title: Pathogenesis of multiple sclerosis via environmental and genetic dysregulation of N-glycosylation.
abstract: Autoimmune diseases such as multiple sclerosis (MS) result from complex and poorly understood interactions of genetic and environmental factors. A central role for T cells in MS is supported by mouse models, association of the major histocompatibility complex region, and association of critical T cell growth regulator genes such as interleukin-2 receptor (IL-2RA) and interleukin-7 receptor (IL-7RA). Multiple environmental factors (vitamin D(3) deficiency and metabolism) converge with multiple genetic variants (IL-7RA, IL-2RA, MGAT1, and CTLA-4) to dysregulate Golgi N-glycosylation in MS, resulting in T cell hyperactivity, loss of self-tolerance and in mice, a spontaneous MS-like disease with neurodegeneration. Here, we review the genetic and biological interactions that regulate MS pathogenesis through dysregulation of N-glycosylation and how this may enable individualized therapeutic approaches.
authors.affiliation: Institute for Immunology, Department of Neurology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Ani
authors.initials: A
authors.lastname: Grigorian
authors.forename: Haik
authors.initials: H
authors.lastname: Mkhikian
authors.forename: Carey F
authors.initials: CF
authors.lastname: Li
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Newton
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Zhou
authors.forename: Michael
authors.initials: M
authors.lastname: Demetriou
mesh_terms: D000217:Acyltransferases / Q000235:genetics; D000818:Animals; D015551:Autoimmunity; D060908:CTLA-4 Antigen / Q000235:genetics; D006031:Glycosylation; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017351:N-Acetylglucosaminyltransferases; D020395:Receptors, Interleukin-7 / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D060908:CTLA-4 Antigen; D053645:Interleukin-2 Receptor alpha Subunit; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D000217:Acyltransferases; C459903:MGAT1 protein, mouse; D017351:N-Acetylglucosaminyltransferases