The Invest in ME Conferences always provides talks on the cutting edge of chronic fatigue syndrome (ME/CFS) research and this year was no exception. This blog provides an overview of some of the talks. The information in the blog was taken from some good tweeting by Maija Haavisto and Phoenix Rising, the researchers abstracts and some other sources.

Maureen Hanson – The search for Biomarkers in M.E.

Bifidobacterium_longum_en_mMaureen Hanson is getting around. She started out on XMRV, moved to the gut and is now working on the mitochondria as well.  This first glimpse of her work on the gut microflora suggested that she’s making progress.  Hanson, a molecular biologist who was formerly focused on plant biology, has become a busy ME/CFS researcher and advocate and is a Scientific Advisor for the Simmaron Research Foundation.  She examined the bacterial microbiome and bacterial by-products in the blood of 48 ME/CFS patients and 39 healthy controls.

She found that bacteria belonging to bacterial families that produce butyrate, an anti-inflammatory (Ruminococcaceae, Bifidobacteriaceae), were significantly lower in ME. The healthy controls also had more bacterial diversity than the ME/CFS patients.

She also found that some patients have very high levels of lipopolysaccharides (LPS). Also known as endotoxins, LPS are large molecules that are found on the outside coats of gram negative bacteria that the bacteria release into the gut.

These toxins can send the immune system into a tizzy causing high amounts of inflammation. We don’t know how high the LPS levels were in these patients but high LPS levels cause a condition called endotoxemia which is a precusor to the sometimes deadly septic shock.  Like all really good immune tweakers, LPS also appear to play a role in autoimmunity.

LPS are clearly bad actors and have gotten a lot of study.  The 2011 Nobel Prize in Medicine was won by a man who demonstrated which parts of the immune system the LPS activated.  A finding of high levels of LPS in a subset of ME/CFS patients would be significant.

Hanson’s work is not refined enough yet to determine which species might be disturbing the balance in ME/CFS patients guts, but she said she was “on the way to identifying some useful markers”. The Lipkin/Hornig group is also on its way to identifying some useful markers. It was encouraging to read that Hornig highlighted butyrate forming bacteria in her talk as well.

Hanson looked for gut products in the blood that which could indicate that damaged gut linings were allowing gut bacteria to leak into the blood and spark a strong inflammatory response.  Using both blood analyses and bacterial composition Hansen was able to identify 83% of ME/CFS patients correctly.

Dr. Hanson is a careful researcher and she stated there’s no evidence yet that gut issues are causing ME/CFS; at this point she appears to be more comfortable saying they are more likely a consequence of ME/CFS than cause.

The gut is a complex place teeming with bacteria and it undoubtedly will take some time to get a handle on what is going on in there. The data thus far, however, suggests something is going on.

The Solve ME/CFS Initiative’s pilot gut/exercise study suggested that exercise was a) causing the gut flora to “bloom” and b) disturbing the gut lining enough to allow gut bacteria entry into the blood. Those bacteria that bloomed in ME/CFS patients (but not healthy controls) remained high for at least three days – long enough to contribute to the postexertional malaise so common in ME/CFS. As we just saw, Hanson has also found evidence of bacterial translocation in the blood.

These weren’t the first studies to find that. Back in 2008 Maes described a  “novel pathway” of ME/CFS causation featuring weakened gut lining which allowed the escape of gut materials into the blood.

We’re not lacking for the possibility that pathogens may be effecting the gut either. One of the speakers at the IIME Conference focused on the effects viruses can have on the gut. The Whittemore Peterson Institute’s preliminary data suggests that endogenous retrovirus infected dendritic cells could be impacting the gut.  Dr. Chia’s finding of enterovirus infections is well-known, if still, for some reason, not validated by an outside group, and Dr. Pridgen has found evidence of herpesvirus infection in the gut tissues of FM patients. Gut symptoms started Pridgen on his quest to develop antiviral protocols for FM.

Dr. Baraniuk

Baraniuk traced back the autonomic nervous system findings to the brainstem. It turns out that the nerves that power the motor and sensory systems of our body pass through the brainstem on the way to the lower body. The brainstem also regulates cardiac and respiratory functioning, the central nervous system and the sleep cycle.

ExerciseTiredHe found that the exercise test produced an explosion of sympathetic nervous system activity and triggered an episode of reversible tachycardia e.g. a temporary case of postural orthostatic tachycardia syndrome (POTS) in about 50% of ME/CFS patients but not in any controls. Finding that exercise dysregulates the autonomic nervous system to such a degree that it temporarily causes POTS is a major finding.

Baraniuk  appeared to reject the broader FM criteria created in 2010 when he argued that tender points are  important signs in FM (the new definition rejects tender points) because they signal central hyperalgesia; i.e. central sensitization or a brain that produces pain.

Dr. Cambridge – B cell Biology and Rituximab treatment in
Patients with ME/CFS (Rituximab II)

Dr. Cambridge revealed that the situation with B-cells and Rituximab is more complicated than one might think.  Most people probably know that Rituximab knocks out B-cells but that’s just the beginning of a fairly complicated story.

Rituximab whacks B-cells very quickly but in autoimmune diseases (as in chronic fatigue syndrome (ME/CFS)), the benefits don’t usually show up for months. That suggests the problem in these diseases is not the B-cells per se, but products the B-cells are producing, that linger in the blood for months after the B-cells are wiped out.

It’s when these products finally disappear and are not replenished (because the B-cells are gone), that patients feel better. When the B-cells come back and start producing those products again, they tend to get ill again.

