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Autoimmune PBC caused by human betaretrovirus

natasa778

Senior Member
Messages
1,774
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
 

Antares in NYC

Senior Member
Messages
582
Location
USA
Wow! Very impressive study!
The two following quotes are remarkable:
and also:
This study has interesting implications for ME/CFS, the autoimmune reactions after decreased immune function, and the viral connection to mitochondrial issues.

When it's all said and done, I am convinced there will find a pathogen at the heart of ME/CFS, likely a difficult enterovirus or even retrovirus. Too bad there's no funding for research on this illness.

For those in the know, could the same techniques like 'representational difference analysis’ be used for ME/CFS? Could samples of spinal fluid, or stomach tissues, be used to confirm a pathogen with these techniques?
Paging @Hip , @alex3619 , @heapsreal , @MeSci
 
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natasa778

Senior Member
Messages
1,774
few bits and pieces on PBC:

... It was previously thought to be a rare disease, but more recent studies have shown that it may affect up to 1 in 3–4,000 people; the sex ratio is at least 9:1 (female to male).

It is predominantly seen in middle-aged women. Typical symptoms are fatigue, pruritus (itchy skin), and abdominal pain...

Fatigue, pruritus, and Sjögren's syndrome are more common in women than men, but other signs and symptoms do not differ in the two sexes. PBC is associated with a large variety of other diseases, like arthropathy, CREST syndrome, autoimmune thyroiditis, and so on, which in addition will or will not produce symptoms.

... Most of the patients (>90%) seem to have anti-mitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria.

Primary biliary cirrhosis is considerably more common in those with gluten sensitive enteropathy than the normal population.[8][9] In some cases of disease protein expression may cause an immune tolerance failure, as might be the case with gp210 and p62, nuclear pore proteins...

... This research revealed parts of the IL12 signaling cascade, particularly IL12A and IL12RB2 polymorphisms, to be important in the etiology of the disease in addition to the HLA region.

... In 2003 it was reported that an environmental Gram negative alphabacterium — Novosphingobium aromaticivorans[15] was strongly associated with this disease. Subsequent reports appear to have confirmed this finding suggesting an aetiological role for this organism.[16][17][18] The mechanism appears to be a cross reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells.[19] The gene encoding CD101 may also play a role in host susceptibility to this disease.



Studies are beginning to elucidate the biological associates of fatigue in PBC, particularly sleep disturbance and autonomic dysfunction
 

natasa778

Senior Member
Messages
1,774
The prevalence of autonomic dysfunction in primary biliary cirrhosis patients is significantly higher than has previously been thought to be the case. Indeed, when sensitive detection modalities are used, it is found to be almost universal at all stages of the disease process. Fatigue in primary biliary cirrhosis is associated with abnormalities of autonomic function.

http://www.ncbi.nlm.nih.gov/pubmed/17272997
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
This all seems very familiar and similar to research in another field of medicine that we're very familiar with. There doesn't seem to be quite such a backlash against these researchers though.

...the sex ratio is at least 9:1 (female to male).
One of the many similarities to ME. I've only recently discovered that retroviruses respond to human sex hormones. (This seemingly exceptionally relevant fact was kept quiet during the XMRV debates. Well, I don't remember it being highlighted anyway.)

Lipkin has quietly mentioned that he has found a retrovirus in his unpublished study of ME patients. And the Paptotka paper (recombination of XMRV1 & XMRV2 in the 22RV1 cell line) has been debunked by its own authors.

But I'm off-topic and it's probably best to keep XMRV discussions on the XMRV threads.
 
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snowathlete

Senior Member
Messages
5,374
Location
UK
If i temember correctly, PBC is an illness that Prof Newton in Newcastle, England has studied and she has noted similarities with some symptoms experienced by those with PBC and ME CFS.
 

Antares in NYC

Senior Member
Messages
582
Location
USA
few bits and pieces on PBC:
... It was previously thought to be a rare disease, but more recent studies have shown that it may affect up to 1 in 3–4,000 people; the sex ratio is at least 9:1 (female to male).
This just chaps my rear end. So PBC affects "up to 1 in 3-4,000 people", yet it gets the right research and the results to unlock it.

Even by the government's conservative estimates, ME-CFS affects about 1 in 300 Americans, and we get jack.

(PS: I strongly believe the true numbers for ME-CFS must be greater, if cases like myself are common. I spent 14 long years bouncing from doctor to clueless doctor without a diagnosis. I bet there are scores of people trapped in that cycle.)
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
One of the issues I raised in a thread on enteroviruses, is that most of the pathogens implicated so far in ME have similar lifecycles and tissue tropism (where they like to live), and have been in the human population for a very long time. It is likely they have co-evolved. I wonder if that co-evolution has led to systems of pathogens causing immune dysfunction to create the perfect host, at least perfect for them. If so then looking for the pathogen will be futile, and we will continue to find evidence of multiple pathogens.
 

natasa778

Senior Member
Messages
1,774

NK17

Senior Member
Messages
592
Natasa778 thank you for starting this thread which has so many interesting finds that make me and many others here on PR salivating and fuming at the same time.
Snowathlete is absolutely right in saying that Prof. Julia Newton in Newcastle has been researching and studying PBC and most importantly seeing many similarities in more than symptoms with ME/Cfs; I think that she'll be participating at this year Invest in ME conference in London.
Sad and funny how many of this important researches in other autoimmune diseases have evident links to ME/Cfs. I don't want to hijack the thread so I stop here ;).
 

