The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem.

[Remy]

Authors Jonathan C.W. Edwards, Simon McGrath, Adrian Baldwin, Mark Livingstone & Andrew Kewley

Full text here.

EDITORIAL
The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is comparable to multiple sclerosis, diabetes or rheumatoid arthritis in prevalence (∼0.2% to 1%), long-term disabil- ity, and quality of life,[1–5] yet the scale of biomedical research and funding has been piti- fully limited, as the recent National Institutes of Health (NIH) and Institute of Medicine reports highlight.[6,7] Recently in the USA, NIH Director Francis Collins has stated that the NIH will be ramping up its efforts and levels of funding for ME/CFS,[8] which we hope will greatly increase the interest in, and resources for researching this illness. Despite scant funding to date, researchers in the field have generated promising leads that throw light on this previously baffling illness. We suggest the key elements of a con- certed research programme and call on the wider biomedical research community to actively target this condition.

Biological questions

For many with ME/CFS life has effectively stopped – so immediate therapeutic studies are attractive. However, although serendipity can help, as in the observation that some patients may benefit from B-cell depletion,[9] lack of biomarkers or an understanding of the illness has held back development of targeted treatments. Study of mechanism there- fore remains a key priority.

Drawing on the experience of one of us (JE) in elucidation of pathogenesis in rheu- matoid arthritis, and its application to therapy,[10,11] we favour starting with broad systems analysis of natural history. Following Stastny,[12] we see such an analysis as including the evaluation of internal stochastic factors (e.g. chance immunoglobulin gene rearrangements encoding auto-antibodies capable of evading deletion) as well as genetic and environmental factors. Stochastic factors, although of major importance in cancer (as cumulative random mutations), have often been overlooked in mechanistic explanations of disease and are likely to be relevant in acquired, largely sporadic con- ditions such as ME/CFS. Additionally, epidemiology provides several clues, most notably the strikingly high proportion of female patients – typically 75% [1,2] – and the apparent bimodal age distribution [13] suggesting an age-dependent susceptibility to initiating events.

There is some family clustering, and sometimes a common history of initial viral or other (chiefly intracellular) infection, occasionally as during an epidemic: examples include Epstein-Barr virus (EBV), Ross River virus and the bacterium Coxiella burnetii (which causes Q fever).[14] Either prolonged exposure to a pathogen or adverse environmental factors, in combination with stochastic factors, could lead biological signalling networks to shift from a healthy steady state into a dysfunctional steady state that perpetuates the illness.[15–17] The occurrence of remission, either spontaneous or following treatment, [9] supports this dysregulatory model rather than one of irreversible damage.

Clues to ongoing mechanism include:

• . unconfirmed hints of genetic linkage, including to cytokine [18,19] and human leucocyte antigen genes [20];
• . repeated but variable observations of defective natural killer cell populations [21,22];
• . variable changes in B and T cell control of EBV reactivation in patients whose illness began with infectious mononucleosis [23];
• . reduced physiological performance on the second of a two-day cardiopulmonary exercise test, despite respiratory exchange ratios indicating maximal effort on both days [24];
• . substantial changes in leucocyte gene expression of metabolite-sensing adrener- gic receptors following physical exertion [25];
• . autonomic dysfunction, including orthostatic intolerance and syncope [26];
• . altered brain imaging, indicating both microglial activation [27] and structural
  changes.[28]

These findings have not been replicated sufficiently to provide firm anchor points for further research, but this may reflect lack of opportunities with scant resources and perhaps cohort heterogeneity. In this context a recent report suggests that plasma cyto- kine levels may be abnormal (including IL-8 and gamma interferon, which have been noticed before), but specifically in illness of under three years’ duration.[29]

 

[Cort]

I don't know what this is - it's clearly from Edwards and

including the evaluation of internal stochastic factors (e.g. chance immunoglobulin gene rearrangements encoding auto-antibodies capable of evading deletion)

and I like this

could lead biological signalling networks to shift from a healthy steady state into a dysfunctional steady state that perpetuates the illness.[15–17] The occurrence of remission, either spontaneous or following treatment, [9] supports this dysregulatory model rather than one of irreversible damage.

Nicely done

 

[Cort]

I think this is probably true

Considering both the clinical picture itself (with widespread cognitive and other global problems such as pain and fatigue), and the likelihood that the chronic disease state may involve a complex regulatory system shifting to an abnormal equilibrium state, it is likely that the pathophysiology involves the central nervous system (CNS), plus or minus the immune system (both with complex regulatory dynamics) in some or all cases.

I wouldn't be surprised if the problem is mostly regulation - un or dysregulated pathways in the brain run amok causing fatigue and pain.

I very much like this

since acquired persistent dysregulation purely at a local cellular or mitochondrial level is hard to explain

because I don't understand how to explain widespread mitochondrial unless they are the result of autoimmune processes.

 

[Remy]

because I don't understand how to explain widespread mitochondrial unless they are the result of autoimmune processes.

Pathogens can also produce proteins that cause channelopathies that cause conformational changes to the mitochondria resulting in dysfunction. I don't think EBV is the be all end all of ME CFS.

And if it's autoimmune, shouldn't we also be looking at B cell REpletion not just Rituximab?

 

[weyland]

because I don't understand how to explain widespread mitochondrial unless they are the result of autoimmune processes.

I think this could be explained by various circulating factors. Antibodies, cytokines (or lack thereof), ROS/NOS, etc, or even lack of adequate circulation.

 

[Strike me lucky]

So its just a review of some of the research so far on cfsme, things most long term cfsers know anyway through their own research.

I hope govt money wasnt wasted on this. Id rather see money going into trying to replicate past research or new research and treatments.

Dr Komaroff has done reviews like this every few years on the current opinions and research of cfsme. Peterson and klimas also do something similar.

I guess each country has to reinvent the wheel?

 

[Cort]

I think this could be explained by various circulating factors. Antibodies, cytokines (or lack thereof), ROS/NOS, etc, or even lack of adequate circulation.

Yes. Ron Davis mentioned that....

I really wonder about lack of adequate circulation and problems with microcirculation....That could be big.

 

[Cort]

So its just a review of some of the research so far on cfsme, things most long term cfsers know anyway through their own research.

I hope govt money wasnt wasted on this. Id rather see money going into trying to replicate past research or new research and treatments.

Dr Komaroff has done reviews like this every few years on the current opinions and research of cfsme. Peterson and klimas also do something similar.

I guess each country has to reinvent the wheel?

Yah, pretty sure no federal dollars used on this one...Glad to see it on the IACFS/ME's new journal.

 

[Cort]

Pathogens can also produce proteins that cause channelopathies that cause conformational changes to the mitochondria resulting in dysfunction. I don't think EBV is the be all end all of ME CFS.

And if it's autoimmune, shouldn't we also be looking at B cell REpletion not just Rituximab?

So pathogens can produce proteins in the blood that whack the ion channels? Is that how it goes.

I agree that other pathogens MUST be involved in some patients - at least in the beginning.

 

[Remy]

So pathogens can produce proteins in the blood that whack the ion channels? Is that how it goes.

I agree that other pathogens MUST be involved in some patients - at least in the beginning.

What, do you mean you missed even one of my scintillating posts? Haha.

http://www.healthrising.org/forums/...ivation-at-the-root-of-mecfs.4139/#post-17075