title: Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses.
abstract: Seasonal changes in disease activity have been observed in multiple sclerosis, an autoimmune disorder that affects the CNS. These epidemiological observations suggest that environmental factors influence the disease course. Here, we report that melatonin levels, whose production is modulated by seasonal variations in night length, negatively correlate with multiple sclerosis activity in humans. Treatment with melatonin ameliorates disease in an experimental model of multiple sclerosis and directly interferes with the differentiation of human and mouse T cells. Melatonin induces the expression of the repressor transcription factor Nfil3, blocking the differentiation of pathogenic Th17 cells and boosts the generation of protective Tr1 cells via Erk1/2 and the transactivation of the IL-10 promoter by ROR-α. These results suggest that melatonin is another example of how environmental-driven cues can impact T cell differentiation and have implications for autoimmune disorders such as multiple sclerosis.
authors.affiliation: Center for Research on Neuroimmunological Diseases (CIEN), Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires 1428, Argentina. Electronic address: mfarez@fleni.org.ar.
authors.forename: Mauricio F
authors.initials: MF
authors.lastname: Farez
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Mascanfroni
authors.affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Buenos Aires 1428, Argentina.
authors.forename: Santiago P
authors.initials: SP
authors.lastname: Méndez-Huergo
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ada
authors.initials: A
authors.lastname: Yeste
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gopal
authors.initials: G
authors.lastname: Murugaiyan
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lucien P
authors.initials: LP
authors.lastname: Garo
authors.affiliation: Center for Research on Neuroimmunological Diseases (CIEN), Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires 1428, Argentina; Department of Neurology, Hospital de Clínicas José de San Martín, Buenos Aires 1428, Argentina.
authors.forename: María E
authors.initials: ME
authors.lastname: Balbuena Aguirre
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bonny
authors.initials: B
authors.lastname: Patel
authors.affiliation: Center for Research on Neuroimmunological Diseases (CIEN), Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires 1428, Argentina.
authors.forename: María C
authors.initials: MC
authors.lastname: Ysrraelit
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Buenos Aires 1428, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: fquintana@rics.bwh.harvard.edu.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Quintana
authors.affiliation: Center for Research on Neuroimmunological Diseases (CIEN), Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires 1428, Argentina.
authors.forename: Jorge
authors.initials: J
authors.lastname: Correale
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D008027:Light; D020935:MAP Kinase Signaling System; D008297:Male; D008550:Melatonin / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D012008:Recurrence; D012621:Seasons; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D022762:CCAAT-Enhancer-Binding Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D008550:Melatonin