title: Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen.
abstract: In the pathogenesis of central nervous system (CNS) demyelinating disorders, antigen-specific B cells are implicated to act as potent antigen-presenting cells (APC), eliciting waves of inflammatory CNS infiltration. Here, we provide the first evidence that CNS-reactive antibodies (Ab) are similarly capable of initiating an encephalitogenic immune response by targeting endogenous CNS antigen to otherwise inert myeloid APC. In a transgenic mouse model, constitutive production of Ab against myelin oligodendrocyte glycoprotein (MOG) was sufficient to promote spontaneous experimental autoimmune encephalomyelitis (EAE) in the absence of B cells, when mice endogenously contained MOG-recognizing T cells. Adoptive transfer studies corroborated that anti-MOG Ab triggered activation and expansion of peripheral MOG-specific T cells in an Fc-dependent manner, subsequently causing EAE. To evaluate the underlying mechanism, anti-MOG Ab were added to a co-culture of myeloid APC and MOG-specific T cells. At otherwise undetected concentrations, anti-MOG Ab enabled Fc-mediated APC recognition of intact MOG; internalized, processed and presented MOG activated naïve T cells to differentiate in an encephalitogenic manner. In a series of translational experiments, anti-MOG Ab from two patients with an acute flare of CNS inflammation likewise facilitated detection of human MOG. Jointly, these observations highlight Ab-mediated opsonization of endogenous CNS auto-antigen as a novel disease- and/or relapse-triggering mechanism in CNS demyelinating disorders.
authors.affiliation: Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Kinzel
authors.affiliation: Department of Neurology, Klinikum rechts der Isar, Technische Universität München and Munich Cluster for Systems Neurology, Munich, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Lehmann-Horn
authors.affiliation: Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Torke
authors.affiliation: Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Darius
authors.initials: D
authors.lastname: Häusler
authors.affiliation: Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Winkler
authors.affiliation: Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.affiliation: Monash Regenerative Medicine Institute, Multiple Sclerosis Research Group, Monash University, Melbourne, Australia.
authors.forename: Natalie
authors.initials: N
authors.lastname: Payne
authors.affiliation: Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Feldmann
authors.affiliation: Service of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Saiz
authors.affiliation: Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Reindl
authors.affiliation: Division of Neurology, Department of Clinical Neurosciences, University Hospital of Geneva, Geneva, Switzerland.|Department of Pathology and Immunology, Faculty of Medicine, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Patrice H
authors.initials: PH
authors.lastname: Lalive
authors.affiliation: Monash Regenerative Medicine Institute, Multiple Sclerosis Research Group, Monash University, Melbourne, Australia.
authors.forename: Claude C
authors.initials: CC
authors.lastname: Bernard
authors.affiliation: Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.affiliation: Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany. martin.weber@med.uni-goettingen.de.|Department of Neurology, University Medical Center, Georg August University, Göttingen, Germany. martin.weber@med.uni-goettingen.de.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Weber
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D018920:Coculture Techniques; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009471:Neuromyelitis Optica / Q000276:immunology*; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001323:Autoantibodies; C485701:Fcgr1 protein, mouse; D007074:Immunoglobulin G; C571326:MOG protein, human; D063308:Myelin-Oligodendrocyte Glycoprotein; D017452:Receptors, IgG
keywords: Auto-antibodies; Experimental autoimmune encephalomyelitis; Fc receptor; Multiple sclerosis; Myeloid antigen-presenting cells; Opsonization