Review Article

Epstein-Barr Virus as a Trigger of Autoimmune Liver Diseases

Table 1

Evidence is support and against a role of Epstein-Barr virus (EBV) in autoimmune liver disease (AiLD). Evidence in support of EBV in the pathogenesis of autoimmune hepatitis (AIH) is largely based around case reports noting the development of AIH following EBV infection. In contrast, studies on EBV and primary biliary cirrhosis (PBC) have been based on the detection of EBV genetic material in PBC patients. As well, molecular mimicry between EBV and self-proteins has also been indicated, with mixed results. Although convincing, it should be noted that EBV is ubiquitous in a large percentage of the population, and thus cannot be causally linked. Evidence linking EBV with PSC is weak, based only on indirect evidence of the role of EBV in the pathogenesis of ulcerative colitis, which is present in many patients with primary sclerosing cholangitis (PSC).

DiseaseEvidence in support of EBVEvidence against EBV

Autoimmune hepatitis (AIH)(i) Several case reports indicating the development of AIH following EBV infection(i) The high prevalence of EBV would indicate a higher development of AIH post-EBV infection, which is not the case
(ii) Strong EBV links with autoimmune diseases, such as systemic lupus erythematosus (SLE) that are not commonly concomitant with AIH
(iii) A CYP2D6259–271 mimicking peptide from BVRF1 EBV is totally unreactive in anti-CYP2D6254–271 positive patients with AIH-2
(ii) Serological evidence of EBV infection in AIH patients
(iii) Strong link between EBV and rheumatoid arthritis, autoimmune thyroid, and Sjögrens syndrome, which are often concomitant in patients with AIH or other AiLDs
(iv) Molecular mimicry and immunological cross-reactivity implicating an EBNA EBV epitope and the immunodominant CYP2D6259–271 epitope is demonstrated in patients with AIH-2

Primary biliary cirrhosis (PBC)(i) Increased EBV DNA found in peripheral blood mononuclear cells, liver and saliva of PBC patients
(ii) Increased EBV early antigen titers in PBC(i) Increased EBV early antigen titers also found in other autoimmune diseases
(iii) Strong link between EBV and rheumatoid arthritis, autoimmune thyroid, and Sjogrens syndrome, which are often concomitant in AiLD(ii) Strong EBV links with autoimmune diseases, such as SLE, that are not commonly concomitant with PBC
(iv) Homologous regions between EBV proteins and sp100

Primary sclerosing cholangitis (PSC)(i) Increased EBV infected B lymphocytes in the intestinal mucosa of ulcerative colitis patients (which is often concomitant in PSC)(i) No direct evidence or case reports linking EBV to PSC