Eriksen’s ME/CFS hypothesis: interview

This interview with Dr. Willy Eriksen, a research professor at the Norwegian Institute of Public Health, is the second of three blog posts on his hypothesis regarding the cause of and potential cure for myalgic encephalomyelitis, aka chronic fatigue syndrome (ME/CFS). Here I ask Eriksen to elaborate on his published hypothesis. So please see the first post for a summary of his hypothesis in relatively plain language—or, if you have access, read his journal article, “The spread of EBV to ectopic lymphoid aggregates may be the final common pathway in the pathogenesis of ME/CFS.”

In the third post, I consider Eriksen’s model in comparison to other recent research and my own experience.

1. How did you become interested in explaining ME?

There are persons in my family with ME/CFS.

2. Could you describe briefly what’s unique about your hypothesis?

The hypothesis that I have presented can explain all symptoms and is consistent with all important research findings. It can be tested in a relatively easy way. And if the test is positive, one has both discovered a major cause of ME/CFS and found a cure. This constellation of aspects is quite unique, I think.

Over the years, many scientists and clinicians have suggested that EBV might play an important role. In my article, I review earlier hypotheses in which EBV plays a role, and I show how those hypotheses differ from mine. I am reluctant to make the comparison shorter than that.

3. Have you consulted with other experts in Norway or elsewhere, such as Fluge and Mella?

I have not consulted with other experts in connection with my work in developing the hypothesis. I have communicated briefly with some cell therapy experts on their experience with cell therapy but not on the pathogenesis of ME/CFS. However, over the years, I have read, literally speaking, thousands of scientific abstracts, articles, and reports on ME/CFS.

4. Does the infecting agent have to be EBV? Some people claim to have ME and test negative for EBV antibodies.

I do not think that all cases of ME/CFS can be explained by the mechanisms I have described. But I suspect that my hypothesis can explain the majority of the cases who meet the Canadian criteria.

Infections with neurotropic microbes, such as Coxsackie B virus, may cause temporary neuroinflammation and induce lymphoid aggregates in nervous structures. In patients who develop ME/CFS after such infections, I suspect that one additional important event takes place. That crucial event is that the lymphoid aggregates in the patients’ nervous structures become colonized by EBV-infected lymphocytes. Thus, what may appear as a postinfectious condition (“postviral fatigue syndrome”), may actually be a chronic infectious disorder, caused by a microbe (EBV) other than the one that triggered the condition in the first place (e.g. Coxsackie B virus). However, I do not dismiss the idea that also other mechanisms may lie behind ME/CFS, including other viruses. Under my hypothesis, HHV-6 may play a contributing role by interacting with EBV. It is possible, however, that HHV-6 also might play the major role in some cases, without any interaction with EBV.

So long as we do not know with certainty the causes of ME/CFS, one should keep an open mind.

5. How do the recent findings from metabolomics studies by Naviaux et al., Armstrong et al., and Hanson et al. fit with your hypothesis?

The findings from these metabolomics studies are fully consistent with my hypothesis. The metabolism of activated glial cells is disturbed. And metabolites from activated glial cells may be secreted into the extracellular space and further into the circulation, where they can be detected. Activated glial cells also produce cytokines that may be secreted into the circulation. Cytokines that are leaked into the circulation will affect many cells in the body and may disturb the metabolism of many types of cells. The metabolites from these cells that are disturbed by the cytokines may also be detected in the plasma.

If you look at the findings of Naviaux (PNAS, 2016), you will see that “the dominant finding from the pathway analysis was that sphingolipids abnormalities constituted close to 50% of all the metabolic disturbances associated with CFS.” Sphingolipids are particularly abundant in the nervous system and are involved in neuroinflammation.

6. Ron Davis and others have found that cells from ME patients turn healthy in blood from healthy people and vice versa, at least by the measures that they are using. (See, starting around 9:30). Does this fit with your hypothesis?

These findings of Ron Davis and others are fully consistent with my hypothesis. These findings indicate that there are substances in the serum of ME/CFS patients that influence the metabolism of healthy cells that are brought in contact with the serum. These substances may be the cytokines secreted from the activated glial cells (see above).

7. Lily Chu noted the following article on PubMed ( It reports a successful transplant of autologous lymph node cells. Does this agree with your hypothesis?

Lily Chu refers to Nancy Klimas and coworkers’ very interesting but uncontrolled trial. Their findings are fully consistent with my hypothesis. Some of the lymphocytes that were taken out, expanded ex vivo, and then reinfused in the patients may have been EBV-specific (i.e., directed toward EBV-infected cells). The EBV-specific lymphocytes must have represented only a small proportion of all the lymphocytes, though. According to my hypothesis, that design would give some effect, but not a major effect. That was exactly what Klimas and coworkers found.

8. Under your hypothesis, could something besides mechanical stress on peripheral nerves induce post-exertional malaise? I’m thinking, for example, of emotional stress or exposure to toxins. Or could these activate a different pathway to glial activation and thus PEM?

Based on my hypothesis, one would expect that the consequences of physical activity partly depend on the intensity of the glial cell activation in the peripheral nerves before the physical activity begins. So, in a situation in which the glial cell activation before the physical activity is at a low level, the patient may tolerate more physical activity than if the glial cell activation before the activity is at a high level.

Now, the glial cell activation before activity may be influenced by the extent and type of EBV-activity in the lymphoid aggregates (e.g., the extent of the lytic replications) before the physical activity takes place. It is known that emotional stress may temporarily weaken a person’s immune defense. So, if a period of emotional stress has temporarily reduced a ME/CFS-patient’s immune defense, and this has resulted in higher EBV-activity and stronger glial cell activation, less physical activity is required before post-exertional malaise is elicited.

