All posts tagged Wyller

NEID Disease? Study Suggests Neuro, Endocrine and Immune Systems Work Together to Produce ME/CFS

Bruun Wyller continues to surprise. When last heard from this erstwhile cognitive behavioral therapy (CBT) proponent asserted that more research into Epstein-Barr virus in chronic fatigue syndrome (ME/CFS) was needed. Now he’s looking at the interaction between the immune and endocrine systems.

The Evolution of a Chronic Fatigue Syndrome (ME/CFS) Researcher? CBT Proponent Calls for More Herpesvirus Research

Transforming growth factor beta (TGF-β) in adolescent chronic fatigue syndrome Vegard Bruun Wyller1,2*, Chinh Bkrong Nguyen1, Judith Anita Ludviksen3,4 and Tom Eirik Mollnes. J Transl Med (2017) 15:245 https://doi.org/10.1186/s12967-017-1350-

Wyller begins his new study reporting that systemic inflammation is probably present and B-cell functioning is impaired (if modestly) in ME/CFS, but that the picture regarding cytokines is muddier. A meta-analysis of 38 ME/CFS cytokine studies examining 77 cytokines found only one standout – a cytokine called TGF-B. It was consistently elevated in 2/3rds of the studies.

cytokines chronic fatigue syndrome

Only one cytokine has more or less consistently shown up elevated in ME/CFS studies – TGF-B

Given its unusual and consistent appearance in cytokine study results, why TGF-B has gotten so little attention in ME/CFS is unclear. The fact that it’s kind of a weird cytokine probably doesn’t help. Secreted by macrophages and some other immune cells, TGF-B can function as both an anti and pro-inflammatory cytokine depending on the situation it’s in.

It’s three forms are involved in a multitude of regulatory processes involving inflammation and immunity.  It does more than participate in the immune system; TGF-B also affects or is affected by the two stress response systems in our bodies – the HPA axis and autonomic nervous system. All that makes TGF-B a complex character indeed.

Take our two stress response systems. During stressful situations increased TGF-B levels appear to be associated with increased levels of cortisol – the main stress hormone of the HPA axis.  An ME/CFS study examining the gene expression of immune cells found an abnormally high expression of genes that interact with the HPA axis and autonomic nervous system. That suggested that a significant immune-hormone component is present. Indeed, ME/CFS has long been characterized as a neuroendocrineimmune (NEID) – a disease that effects all three systems.

In this study Wyller, a Norwegian researcher, again used his own broad definition of ME/CFS to find patients, but this time he did post hoc analyses using the Fukuda and Canadian Consensus criteria to determine if different definitions of ME/CFS made a difference – they didn’t). As always, Wyller studied adolescents – a lot of them (n=120) and 68 controls to produce a very nice sized study. The data analysis took a long time; the data itself was collected from 2010-2012.

TGF-B actually comes in three forms ((TGF‑β1, TGF‑β2 and TGF‑β3). For the first time ever in ME/CFS Wyller tested for all three forms of TGF-B, as well as norepinephrine, epinephrine and cortisol (urine) and c-reactive protein (serum).   He also assessed heart rate variability, and in 29 patients examined their whole blood gene expression.  Questionnaires assessing fatigue, inflammatory symptoms, post-exertional malaise, sleep, mood and anxiety were also given.

Results

Wyller expected TGF-B levels to be higher in his adolescent ME/CFS patients, but to his surprise even using the CCC and Fukuda criterias, they were not. Nor was TGF-B associated with any clinical markers such as fatigue, PEM, sleep problems, etc.

cortisol

Wyller suggests an unusual neuroimmune connection involving TGF-beta and stress hormones such as cortisol (pictured) may be present

The study was looking like a bust until Wyller dug a little deeper. It turned out that TGF-B levels were associated with increased levels of the stress hormones cortisol, norepinephrine and epinephrine in the ME/CFS patients but not in the healthy controls.

An unusual immune-endocrine interaction was occurring in ME/CFS patients that was not found in the healthy controls. For some reason, TGF-B  levels rose in conjuction with stress hormones in the ME/CFS patients but not in the healthy controls.  All three TGF-B isoform displayed this association.

Plus that association also correlated with symptom severity. Wyller found that the TGF-B-cortisol-autonomic nervous system correlation was strongest in the most fatigued ME/CFS patients.  Less fatigued ME/CFS patients, on the other hand, had much less of this association.

Once again, context appeared to be king in the ME/CFS patients. The levels of TGF-B didn’t matter but the network they were embedded in did. A similar scenario showed up in the huge cytokine study conducted by Dr. Montoya and Mark Davis of Stanford. That study, like Wyller’s, didn’t find high levels of cytokines, but it did find that even normal cytokine levels affected symptoms. That suggested some sort of immune hypersensitivity, perhaps associated with some unusual network functioning, was present.

Now Wyller apparently finds an immune and autonomic nervous sensitivity to TGF-B. It’s not the cytokine levels themselves but the effect they have on stress hormones.  Indeed, Wyller suggested that the primary disease mechanism in ME/CFS is not altered immune production but altered immune control. Somehow the immune system is affecting other systems in unusual ways.

