The evidence supports a viral aetiology for primary biliary cirrhosis

Abstract

Several lines of evidence implicate an infectious process in patients with primary biliary cirrhosis (PBC). For example, the disease clusters in specific geographic areas and children emigrating from a low incidence area develop the relative incidence of their new home [1]. Also, unrelated members in the same household, such as spouses and care providers, have been reported to develop PBC. The disease reoccurs following liver transplantation, and more potent regimens using tacrolimus have resulted in earlier and more severe recurrence. In contrast, cyclosporine protects against the development of recurrent PBC, which is interesting because it is a weaker immunosuppressant that has antiviral activity against several viral agents, including betaretroviruses [2]. In co-cultivation studies, there are data showing that a transmissible agent from PBC patients’ lymph nodes can trigger a PBC specific phenotype with aberrant expression of mitochondrial proteins on the surface of normal biliary epithelial cells in vitro [3]. A few clues emerged to suggest that a virus might be implicated in PBC. With the help of Bob Garry, my laboratory found evidence of antibody reactivity to retroviruses in PBC serum [4] and James Neuberger’s laboratory found electron microscopy evidence of viral particles in PBC biliary epithelial cells (BEC) in collaboration with Bill Carmen [5]. We then used a PCR method capable of amplifying any retrovirus reverse transcriptase gene and cloned a human betaretrovirus (HBRV) sequence with 95% nucleotide homology to the mouse mammary tumor virus (MMTV) from a PBC biliary epithelium cDNA library [5]. We found that HBRV was detected in 75% PBC patient’s lymph nodes by RT-PCR and immunochemistry. However, the virus was difficult to detect in liver samples and was only observed in 30% of PBC samples by RT-PCR [5]. Indeed, the low viral burden has led to considerable controversy, as others have been unable to link HBRV with PBC. Specifically, Selmi and colleagues found no proviral DNA sequences in any patients’ livers [6] and Johal found that a low frequency of patients without PBC bore proviral DNA sequences [7], which is to be expected as there is general agreement that both genetic susceptibility and an environmental factor are required to trigger disease [1]. On close inspection all these PCR studies are concordant but interpretation varies considerably depending on the author. As