Question

Epstein-Barr virus (EBV) has been implicated as an environmental trigger to induce autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), and rheumatoid arthritis (RA). Outline 3 possible immunological mechanisms to explain the association of this viral infection with those autoimmune diseases.

Answer 1

1) Viral mechanisms

Infection and Immortalization of Autoreactive B-cells:

EBV infects B-cells by binding to the viral envelope glycoprotein 350 to the B-cell complement receptor 2, CD21. Infection of naive B-cells leads to the expression of nine virally encoded proteins (EBNA 1-6 and three LMPs), and the expression pattern is referred as the latency III program. Infected cells enter the germinal center (GC) in the tonsil and change their viral transcription program to express only EBNA-1, LMP-1 and LMP-2 (latency II). LMP-1 acts as a signal that comes from the CD40 signal transduction pathway initiated by CD4+ T-cells, whereas LMP-2A mimics a constitutively activated B-cell receptor. LMP-1 and LMP-2A assist infected naive B-cells in the GC process and help EBV to gain access to the memory B-cell pool, where it enters a truly latent state (latency 0/I).

It has been hypothesized that EBV might infect autoreactive naive B-cells, and drive these into latently infected memory B-cells resistant to apoptosis. These cells could then lodge in the organs, where their target antigens are expressed and act as antigen presenting cells (APC) rescuing autoreactive T-cells. Based on in vitro studies, it was previously thought that LMP-1 and LMP-2A were sufficient to drive infected B-cells through the GC even in the absence of antigen and that this mechanism could allow the escape of autoreactive B-cells.

EBV Infection of Other Cell Populations:

In addition to B-cells, EBV has found also targeting other cells in vivo such as T-cells and NK cells. It has been proposed that infection of T-cells could impair T-cell apoptosis through inactivation of NF-?B by the expression of the EBV ZEBRA protein and enhanced p53 signaling. Apoptosis of autoreactive T-cells is believed to be fundamental for the maintenance of self-tolerance, but it remains to be established whether EBV-mediated impairment through the proposed mechanism is relevant in the pathogenesis of autoimmune diseases.

EBV infection of human astrocytes and brain microvascular endothelial cell lines has been demonstrated in vitro. It has been proposed that reactivation of latent EBV infection in brain endothelial cells could up-regulate cytokines, chemokines and adhesion molecules that could facilitate access of lymphocytes to the brain. The relevance of this hypothesis, which rests on the unproven assumption that EBV infects human endothelial cells in vivo, remains to be shown. Notably, evidence of the latent or active EBV infection of endothelial cells has so far not been reported in MS brains.

Transactivation of Human Endogenous Retroviruses: Human endogenous retroviruses (HERVs) have been proposed to link infection and autoimmunity. Hence, EBV induces transcription of the endogenous retrovirus HERV-K18 that encodes a superantigen that activates the T-cells carrying the T-cell receptor (TCR) V?7 and V?13 families. The expression of HERV-K18 has been shown to be elevated in peripheral blood and inflamed joints of patients with juvenile RA but not in the peripheral blood of pediatric patients with SLE. One of the three HERV-K18 Env alleles was reported to be associated with MS in a case-control study although the replication analysis in an independent sample set was non-significant. Interestingly, human herpesvirus-6A may also be associated with MS and is, like EBV, also shown to transactivate HERV-K18. However, there is no evidence for the selective expansion of T-cells carrying the TCR V?7 and V?13 families in the brain, blood or CSF of MS patients, or in the synovial tissue from joints of RA patients.

Recently, EBV has also been demonstrated in vitro to activate HERV-W, also known as MS-associated retrovirus (MSRV), in astrocytes, B-cells and monocytes from MS patients [161]. MSRV has repeatedly been isolated from patients with MS [162,163,164] and in vitro to stimulate T-cells carrying TCRs of the V?16 family [165] and to induce the production of several cytokines [166,167,168].