III, INSERM U1043, CNRS UMR 5282, 31024 Toulouse, France; FAU - Dauvilliers, Yves AU - Dauvilliers Y AD - National Reference Center for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia, and Kleine-Levin Syndrome, Department of Neurology, Gui-de-Chauliac Hospital, Centre Hospitalo-Universitaire de Montpellier, INSERM U1061, 34295 Montpellier, France; FAU - Peyron, Christelle AU - Peyron C AD - Center for Research in Neuroscience, INSERM U1028, CNRS UMR 5292, 69675 Bron, France; FAU - Liblau, Roland S AU - Liblau RS AD - Center for Pathophysiology Toulouse Purpan, Universite Toulouse III, INSERM U1043, CNRS UMR 5282, 31024 Toulouse, France; Department of Immunology, Toulouse University Hospitals, 31059 Toulouse, France roland.liblau@inserm.fr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160912 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Autoantibodies) RN - 0 (Autoantigens) RN - 0 (Hemagglutinins) RN - 0 (Orexins) SB - IM MH - Animals MH - Autoantibodies/metabolism MH - Autoantigens/metabolism MH - CD8-Positive T-Lymphocytes/*immunology MH - Cell Communication MH - *Cytotoxicity, Immunologic MH - Hemagglutinins/metabolism MH - Hypothalamus/metabolism MH - Inflammation/pathology MH - Macrophages/metabolism MH - Mice, Inbred C57BL MH - Narcolepsy/*immunology/*pathology MH - Neurons/metabolism/*pathology MH - Orexins/*metabolism MH - Phenotype MH - T-Lymphocytes, Cytotoxic/metabolism MH - Th1 Cells/metabolism PMC - PMC5047186 OTO - NOTNLM OT - CD8 T cells OT - autoimmunity OT - narcolepsy OT - orexin OT - sleep disorders COIS- The authors declare no conflict of interest. EDAT- 2016/09/14 06:00 MHDA- 2018/01/27 06:00 PMCR- 2017/03/27 CRDT- 2016/09/14 06:00 PHST- 2016/09/14 06:00 [entrez] PHST- 2016/09/14 06:00 [pubmed] PHST- 2018/01/27 06:00 [medline] PHST- 2017/03/27 00:00 [pmc-release] AID - 1603325113 [pii] AID - 201603325 [pii] AID - 10.1073/pnas.1603325113 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2016 Sep 27;113(39):10956-61. doi: 10.1073/pnas.1603325113. Epub 2016 Sep 12.