This study looked at broken up bits of old retroviruses called Human Endogenous Retroviruses (HERV’s) that have been collected over time in our DNA and probably used successfully. (Did you know you were part retrovirus?). Most of these old retroviruses are too broken and mangled to do anything but a few have enough punch in them to worm their way out of the DNA and come at least halfway alive in our tissues…That wouldn’t be a good thing; no one wants a live, even debilitated retrovirus on the loose in their tissues.
Loose bits of reactivated retroviruses, no one wants HERV’s at loose in their system.
For one thing HERV’s are now so integrated into our genome that an immune response directed against a ‘live virus’ would very likely misfire and hit our own cells – causing an autoimmune reaction. HERV’s have been shown to spark such massive T-cell and antibody responses that they’re called ‘superantigens’.
Huber’s data suggesting active HHV6/7 viruses could trigger HERV reactivation made HERV’s particularly interesting in chronic fatigue syndrome and she good enough preliminary data of HERV reactivation for the NIH to fund a multi-year study. The study, recently released, failed to find evidence of either HERV or HHV6 activation in ME/CFS patients blood.
DeMeirlier and the WPI, however, weren’t looking in the blood. With HERV’s sparking more and more interest in autoimmune disorders, and ME/CFS looking more like an autoimmune disorder, the WPI/De Meirler team headed for the one of the biggest immune environments in the body – the gut.
In this study an international team (from the US, Belgium, Russia and Hungary) under the leadership of Dr. Lombardi at the WPI and Dr. De Meirleir dug into eight ME/CFS patients gut tissues to see if they could find evidence of HERV infection.’
This study found that 8/12 biopsies of people with ME (yes, they called them ME ), reacted to antibodies associated with HERV infection but none of the controls did.
Antibodies attack and attach themselves to proteins from invaders. The researchers exposed gut biopsies from patients to antibodies to HERV’s to see if they would attack them and they did. The cells the antibodies attacked were called plasmacytoid dendritic cells (pDC’s) which have been implicated, interestingly enough, in many autoimmune disorders.
Dendritic cells are found on the front lines of every pathogen conflict. Swarming every possible entry site- the skin, the mouth, the nose, the lungs, the intestines – dendritic ells are constantly sampling these areas for invaders. If they encounter a pathogen, they snatch a piece of it and rush back to the lymph nodes where they present their prizes to killer T and B cells for inspection.
Dendritic Cells, Fatigue and Hepatitis (Hepatitis?)
The activation of dendritic cell genes in interferon treated hepatitis patients who display similar types of exhausting fatigue suggests these cells could play a large role in producing fatigue. Interferon treated hepatitis patients who experience flu-like symptoms, fatigue, cognitive ‘slowing’ and depression have long been thought to be a potential model for ME/CFS and work in that area could very well shed light on what’s happened.
Researchers are chasing down many of the same suspects in interferon related fatigue as they are in ME/CFS including endocrine failure, autoimmunity, cytokine problems and neuropsychiatric disturbances.
The interferon/RNase L system in ME/CFS has not been studied recently but the theory got a boost when it popped up in a study examining the roots of the severe fatigue found in IFN treated hepatitis patients.
Indeed, De Meirleir et al. noted that several immune findings in ME/CFS make sense given their findings. Since these dendritic cells interact with NK cells, for instance, dysfunctional pDC’s could explain some of the NK cell problems. The gamma clonal T-cells found in some people with chronic fatigue syndrome are also found in HERV activated MS and rheumatoid arthritis patients.
There are some novelties here, as well. Nobody has proven that HERV’s cause autoimmune disorders, and no one, until now has found them in pDC’s, but the case that HERV’s contribute to autoimmunity appears to be strengthening over time.
It’s also possible that the HERV’s are present and doing nothing harmful .
The Gut Connection
Thus far, the gut is two for two in pathogen studies with both the Chia and DeMeirleir studies coming up aces once they got in and sampled tissues. The gut as an area of study/treatment is definitely heating up in ME/CFS.
Dr. DeMeirleir fashioned a gut hydrogen sulfide test he believes may be diagnostic for ME/CFS and we have that fascinating CFIDS Association microbiome study that will characterize all the bacteria in the gut before and after exercise that should be out soon.
De. DeMeirleir and other ME/CFS doctors now commonly focus on gut issues and most believe the gut must be healed for substantial progress to occur. I know of one ME/CFS patient who’s first sign of progress came after he re-engineered his gut flora using Xafaxin (Rifaxamin).
If you have an immune problem it’s probably going to show up in the gut. For instance, some evidence suggests cytotoxic T-cells are whacked in chronic fatigue syndrome, and if they are, with 60% of cytotoxic T-cell showing up in the small intestine, the guts ability to ward off pathogens is probably going to be hit as well.
Arthritis and other disorders have been linked to differences in gut flora. Dr. Hornig’s studies suggest the gut may play a key role in autism and, indeed, it’s not so far from the gut to the brain – obviously a key area in ME/CFS – as you might think. With the ‘second brain’ (the gut) containing many of the same neural pathways and neurotransmitters, etc., as the first brain, it’s perhaps no surprise that the two are being linked more and more over time.