That’s an intriguing idea given what we’ll shortly see from Dr. Klimas, whose intense testing during exercise suggests that exercise induced immune activity trips off autonomic nervous system problems in ME/CFS. Gordon Broderick’s network studies suggest that cytokine levels don’t need to be high to have untoward effects on ME/CFS patients – they simply have to be embedded in an unusual immune network.

Wyller - neuro-endocrine-immune disease

Wyller believes a complex neuro-endocrine-immune interaction may be contributing to the fatigue and possibly the EBV issues in ME/CFS.

Dr. Klimas will be trying in a series of small studies to move those systems back to normal this year. (More on that later.)

Wyller’s findings suggest that his “sustained arousal” hypothesis may be correct and that the “sustained arousal” he believes is present in ME/CFS is being triggered by the immune system. His small gene expression study possibly bares this out. Wyller warned about reading too much into the gene expression analysis because of the small sample size (n=29). The analysis found, though, that the TGF-B3 isoform was negatively associated with reduced expression of two B-cell genes (TNFRSF13C and CXCR5).

Wyller suggested that TGF-B3 may be altering the effect that cortisol – the master immune regulator – has on B-cell genes in ME/CFS.  If TGF-B and cortisol combine to smack B-cell genes in ME/CFS, Wyller suggests that could translate into problems reining in Epstein-Barr virus (EBV) – a common trigger in ME/CFS.  Wyller’s earlier gene expression study, in fact, suggested that B-cell problems could be the key to the EBV problems seen in ME/CFS. Now Wyller suggests that these B-cell problems could result from a complex interaction between TGF-B and cortisol.

Wyller’s going to check out that interaction in a study which will determine how effectively the B-cells in ME/CFS patients respond to EBV in the presence of neuroendocrine hormones. If cortisol or other neuroendocrine hormones impair the ability of B-cells to whack EBV in ME/CFS, Wyller may have uncovered one reason why mononucleosis is such a common trigger for ME/CFS.

Mold Connection?

Wyller’s focus on the research literature apparently precluded him from exploring another TGF-B angle. Mold has become a hot if little studied topic in ME/CFS. For over a decade, mold doctor Ritchie Shoemaker has asserted that elevated TGF-B levels play a major role in mold related illnesses.  Instead of B-cells, though, Shoemaker ties TGF-B issues to T cell problems and reduced blood flow in the capillaries, which translate into reduced oxygen uptake and problems with producing energy in the mitochondria – a key theme in ME/CFS.

Shoemaker, interestingly, asserts those blood flow and immune problems mirror what is happening in sepsis. In fact, Shoemaker believes that the chronic inflammatory response syndrome (CIRS) he sees in his patients is a chronic form of sepsis. Over ten years ago ME/CFS specialist Dr. David Bell proposed a chronic form of sepsis exists in ME/CFS as well.

Could Chronic Fatigue Syndrome (ME/CFS) Be a Chronic Form of Sepsis?

 

The Evolution of a Chronic Fatigue Syndrome (ME/CFS) Researcher? CBT Proponent Calls for More Herpesvirus Research

At times Dr. Wyller of Oslo University has seemed more like a Norwegian version of Simon Wessely than anything else. He’s shown that biological issues were present in ME/CFS, but always manages to come back to the psychological or behavioral elements he believes are perpetuating the disease. His new research, however, is taking him in another direction.

anxiety-fear

Wyller appears to believe that the fatigue in ME/CFS is the result of a false alarm in the same way that pain is in fibromyalgia

Wyller’s research group has highlighted sympathetic nervous activation and inflammation in chronic fatigue syndrome (ME/CFS) adolescents. His “sustained arousal” hypothesis, however, is a mishmash of physiological (infections, genetics) and psychological components (psychosocial challenges, illness perceptions, poor control over symptoms, “inappropriate learning processes”, personality traits, etc.).

That hypothesis posits that a “false-fatigue alarm” state exists in ME/CFS which is largely held in place by classical and/or operant conditioning. That conditioning can be ameliorated by behavioral techniques which tamp down the “alarm” and the sympathetic nervous system activation.

Wyller’s belief that ME/CFS is an infection/stress triggered disease of sympathetic nervous system (SNS) activation, however, took a hit when clonidine – an SNS inhibitor – actually made ME/CFS adolescents worse. Since SNS activation is arguably present and would certainly contribute to the inflammation in ME/CFS, that result probably shocked just about everyone. It suggested, though, that just as in some cases of POTS, the sympathetic nervous system activation found might be a compensatory, not pathological, response to the illness.

Wyller  admits that that CBT’s “effect size” is “modest” and that there is little evidence that it helps sicker patients, but asserts that the evidence-base is “so-solid” that it should be attempted in every patient.

“We believe the evidence base for cognitive behavioural therapy is so solid that all patients with chronic fatigue syndrome/myalgic encephalomyelitis should be offered this treatment.” Wyller et. al.

