Epstein-Barr virus (EBV) is a human B-lymphotropic DNA γ-herpesvirus that establishes an asymptomatic latent infection and can cause infectious mononucleosis in adolescence. EBV is characterized by an active lytic cycle during which the virus replicates and propagates and a latent cycle when the virus remains silent in rare B cells, although latent EBV can also replicate in its episomal plasmid form. EBV has long been associated with several chronic rheumatic autoimmune diseases, with increased viral load, anti-viral antibodies titers, anti-EBV CD8+ T cells and EBV nucleic acids described in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). However, the pathogenic role of this virus in autoimmune conditions has remained elusive, mostly due to the absence of suitable animal models. In this presentation, the main evidence in support of a direct and indirect role of EBV in contributing to breach of self-tolerance and autoimmunity, particularly in the B cell compartment, will be discussed.
First, EBV infection has been advocated as a plausible mechanism allowing potentially pathogenic autoreactive B cell clones to escape deletion and cause autoimmunity. In particular, EBV latent antigens LMP1 and LMP2A are potent B cell activators mimicking the CD40 and the B-cell-receptor signalling pathways, respectively. As a result, EBV can directly promote the survival of autoreactive B cell clones and can lead to a breakdown in B cell tolerance, as shown in LMP2A transgenic mice.
Additionally, EBV can contribute to the induction and maintenance of autoimmunity through molecular mimicry between EBV proteins and the post-translational modification of autoantigens. In this regard, anti-Ro/La autoantibodies from SLE and SS patients can precipitate protein antigens linked with EBV-encoded small RNA (EBERs) while the EBV transcriptional transactivator EBNA1 mimics Ro52. Conversely, antibodies against citrullinated EBNA1 peptides have been described in patients with RA and EBV can induce the cleavage of α-fodrin, a putative autoantigen in SS.
However, the most recent observation which has sparked novel interest in the contribution of EBV to autoimmunity is the evidence that ectopic B cell follicles forming in the target organs of several autoimmune diseases, including the RA synovium and SS salivary glands are preferential niches of EBV infection. In particular, we have demonstrated that tertiary lymphoid structures (TLS) in SS and RA display evidence of latent EBV infection, as demonstrated by the detection of EBERs, LMP1 and LMP2a, and lytic reactivation in a subset of perifollicular CD138+ plasma cells, as detected by the expression of BFRF1 and BZLF1, two early lytic EBV antigens. Moreover, EBV infected plasma cells are frequently reactive against the SS-associated antigen Ro52 in the salivary glands and citrullinated fibrinogen in the RA synovium, but not vice versa.This suggests that autoreactive B cell clones harbouring EBV can be selected upon antigen stimulation from disease-specific antigens within ectopic germinal centres where they undergo differentiation to autoreactive plasma cells, a process that, in turn, can lead to EBV reactivation.
Overall, the above evidence strongly suggest that intimate and complex interactions between EBV and the host immune systems take place in patients with autoimmune diseases with profound repercussion on the survival and perpetuation of disease-specific autoreactive B-cells.
Disclosure of Interest None declared