In her NSU talk Dr. Hornig noted that gut issues could even explain autism. Her model something like this; low levels of gut enzymes and gut issues => little food breakdown => low antioxidant level passage to the blood => increased inflammation => penetration of the blood/barrier => problems in the brain => (gulp) autism? It’s one of many possibilities researchers are pursuing in that disorder.
Health Rising will be focusing on the gut in a series of blog over the next couple of months.
New possibilities are exciting and promising pathogen results have bit the ME/CFS community big time in the past – so caution is in order. The De Meirleir/Lombardi study suggested a gut HERV infection was present in 2/3rds of a very small group of, no doubt, carefully selected patients and the immune cell (pDC’s) the HERV’s were found in has not been associated with HERV infection before. It was small enough for Dr. Lombardi to call it an ‘observation’.
Huber’s pilot data on HERV activation in ME/CFS patients, gathered over two years using a CFIDS Association grant was probably more extensive and garnered her a big NIH grant, but that study doesn’t appear to have worked out.
The ‘First Study Syndrome’
We should all keep in mind the ‘First Study Syndrome’, as well, which suggests that first studies tend to work out more than second studies.
First studies tend to be frontloaded to produce positive results and are often not representative. In Dr. Peterson’s alluded to the cherry-picking of patients that almost inevitably occurs in first studies as researchers pick the patients they believe will get positive results, in his NSU talk. This isn’t bad or wrong, on the contrary, the intense competition for an ever smaller pool of grant monies at the NIH necessitates that. The big Hornig/Lipkin CFI pathogen study, for instance, almost certainly studied very ill patients whom ME/CFS doctors had already found evidence of infection in. Whatever positive findings come out of that study be sure to reduce them a bit for the larger ME/CFS population.
That’s not such a bad thing; even carving 20% of the ME/CFS population out of the whole group would be a huge breakthrough, not only for them, but for the other group.
If the HERV study is validated it will open new research avenues and treatment possibilities for a set of ME/CFS patients and even possibly for people with other autoimmune disorders. That’s more than good enough..
Dr. Lombardi graciously agreed to answer some questions about the study. The first was naturally about the negative Huber HERV study.
Dr/ Lombardi is proceeding cautiously with his results.
Dr. Lombardi Interview
Dr. Huber’s finding that herpesvirus infections (which have been found in gut materials of ME/CFS patients) could activate HERV-K18, seemed to set the stage for an explosive HERV finding but just last week Huber’s study suggesting that neither HERV-K18’s or HHV-6 or 7 were factors in ME/CFS was published. How does this relate to the Huber study which didn’t find evidence of HERV-K18 in PBMC’s of ME/CFS patients. Should the HERV’s you found be showing up in those cells, and if they did, should Huber have caught them?
Dr. Huber has previously showed that EBV can transactivate HERV K18. She has also reported HHV-6A can induce expression of HERV K18. However, in her recent study she did not observe any correlation between HHV-6A and ME/CFS. Therefore, its not surprising that she didn’t find HERV K18. There are many kinds of HERVs and Dr. Huber was looking for only one kind of HERV using very specific methods. We were using methods that have the potential to identify several types of HERV. Additionally, Dr. Huber was looking in blood and we were looking in tissue. Although the cells we identified as expressing HERVs are also found in the blood they are only about 0.2% of total white blood cells. The presence of HERVs in circulating plasmacytoid dendritic cells would be a very difficult target to identify unless you are specifically looking for it in those cells. But clearly, the two studies were different so it’s difficult to compare the results.
HERV’s can be activated by inflammation and you did a fecal analysis that found higher levels of pathogenic microbes in the ME/CFS patients. Could those higher loads of harmful bacteria be helping to create an environment in which HERV’s might show up?
The possibility of inflammation or some other factor being responsible for the HERV expression is definitely reasonable This is an area of investigation that we are actively pursuing.
The cells the HERV’s appear to be present in – dendritic cells – are antigen presenting cells; that is, they snip off proteins from invaders, staple them on their outsides and then present them to the immune system for analysis. If these cells are infected or defective, might they represent a weak spot in our immune defenses that might make pathogen invasion more likely?.
This particular subset of dendritic cell serves two roles; one as the principal producer of type I interferon and the other as an antigen-presenting cell. Both of these functions are important in a healthy immune system. A defect in these cells could certainly represent a weak spot in our immune system.
What about the presence of enteroviruses in the gut tissues of ME/CFS patients. Could they be creating or contributing to inflammation that is activating these HERV’s?
I can’t say for sure but it’s a possibility.
Do researchers know why HERV’s provoke such strong immune responses (as superantigens?)
I don’t believe that it is known why some HERVs elicit such a strong immune response. It may be related to their ancestral origin but this would just be speculation on my part. However, in that HERV protein expression does not appear to be a normal process this suggests that the body may see them as foreign and therefore, its conceivable that they would elicit an immune response.
What is the next step for you with the HERV findings?
Our recent publication merely describes an observation. The next step is to characterize it. That‘s what we are doing.
What does the next HERV study need to do to really lock down (or lock out) this finding in ME/CFS and is the WPI going to be able to do it?
A. HERV research is an active area of investigation in many other diseases. It’s possible that this observation will open the door to new areas of investigation of ME/CFS as well. It is too preliminary to determine how it will pan out. However, for us, it is at least a path worth following at the moment.
Coming up shortly an interview with Annette Whittemore and Vincent Lombardi…