Cocapture of cognate and bystander antigens can activate autoreactive B cells
Significance The immune system normally produces antibodies against pathogens and avoids making antibodies against self-proteins. In some individuals, antibodies against self-proteins (autoantibodies) are made and can cause debilitating disease, but the reasons for this failure of self-tolerance are not known. The experiments described test the following hypothesis linking viral infections and production of autoantibodies: A B cell whose immunoglobulin receptor recognizes a self-membrane protein can capture that protein from the membrane of a virus-infected cell and simultaneously cocapture viral proteins; fragments of the viral protein can then be presented to antiviral T cells and qualify for the positive signals for proliferation and antibody production known as T-cell help. We observed this phenomenon in vitro and in vivo. 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.
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