The question must have rattled through everyone’s mind at some point. Why me and not you? Why did you get over that cold while I never did? It’s one of the great questions in the chronic fatigue syndrome (field).

blood chronic fatigue syndrome

Jason has blood samples from before people came down with ME/CFS.

Stabs have been taken at it before – but not many. Studies which assessed psychological comorbidities, for instance, attempted to see if there was a psychological predisposition to getting ME/CFS. (There wasn’t).

The Gist

  • Leonard Jason has blood samples from before college students came down with infectious mononucleosis (IM) and afterwards. He’s following them to see who comes down with ME/CFS.
  • He’s been using those blood samples to see if he can spot an immune hole which was present when the students were healthy which put them at risk for ME/CFS.
  • Jason’s last study suggested that low levels of three cytokines (IL-5, 6 and 13) might be putting college students at risk of getting ME/CFS if they come down with infectious mononucleosis.
  • In this study Jason et. al. did a more powerful analysis of the networks cytokines are embedded in. Cytokine networks are believed to more reflect disease processes than assessing the levels of individual cytokines.
  • This study found that the college students who failed to recover from infectious mononucleosis had more restricted, inflexible cytokine networks while those who were able to recover from it had more flexible, less interconnected networks.
  • It was as if the cytokine networks of the students who failed to recover didn’t have as many options or opportunities for action as the students who did.
  • A prior study using the same kind of network analysis came to a similar conclusion. For whatever reason the ME/CFS patients immune systems were kind of  already “locked in”.
  • The study also found less involvement of an immune network designed to fight off pathogens in the students who failed to recover from IM.
  • In further studies Jason hopes to be able to build a model which predicts who is likely to come down with ME/CFS after an infection.
  • Jason, I believe, also has blood samples from college students before and after they came down with long COVID.


If I understood correctly, long-COVID studies getting underway at the NIH are going to sweep though vast swathes of medical data to determine if underlying vulnerabilities exist.

No one, though, to my knowledge, has what Leonard Jason has. Jason has blood samples from before college students came down with infectious mononucleosis (IM) and afterwards.

That means he can compare baseline status of those who failed to recover from infectious mononucleosis and came down with ME/CFS – with those who were able to recover from IM. Jason, then, can at least take a swing at the question – why did I get sick while you didn’t.

The Study

Jason has already found that college students with reductions in several cytokines (IL-5, IL-6, and IL-13) were more likely to come down with ME/CFS after IM. His new cytokine network analysis paper, “Cytokine networks analysis uncovers further
differences between those who develop myalgic encephalomyelitis/chronic fatigue syndrome following infectious mononucleosis”, presents something arguably more important.

Because cytokines operate in complex, multidimensional networks, the functioning of a network is always more impactful than the functioning of a single cytokine. If you find out that a network devoted to fighting off pathogens has gone wonky – that gives you more does information than does the reduced levels of a cytokine or two.

Plus, the data on cytokines in ME/CFS has been mostly inconsistent – making it difficult to pin down what, if anything, is going on.

Jason’s network analysis found that the low levels of IL-6 found in the former study didn’t seem to matter much to the networks in which IL-6 was embedded. That authors pointed out that because “The ability of IL6 to influence other cytokines” did not differ amongst those who recovered and those who didn’t, IL-6 was probably ‘less of a critical predisposing immune irregularity leading to ME/CFS‘”.

That’s an important finding. Il-6 is believed to be a major player in many inflammatory and autoimmune diseases. If this study is correct, though, it’s probably not a major factor in post-infectious ME/CFS.

The two other cytokines with low levels (IL-5, IL-13) were, on the other hand, associated with disturbed immune networks in the students who failed to recover. They present the possibility of a double whammy: not only are their levels low, but they’re operating within a possibly dysfunctional network.

 Flexible vs Rigid Cytokine Networks

cytokine networks

People who recovered from infectious mononucleosis had more open cytokine networks.

immune network

People with more severe illness had pinched, more constricted cytokine networks.

