Abstract
Epstein–Barr virus (EBV) mainly persists in B cells, which differentiate into antibody-producing cells, and thus, EBV has been implicated in autoimmune diseases. We aimed to describe the EBV reactivation and its relevance to autoimmune disease, focusing on Graves’ disease, which is an autoimmune hyperthyroidism caused by thyrotropin receptor antibodies. Circulating autoreactive B cells that have evaded from the selection have difficulties differentiating to produce antibodies. However, once EBV infects such B cells and reactivates, the B cells may become plasma cells and produce autoantibody. We herein proposed an EBV reactivation-induced Ig production system, which is a distinct pathway from the antibody production system through germinal centers and bone marrow and has the following characteristics: 1. IgM dominance, 2. ubiquitous Ig production, and 3. the rescue of autoreactive B cells, which skews Ig production toward autoantigens. IgM autoantibodies induced by EBV reactivation may activate the classical complement pathway and injure healthy tissue, which supply autoantigens for the production of affinity-matured IgG autoantibodies. Antibodies induced by EBV reactivation may play important roles in the development and exacerbation of autoimmune diseases.
Highlights
Epstein–Barr virus (EBV) has been implicated in autoimmune diseases [1,2,3,4]
In our results, the B cells differentiated to be plasma cells and secreted antibodies without germinal centers. These findings primarily suggest that thyrotropin receptor antibody (TRAb)(+) EBV(+) cells are present in peripheral blood, and EBV reactivation induces TRAb secretion from these cells
We proposed an EBV reactivation-induced Ig production system that is an alternative system of antibody production with the following characteristics: IgM dominance, ubiquitous Ig production, and the rescue of autoreactive B cells
Summary
Epstein–Barr nuclear antigen (EBNA) was previously shown to exhibit cross-reactivity with the myelin antigen of multiple sclerosis (MS) [5] or with the Ro (ss-A) protein, which appears prior to the onset of systemic lupus erythematosus (SLE) [6], and patients with a high EBNA1 titer were found to be at risk of developing MS and SLE. Despite these epidemiologic evidences, a pathophysiological link between EBV and autoimmune disease remains controversial. Tamoto et al recently reported that serum thyrotropin receptor antibodies (TRAbs) may be present even in asymptomatic EBV primary infection [22]. These findings support a relationship between EBV infection and autoimmunity
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