Wyller 2017: the Evolution of an ME/CFS Researcher?

Wyller may be a CBT/GET apologist, but he’s mostly done physiological research, and whatever his CBT/GET beliefs, it’s difficult to pigeonhole him. His failed Clonidine trial constituted a biological approach to ME/CFS plus his 2016 followup study suggested that a genetic polymorphism in the COMT gene may be responsible for reduced physical activity and impaired sleep and quality of life in some ME/CFS patients.

It’s Wyller’s latest study, however, that takes him into entirely new ground. To his credit, he’s allowing the data to lead him where it will.

Wyller is clearly heavily invested in CBT/GET, while his Norwegian counterparts, Drs. Fluge and Mella, eschew CBT/GET and focus on Rituximab and immune modulation. Wyller mentioned Rituximab in his 2015 overview, but not surprisingly gave it short shrift because of the lack, what else, of follow up studies. But here’s Wyller in 2017 with a study that’s pointing an arrow right at the B-cells in ME/CFS and perhaps even Rituximab.

Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival. Chinh Bkrong Nguyen,1,2 Lene Alsøe,3 Jessica M. Lindvall,4 Dag Sulheim,5 Even Fagermoen,6 Anette Winger,7 Mari Kaarbø,8 Hilde Nilsen,3 and Vegard Bruun Wyller. J Transl Med. 2017; 15: 102. Published online 2017 May 11. doi:  10.1186/s12967-017-1201-0

Using his own definition of ME/CFS, Wyller and his research team took a deep look at gene expression using a technology called high throughput sequencing (HTS) which has not been used before in ME/CFS. You never know what exploratory studies like this will turn up.

The 176 genes whose expression was highlighted in the ME/CFS group most prominently featured a down-regulation of genes involved in B-cell differentiation. The activity of five genes involved in B-cell development, proliferation, migration and survival were significantly reduced in Wyller’s ME/CFS adolescents.

Wyller chronic fatigue syndrome

Wyller’s research is leading him into some unexpected areas

This finding, Wyller reported, jived with findings from the Australians of decreased levels of some B-cells and increased levels of others. (Decreases in the gene expression of genes regulating B-cell proliferation could result in either reductions or increases in different types of B-cells).

At the same time the B-cells in his ME/CFS adolescents were taking a hit, the expression of their innate immune system genes were being upregulated. Interestingly, given the idea that a pathogen is whacking the B-cells in ME/CFS, the expression of several genes associated with pathogen defense were increased in ME/CFS. (Wyller, in fact, reported this was the first time that increased expression of genes associated with innate antiviral responses has been seen in ME/CFS.)

Then, remarkably, Wyller – who recently criticized antivirals as he argued that CBT/GET should be the treatment of choice in ME/CFS – asserted that this finding could reflect problems his ME/CFS adolescents were having with clearing latent herpesviruses.

They “might suggest less efficient viral clearance or reactivation of latent viruses such as members of the herpes virus family, in the CFS group” Study Authors.

Then Wyller suggested that “inefficient viral clearance or reactivation” or chronic viral infection-triggered immune dysfunction warrants further study in ME/CFS.

Then he referred to a remarkable 2014 German study which suggested that a deficient B- and T-cell memory response to EBV may be making it difficult for ME/CFS patients to control EBV infections. That’s really no surprise to the ME/CFS community; it’s long been clear that infectious mononucleosis is a common trigger for people with ME/CFS and FM – but it’s for a CBT proponent to make the connection.

Herpes viruses continue to show up ME/CFS research

Herpes viruses continue to show up ME/CFS research

Finally, Wyller’s study suggested that neither inactivity nor mood disorders had any effect on the biological findings presented. (One of his earlier studies discounted the idea that deconditioning was a relevant factor. )

Wyller’s findings are good news, not just because he’s been so committed to his idea that “classical or operant conditioning” perpetuates ME/CFS, or that he’s been such a robust CBT/GET advocate, but because he has shown the ability to get funding.

His next step is to determine how effectively the B cells in ME/CFS are responding to EBV antigens (VCA, EBNA-1) before and after the introduction of stress hormones. If he finds that B-cells are not doing their job with respect to EBV, then both Wyller and the ME/CFS research field are going to have a take a closer look at the role EBV plays in ME/CFS. What a switch that would be!

Wyller isn’t the only one diving back into the herpesviruses.  Two Solve ME/CFS Initiative studies are examining metabolic issues in B-cells and cells infected with HHV-6. Plus studies into B-cell issues in ME/CFS are continuing.

One wonders what further positive results would do to Wyller’s view of the appropriate treatments for ME/CFS. Given the tendency of herpes viruses to reactivate during stressful situations, stress reduction techniques (CBT, meditation, MSBR) might, in fact, be useful, but more importantly, so might antivirals, and immune  modulating drugs like Rituximab or cyclophosphamide.

It’s possible that at some point that researchers on both sides of the ME/CFS divide will someday meet in the middle.