The network analysis showed an intriguing and promising pattern. People who recovered from IM had broader, more loosely linked networks. People who came down with ME/CFS, but were less ill, had denser, more closely packed immune networks, while people who became more ill displayed the smallest, most densely connected immune networks. This was all prior to becoming ill.

A 2010 network analysis found a similar pattern. People with ME/CFS are on the right.

It was as if the ME/CFS patients’ immune systems didn’t have the breadth or suppleness needed to cope successfully with EBV.

Instead, they appeared to be locked into a more limited immune response.  The wider range of resources available to those with looser and broader immune networks may have helped them fight off IM and recover.

This isn’t the first study to suggest that congested and inflexible immune networks are present in ME/CFS. A 2010 cytokine network analysis found a similar pattern.

Simply being exposed to CMV produced large immune system shifts

A study found that a cytomegalovirus infection produced a huge immune network shift.

A great question, of course, is how a healthy person gets their immune system shifted like that? A prior infection or traumatic event could have done it.

Studies indicate, for instance, that prior cytomegalovirus infections dramatically impact cytokine networks.

The Chicken or the Egg? Stanford Study Suggests Immune Problems are Made Not Born

Smoking Gun Found?

The missing immune links in the soon-to-be ME/CFS patient seemed apropos indeed. Both the ME/CFS and the severe ME/CFS group displayed a “lack of involvement” in networks associated with interferon-gamma (IFN-y) – a key player in the antiviral response.

IFN-y has been called “critical for innate and adaptive immunity against viral, some bacterial and protozoan infections” and aberrant IFN-y responses have been associated with a number of autoimmune and inflammatory diseases. Not only does IFN-y directly inhibit viral replication, but it has also immuno-stimulatory and immunomodulatory effects. Interestingly, it’s mostly produced by two problematic immune cells in ME/CFS: natural killer and natural killer T-cells.

The finding suggests that the immune systems of people who later came down with ME/CFS may have had trouble fighting off the Epstein-Barr virus (EBV). Jason’s studies are the first to possibly identify an immune hole that existed prior to becoming ill, but they aren’t the first to suggest people with ME/CFS have trouble with EBV.


Has Jason uncovered an immune hole which allowed pathogens like EBV to take root?

In 2014, Loebel found a “deficient EBV-specific B- and T-cell memory response in CFS patients”, which suggested people with ME/CFS might have trouble controlling EBV.  Another study suggested that one part of the immune system in ME/CFS may be responding more actively than usual to an EBV protein. (Overactivation is as bad as underactivation.)

EBV may also be hyperactivating a “critical” gene in the immune and central nervous system in a subset of patients. A smoldering EBV infection also appears to be producing an enzyme that is sending the immune systems of some people with ME/CFS into a tizzy.

Plenty of options, then, exist, which could explain why people with ME/CFS might have trouble with EBV. One wonders, though, if Jason might have identified a key one – an essential difficulty engaging parts of the immune system to fight off EBV in the first place.

Jason et al. readily admitted that the cytokine studies in ME/CFS have produced mostly inconsistent, even contradictory results but argued that cytokine network analyses are more likely “to drive disease processes”.

Next Steps

step by stepThey noted that this one study alone was not sufficiently “predictive”; i.e. it was not enough to predict who might or might not come down with ME/CFS after an infection. Intriguingly, though, the authors predicted that they will be able to do that in the future – after their other studies and findings are published.

Nancy Klimas made a similar point in talk to long-COVID patients in a Body Politic webinar. Because ME/CFS is a whole system disease, she believes that whatever explains it is going to have to show – from the cellular level to the whole body –  how this disease has evolved. In other words one finding is not going to do it. It’s going to take multiple findings that get pieced together to understand ME/CFS.

This study, then, is just one potential step on that process. Jason also has blood samples from pre-COVID college students, as well. As the keeper of these precious blood samples, Jason, if he has the funds, could conceivably uncover the immune and other holes present before the illness, as well as what happens as these illnesses progress over time.


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