primary biliary cirrhosis (PBC), a chronic condition that predominantly affects middle-aged women. In cases of PBC, the immune system attacks the interlobular bile ducts in the liver ...
... Similar to other autoimmune diseases, PBC is poorly understood. Whilst it is widely believed that the condition is caused by a combination of genetic and environmental factors, a clear understanding of the disease has only recently been forthcoming. In 2003, at the same time the Human Genome Project was nearing completion, evidence began to emerge that the autoimmune response that leads to healthy tissue destruction by the immune system was linked to an inadequate response by the body to an unknown pathogen. The findings were reported by Professor Andrew Mason ...
... Having found no sign of bacteria or microbes in the liver of PBC patients, the team used ‘representational difference analysis’, a technique used to discover Kaposi’s sarcoma virus, to uncover the presence of retroviral sequences. Retroviruses, such as HIV, integrate themselves into the DNA of their host, then replicate and spread around the body. Mason is unequivocal about the significance of the clinical observations from patients with AIDS: “Patients with HIV infection often make lots of auto-antibodies when their lymphocyte counts drop. So we now have an understanding that when the immune system’s function is diminished, autoimmune responses are more common,” he asserts.
Moreover, the researchers found that patients with PBC had antibodies to retroviruses and microscopic virus-like particles on the surface of the damaged bile ducts, furthering the suggestion of a link between a virus and a destructive autoimmune response. Mason’s team used a direct cloning approach to identify and characterise a full length human betaretrovirus (HBRV) in liver samples with PBC. It was found that the HBRV’s DNA sequence shared 95 per cent homology with the mouse mammary tumour virus (MMTV), a betaretrovirus linked with breast cancer in mice and the human mammary tumour virus.
Seemingly, Mason had unearthed early evidence linking virus infection to disease. However, he notes that the retroviral community remains unconvinced that HBRV can indeed infect humans: “In the 1990s, with the advent of polymerase chain reaction, Dr Beatrice Pogo found an MMTV-like sequence in patients with breast cancer. At that time, multiple groups were able to confirm her findings, but equally as many groups could not, and interest in this subject was lost”. In light of this, the team aims to provide layers of evidence linking virus infection with diseases and to develop new treatment modalities for autoimmune diseases.
Lymph nodes are considered a major reservoir for viruses. Initial studies of samples taken from the lymph nodes of PBC patients demonstrated that HBRV was present in around 75 per cent of cases. Also, PBC patients were found to make antibodies and auto-antibodies that react with betaretrovirus. Subsequently, the researchers have isolated an infectious betaretrovirus from the PBC patients’ lymph nodes and, in doing so, discovered that the virus could infect multiple cell types. After analysing lymph nodes and biliary epithelial cells for evidence of viral integration into the host genome, the team has derived concrete evidence for HBRV infection in the majority of PBC patients.
Using next generation DNA sequencing, the group’s collaboration with Dr Gane Ka-Shu Wong, also at the University of Alberta, led to the discovery of not only multiple betaretrovirus integration sites but also a site-specific sequence in the human genome – the first example of betaretrovirus integration. Mason expounds the magnitude of the results: “Detecting integration sites cannot easily be generated by artifactual processes. Therefore, they are considered gold standard. The implication of finding the HBRV integrated into the human genome is that the virus truly infects humans”.
The second layer of evidence centres on the link between betaretrovirus and a disease-specific phenotype. Utilising both cell culture and mouse models of PBC, Mason’s studies have shown a connection between viral infection and the production of anti-mitochondrial antibodies (AMAs) ... The implication of this link is that betaretrovrius infection can be directly associated with intolerance to mitochondrial proteins. ...
...
The ongoing work at the University of Alberta
could signal a revolution in the treatment of PBC
and other autoimmune diseases. As research
continues into HBRV and the use of antiviral
therapy, these groundbreaking findings have the
potential for translation across the spectrum
of disease.
full article incl interview with Mason