Since people with high levels of autoantibodies tend to do better on Rituximab, that illness making product may very well be an autoantibody.

B-cell-signallingA “considerable proportion” of B-cells remain, however, even after Rituximab treatment. Plus autoantibody levels remain high in some patients who do well on the drug. Those factors suggest that only certain types of B-cells and autoantibodies are causing problems.

It’s clear as well, that since people on Rituximab generally relapse at some point after taking the drug, the drug doesn’t quite get at the core of the problem.

Thankfully, despite the fact that Rituximab was developed as a chemotherapy drug, side-effects are rare. Many people are worried that wiping many of the B-cells out will leave patients open to infection, but Dr. Cambridge reported that “the effects on protective immunity are mild and serious infections rare”.

Rituximab and ME/CFS

All that information came about from studying Rituximab’s effects on autoimmune disorders.  ME/CFS is a bit different story. Dr. Cambridge stated that their journey with Rituximab and ME/CFS is just beginning, and it’s complicated by the fact that ME/CFS is such a heterogeneous disease.  Put together a heterogeneous disease and the notoriously complex immune system and you have a knotty problem.

Dr. Cambridge is approaching that problem, though, by learning as much as possible about what’s going on in the B-cells in people with ME/CFS. If I have this right, she believes that B-cells may be reprogrammed as they regenerate themselves to produce autoantibodies.

Thus far she’s confirmed that a protein called CD24 protein that has been implicated in immune and autoimmune diseases is being over-expressed on B-cells from ME/CFS patients. CD24 is expressed on many cells; as of 2010 the role it played in them was mostly unclear but it’s a subject of interest in diseases ranging from autoimmune disorders to cancer. Even back in 2010 it was clear that it played a role in T-cell stimulation.

Dr. Cambridge is tweaking B-cells from ME/CFS patients and healthy controls with different stimuli such as cytokines, antibodies and agonists/antagonists to see how they respond. Something, after all, has to trigger the B-cells in ME/CFS to a) slap that CD24  receptor on their surface and b) to get them to produce the autoantibodies she believes are responsible for ME/CFS.

If she finds a substance – a cytokine or some other factor – that gets the B-cells in some ME/CFS patients to go bonkers, she may get close to how the immune dysregulation begins.  That would be exciting news indeed.

She’s also hoping to be able to identify who the drug is going to work in and who it won’t work in. If she can do that then expect a clinical trial that will surely work – and an FDA approved drug for a subset of people with ME/CFS.

Dr. Scheibenbogen -Autoantibodies to adrenergic and acetylcholine receptors in CFS/ME (Rituximab # II)

Dr. Cambridge believes autoantibodies are in play in ME/CFS and Dr. Scheibenbogen, a German researcher, and Drs. Fluge and Mella, are looking for them also.  Scheibenbogen is particularly interested in autoantibodies that might be attacking receptors on neurotransmitters in ME/CFS patients.

Thus far they’ve found increased levels of antibodies against two types of receptors in a subset of patients. The receptors were

  • the beta 2 adrenergic receptor – this receptor binds with epinephrine (adrenaline) and plays a key role in regulating the blood flows, muscle activity and breathing.
  • muscarinic acetylcholine receptors – these receptors regulate the activity of acetylcholine, the neurotransmitter associated with the parasympathetic nervous system.

The two receptors that popped up in this study, just happen to regulate both branches of the autonomic nervous system and play a major role in blood flows.  That, of course, fits ME/CFS in spades – a good sign.

The fact that the antibodies to these receptors dropped in ME/CFS patients who responded to Rituximab suggested that Rituximab was doing its good work by re-regulating the autonomic nervous system. The fact that several immune markers were also highlighted in these patients suggested that the autoantibodies were activating B and T cells.


Could autoantibodies be causing the mischief in ME/CFS?

Rather quickly, it appears we have the outlines of a multisystemic model that incorporates several key elements in ME/CFS. Some factor (pathogen) activates the B-cells which begin producing autoantibodies to receptors that govern blood flows, muscle contraction, etc. and sympathetic nervous system functioning. Rituximab knocks down the B-cells quickly but the autoantibodies hang around until they die off. When they do both the immune and autonomic nervous systems of at least some people with ME/CFS begin to return to normal and they feel much better.

It appears that about 30% of ME/CFS patients thus far have elevated antibodies to these B adrenergic or acetylcholine receptors. This isn’t the first time one of these autoantibodies have been found in ME/CFS, by the way, a Japanese study found elevated muscarine receptor autoantibodies in about 50% of patients.

Dr. Scheibenbogen proposed that the kind of ME/CFS you have may depend on which autoantibodies are present. According to the tweets, she suggested treatment programs consisting of Rituximab, high dose IgG and M3 acetylcholine stimulation might be helpful.

The stars seem to be aligning a bit for Rituximab.  As researchers have expanded their understanding of what the drug is doing in ME/CFS they produced a model that seems to fit ME/CFS very well.

I don’t think anyone thinks Rituximab will help everybody with ME/CFS but if it works in a substantial percentage – and if researchers can pinpoint who those people are – Rituximab will be way ahead of the game.

Health Rising is Almost Entirely Supported by Donations

Join Health Rising's ME/CFS, FM and Chronic Pain Forums!

ForumsShare your pain, make friends, find new treatment options, check out recovery stories and more in the Health Rising ME/CFS, FM and Chronic Pain Forums here

Don't Miss Another Blog!

Like this blog? Make sure you don’t miss another by registering for our free ME/CFS and Fibromyalgia blogs here..

Share This