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.tolerance | autoantibodies | antigen capture | antigen presentation | influenza

Dendritic cells, T cells and their interaction in rheumatoid arthritis

“…Interestingly, in this model, transferred OVA-specific T cells could drive activation of autoreactive B cells and production of autoantibodies, thus contradicting the requirement for cognate T cell-B cell interactions to break tolerance. Autoreactive B cells may elicit help from activated OVA-specific T cells in a bystander manner, or autoreactive B cells may co-capture and present HAO and self-antigen liberated in the inflamed joint to mount an autoantibody response dependent on OVA-specific T cells, as has been recently reported in other mouse models of autoimmune disease [114].…”

“…Challenge with non-specific inflammatory lipopolysaccharide (LPS) alone was insufficient to break self-tolerance. Autoreactive B cells may elicit help from activated OVA-specific T cells in a bystander manner, or autoreactive B cells may co-capture and present HAO and self-antigen liberated in the inflamed joint to mount an autoantibody response dependent on OVA-specific T cells, as has been recently reported in other mouse models of autoimmune disease [114]. Bacterial DNA and peptidoglycans are detectable in synovial tissue of RA patients, which could stimulate both innate and adaptive immune responses [113].…”

The multiple pathways to autoimmunity

“…Molecular mimicry by foreign antigens with sufficient sequence or conformational similarity to self-antigens can also result in activation of non-tolerant lymphocytes 41,42 . Another mechanism by which microbes can promote autoimmunity is co-capture of self-antigens together with viral antigens by B cells, leading to self-antigen presentation, T cell engagement and disease 43 . Examples of the above mechanisms have been reported in experimental models, but information on their involvement in the pathogenesis of human autoimmune diseases is limited.…”

The genetic pathogenesis, diagnosis and therapeutic insight of rheumatoid arthritis

“…Exported self‐reactive T‐ and B‐cells can be activated in the periphery under inflammatory conditions by the recognition of cryptic determinants, which had been presented inadequately in the thymus or bone marrow . Molecular mimicry by foreign antigens, or cocapture of self‐antigens with viral antigens by B‐cells can also activate autoreactive B‐ and T‐cells over several years …”

“…1,29 Molecular mimicry by foreign antigens, or cocapture of self-antigens with viral antigens by B-cells can also activate autoreactive B-and T-cells over several years. 1,30 Many innate immune cells including macrophages release inflammatory cytokines in the synovium. 31 RF and ACPA contribute to activation of macrophages and cytokine production and their interactions potentiate the effect on the inflammatory and destructive response.…”