One should also keep in mind that psychological distress is associated with changes in the pattern of body movements. For example, sitting at a table and reading a book when one is relaxed is different from sitting at the same table and reading the same book in a state of psychological distress. This is because the muscles are more tense in the latter situation. Tense muscles are obviously associated with increased mechanical stress on peripheral nerves.

Exposure to neurotoxins may affect the glial cells in a chemical way and thereby influence the level of glial cell activation. So, if an ME/CFS-patient has been exposed to such toxins, and this exposure has resulted in increased glial cell activation, the person may tolerate less physical activity.

9. Could you explain, for non-specialists, how your potential cure might work? That is, how are autologous EBV-specific T-lymphocytes produced, how frequent might infusions be, etc.? Is this treatment used against another disease?

I am not a cell therapy expert, and what I know about this is what I have learned from reading articles and from communicating with experts in the field. The methods used to produce EBV-specific T-lymphocytes vary between different cell laboratories. There are variations in the way the cells are activated and in the way the EBV-specific T-cells are identified and extracted. In short, the method is as follows: a) Blood is drawn, and blood cells are extracted from this blood sample. If one is going to use autologous T-cells, as I have suggested in my article, one extracts the cells from the patient’s own blood. b) The blood cells are activated with a mix of synthetic EBV-antigens and some other reagents. c) The cells are cultured in a way that makes the cells proliferate. d) T-lymphocytes are then isolated, harvested, controlled, and cryopreserved before clinical use. e) The T-lymphocytes are transferred to the patients intravenously. The number of cells in each dose and the frequency of infusions may vary with the condition that is treated. The number of T-cells given in one infusion may be around 10-20 million. One or a few infusions may be enough. Other patients may perhaps need “refilling.”

The effects of infusions of EBV-specific T-cells have been tested on patients with various EBV-related disorders. In many trials, T-cells from donors have been used. In some trials, T-cells from the patients themselves (autologous T-cells) have been used. Positive effects have been shown on EBV-related blood cancers and on multiple sclerosis. In many trials, one has had success in preventing or treating reactivations of EBV in immunocompromised patients. [That is, many trials have had success –ed.]

10. Do you plan to try this potential cure on patients or do you know of any lab that has such plans?

I will do what I can to make this happen. There are some hurdles, however. And much will depend on funding. Until recently, the methods used to make such cell products were so difficult, time-consuming, and costly that only a few laboratories in the world had the capacity to do it. With simplified methods and better equipment, this situation is now changing rapidly. So far, however, there is no laboratory in Norway with the production of EBV-specific T-cells in its repertoire. Thus, until further, testing the effects of EBV-specific T-cells will require cooperation with laboratories abroad.

I know of at least one research team outside Norway interested in doing the same. But, as far as I know, they are also short of money at the time being.

11. What’s next? Do you plan to work further on ME?

Yes, I am going to work further on ME. I am also involved in other projects at the Norwegian Institute of Public Health, but those projects are not related to ME/CFS.

After reading my comments on the original interview, Eriksen sent me an email explaining gut problems and the timing of processes:

There are two gut-related aspects of ME/CFS that a comprehensive hypothesis like mine should be able to explain: A) Many people with ME/CFS have symptoms that seem to stem from the intestinal system, such as abdominal pain, bloating, diarrhea, and food sensitivity. B) Some studies suggest that the intestinal bacterial flora of ME/CFS patients is different from that of healthy controls.

These aspects can be explained by my hypothesis. Understanding the anatomy and the role of the nervous system is the key. The intestinal wall and the connective tissue around the gut are, literally speaking, full of nerves, nerve endings, and bundles of nerve cells. These nervous structures control the peristaltic movements of the gut, they control the composition and magnitude of the secretions into the gut, and they convey sensations of pain. There are also nervous sensors that surveil the microenvironment in the gut. The majority of these nervous structures are linked to the autonomic nervous system and the central nervous system. So, a widespread glial activation may influence many aspects of how the gut functions. And fluctuations in the glial activation (e.g. after physical activity) may induce fluctuations in how the gut functions. Glial activation can, therefore, explain the ME/CFS-symptoms that stem from the intestinal system.

The intestinal bacteria are dependent on the “foodstuff” they get inside the gut. This “foodstuff” that the bacteria get inside the gut is determined not only by our diet but also by the quality and magnitude of the food components that reach different parts of the intestine. And the composition of these food components depends on the secretions from the intestinal wall, secretions from the liver via the biliary duct system, and the secretions from the pancreas. For example, when we eat fat, biliary secretions from the liver are poured into the small intestine, decomposing the fat, and making it easily absorbed from the gut. Without biliary secretions at the correct time after the meal, a lot of fat will reach the colon instead of being absorbed. Bacteria in the colon that like fat will then proliferate. And so on. Thus, it seems obvious to me that the intestinal bacterial flora will be influenced by disturbances in the nervous system that control the intestinal functions. Those who are in doubt could take a look at this paper: Rolig et al., Plos Biol February 16, 2017.

If PEM is due to further glial cell activation, then why does it take only a few days to run its course when Eriksen suggests that it takes many weeks for glial activation to die down after treatment with rituximab?

Glial cell activation is often a complex process with several elements and different types of cell reactions. Some of the reactions (e.g., cell proliferation) may build up over weeks and months, and may take a long time to cool off. Other reactions (e.g., waves of calcium-flux disturbances) can perhaps best be likened to a hurricane that comes in from the Caribbean Sea, sweeps across Cuba and Florida, and subsides after a few days.


One response to “Eriksen’s ME/CFS hypothesis: interview

  1. Pingback: ME/CFS: Eriksen on gut issues and timing | Tracy Duvall

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