title: Puberty in females enhances the risk of an outcome of multiple sclerosis in children and the development of central nervous system autoimmunity in mice.
abstract: BACKGROUND
  For reasons that remain unclear, three times more women develop multiple sclerosis (MS) than men. This preponderance among women is evident only after 12 years of age, implicating pubertal factors in the risk of MS.
  
  
  OBJECTIVE
  To investigate the influence of female puberty on central nervous system (CNS) autoimmunity.
  
  
  METHODS
  We examined the relationship between age of menarche on MS outcomes in 116 female children (< 16 years old) whom presented with incident 'acquired demyelinating syndromes' (ADS) and were followed prospectively in the national Canadian Pediatric Demyelinating Disease Study, from 2004-2013. Furthermore, we directly investigated the effects of puberty on susceptibility to experimental autoimmune encephalomyelitis (EAE) in two groups of female mice that differed only in their pubertal status.
  
  
  RESULTS
  In the ADS children, a later age of menarche was associated with a decreased risk of subsequent MS diagnosis. This relationship persisted, after accounting for patient age at ADS presentation and the presence of ≥1 T2 lesions on brain magnetic resonance imaging (MRI), with a hazard ratio (HR) of 0.64; and additional factors that associate with MS outcomes in ADS children, including low vitamin D levels. Furthermore, we found female mice that had transitioned through puberty were more susceptible to EAE than age-matched, pre-pubertal mice.
  
  
  CONCLUSIONS
  Puberty in females enhances CNS autoimmune mechanisms that lead to MS in humans and EAE in mice.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON, Canada.
authors.forename: Jeeyoon Jennifer
authors.initials: JJ
authors.lastname: Ahn
authors.affiliation: Institute of Health Policy, Management and Evaluation, the University of Toronto/The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Julia
authors.initials: J
authors.lastname: O'Mahony
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Marina
authors.initials: M
authors.lastname: Moshkova
authors.affiliation: Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Hanwell
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Hargurinder
authors.initials: H
authors.lastname: Singh
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON, Canada.
authors.forename: Monan Angela
authors.initials: MA
authors.lastname: Zhang
authors.affiliation: Departments of Internal Medicine and Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Ruth Ann
authors.initials: RA
authors.lastname: Marrie
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.affiliation: Department of Medical Genetics and Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Dessa A
authors.initials: DA
authors.lastname: Sadovnick
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON, Canada/Toronto General Research Institute, University Health Network, Toronto, ON, Canada/Women's College Research Institute, Toronto, ON, Canada sdunn@uhnresearch.ca.
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Dunn
authors.affiliation: Division of Neurology, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Banwell
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000818:Animals; D002648:Child; D020278:Demyelinating Autoimmune Diseases, CNS / Q000276:immunology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008572:Menarche / Q000276:immunology*; D051379:Mice; D009103:Multiple Sclerosis / Q000276:immunology*; D012307:Risk Factors; D012737:Sex Factors; D012741:Sexual Maturation / Q000276:immunology*
keywords: Acquired demyelinating syndrome; antigen-presenting cells; autoimmune disease; central nervous system; experimental autoimmune encephalomyelitis; human study; menarche; mouse study; multiple sclerosis; puberty; risk factors; vitamin D