NK17

Senior Member
Messages
592
Yes pathogens (bacteria, viruses and protozoa such as Toxoplasma Gondii) in order to survive and enhance their transmission manipulate their hosts by subverting cell signaling and many other pathways.
It's a fact that many scientists and medical doctors don't keep in mind or just plainly ignore ...
 

NK17

Senior Member
Messages
592
Dr. Andrew Mason's research deserves to be closely followed. There is a very interesting article about his idea of "Challenging the idea of Autoimmunity" on the web site of Alberta Innovates - Health Solutions. Not only is he brilliant but he persevere in translating into clinical studies this paradigm shift about the concept of autoimmunity! Not many clinician/researchers are bold enough and probably independent and influential enough to do that!
The fact that he is in Canada might be an advantage ;).
Now if I'd only be able to upload the file, I'd be a very happy PWME ...
Please cope with my PR poster rookie skills and the classic late afternoon brain mush:(
 

natasa778

Senior Member
Messages
1,774
Dr. Andrew Mason's research deserves to be closely followed. There is a very interesting article about his idea of "Challenging the idea of Autoimmunity" on the web site of Alberta Innovates - Health Solutions. Not only is he brilliant but he persevere in translating into clinical studies this paradigm shift about the concept of autoimmunity! Not many clinician/researchers are bold enough and probably independent and influential enough to do that!
/quote]


Is it this article?

He has been challenging the widely held belief that many gastrointestinal diseases are caused by the body turning against its own cells. He suspects that at least some of these diseases are really viral diseases, and his evidence comes from his own research. He has identified a virus associated with primary biliary cirrhosis (PBC), a disease in which the bile ducts of the liver are slowly destroyed, and scarring of liver tissue results. Although medication can slow the progression of the disease, a substantial proportion of patients will eventually require liver transplants. PBC is the reason behind more than 10% of all liver transplants worldwide. It is considered an autoimmune disease.

"I've always been skeptical about how autoimmunity is hypothesized as the cause for so many diseases," says Dr. Mason. "If you take a look at livers from patients with PBC or autoimmune hepatitis and compare them to livers from patients with hepatitis B or C, they don't look that much different. We know that hepatitis B and C are viruses—so why not look for viruses?"
 

NK17

Senior Member
Messages
592
Yes, that is the article.

Of pertaining interest is the book by Noel R. Rose, Y. Shoenfeld and Nancy Agmon Levin titled: Infection and Autoimmunity, you can find it on Google books.

The introduction makes it very clear that autoimmune diseases are due to our bodies responding to infectious agents, in all of them there is inflammation, sometimes systemic, other times specific to an organ.
The logical step is helping the immune system respond to the infectious agent/s attack by modulating it, by enhancing its capabilities and not suppressing it like it's still done as a first line of attack in SLE, MS etc.

Noel R. Rose will be speaking on March 21 at the IACFSME in San Francisco. He is the director of the Center for Autoimmune Disease Research at Johns Hopkins University School of Medicine.
 

Antares in NYC

Senior Member
Messages
582
Location
USA
One of the issues I raised in a thread on enteroviruses, is that most of the pathogens implicated so far in ME have similar lifecycles and tissue tropism (where they like to live), and have been in the human population for a very long time. It is likely they have co-evolved. I wonder if that co-evolution has led to systems of pathogens causing immune dysfunction to create the perfect host, at least perfect for them. If so then looking for the pathogen will be futile, and we will continue to find evidence of multiple pathogens.
Hi Alex,
I think you bring an important point. Oftentimes I feel that the pathogen(s) at the heart of ME/CFS evolved to indeed debilitate the immune system and perpetuate their survival.

I also have the theory that whatever pathogen did this to us (be it viral or bacterial), may be common among the general population, but only be able to "take over" our immune system under very specific circumstances. For instance, genetic predisposition, situations where the immune system is at its weakest. This would explain the fact that most of us became ill under duress (in my case, I was going through some major stressful situations and then I got a major flu/mono-like illness; I know that my own immune system always tended to weaken when I'm stressed).

This would also explain why researchers like Dr. Lipkin didn't find statistical differences between CFS patients and the control group when he looked for pathogens. In his still unpublished study, he mentioned he found traces of retroviruses, but he also found them in the control group.
Could it be that this retrovirus/enterovirus/pathogen is more common than we think, but it takes a very specific set of circumstances for it to take over the human body?

Just food for thought.