Cocapture of cognate and bystander antigens can activate autoreactive B cells

Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):734-739. doi: 10.1073/pnas.1614472114. Epub 2017 Jan 5.

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.

Keywords: antigen capture; antigen presentation; autoantibodies; influenza; tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Viral / immunology*
  • Autoantibodies / immunology
  • Autoantigens / immunology*
  • Autoimmunity / immunology
  • B-Lymphocytes / immunology*
  • Cell Line
  • Cell Membrane / immunology
  • HEK293 Cells
  • Hemagglutinin Glycoproteins, Influenza Virus / immunology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Receptors, Antigen, B-Cell / immunology
  • T-Lymphocytes / immunology

Substances

  • Antigens, Viral
  • Autoantibodies
  • Autoantigens
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Myelin-Oligodendrocyte Glycoprotein
  • Receptors, Antigen, B-Cell