title: Cocapture of cognate and bystander antigens can activate autoreactive B cells.
abstract: Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) are associated with autoimmune central nervous system diseases like acute disseminated encephalomyelitis (ADEM). For ADEM, it is speculated that a preceding infection is the trigger of the autoimmune response, but the mechanism connecting the infection to the production of MOG antibodies remains a mystery. We reasoned that the ability of B cells to capture cognate antigen from cell membranes, along with small quantities of coexpressed "bystander" antigens, might enable B-cell escape from tolerance. We tested this hypothesis using influenza hemagglutinin as a model viral antigen and transgenic, MOG-specific B cells. Using flow cytometry and live and fixed cell microscopy, we show that MOG-specific B cells take up large amounts of MOG from cell membranes. Uptake of the antigen from the membrane leads to a strong activation of the capturing B cell. When influenza hemagglutinin is also present in the membrane of the target cell, it can be cocaptured with MOG by MOG-specific B cells via the B-cell receptor. Hemagglutinin and MOG are both presented to T cells, which in turn are activated and proliferate. As a consequence, MOG-specific B cells get help from hemagglutinin-specific T cells to produce anti-MOG antibodies. In vivo, the transfer of MOG-specific B cells into recipient mice after the cocapture of MOG and hemagglutinin leads to the production of class-switched anti-MOG antibodies, dependent on the presence of hemagglutinin-specific T cells. This mechanism offers a link between infection and autoimmunity.
authors.affiliation: Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland; nicholas.sanderson@unibas.ch tobias.derfuss@usb.ch.
authors.forename: Nicholas S R
authors.initials: NS
authors.lastname: Sanderson
authors.affiliation: Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Eilinger
authors.affiliation: Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Gubser
authors.affiliation: Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schaeren-Wiemers
authors.affiliation: Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
authors.forename: Raija L P
authors.initials: RL
authors.lastname: Lindberg
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Dougan
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
authors.affiliation: Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.|Clinic of Neurology, Department of Medicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.|Department of Clinical Research, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.|Department of Biomedical Engineering, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.affiliation: Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland; nicholas.sanderson@unibas.ch tobias.derfuss@usb.ch.|Clinic of Neurology, Department of Medicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Derfuss
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology; D057809:HEK293 Cells; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D001323:Autoantibodies; D001324:Autoantigens; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D063308:Myelin-Oligodendrocyte Glycoprotein; D011947:Receptors, Antigen, B-Cell
keywords: antigen capture; antigen presentation; autoantibodies; influenza; tolerance