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This is the third in a series of blog covering the IACFS/ME Zoom conference.

Back to the B-Cells: “Immune Dysregulation with Deviated B-Cell Receptor Repertoire in ME/CFS”

It was great to see the IACFS/ME reach across the ocean and get a Japanese researcher, Dr. Wakiro Sato, to present. Japan, which has done a ton of work on chronic fatigue syndrome (ME/CFS), is best known for Nakatomi’s groundbreaking work on neuroinflammation, but it’s done a lot of work on the brain in general.

plasmablast

A plasmablast (B-cell) emitting antibodies.

Sato has co-authored two studies on the brain in ME/CFS in the past two years – one of which found that increased levels of antibodies to adrenergic receptors were associated with changes in the brain. All in all, he’s co-authored eight studies that have been cited in PubMed and has probably co-authored dozens more that have been published in the Japanese medical literature.

You might have thought that B-cell research in chronic fatigue syndrome (ME/CFS) was done after the Rituximab study – Rituximab being a B-cell inhibitor – failed, but no. So far as I can tell the B-cell findings in ME/CFS have been up and down, but Sato appears to have produced a pretty strong result.

First he found increased expression of two IGH genes that are involved in antibody production. The genes evidenced something rather rare in ME/CFS: high sensitivity and specificity; i.e. they were great at correctly identifying who had ME/CFS and who didn’t. That’s the kind of precise finding that could, if it’s validated, ultimately result in a biomarker.

Then, an “unbiased comprehensive analysis of B-cell repertoires” revealed oligoclonal expansion; i.e. the B-cells in some patients had started producing large numbers of clones of themselves – presumably to fight off a pathogen. Right off we had two signs of increased B-cell activity, and therefore, possibly a tendency towards autoimmunity.

Sato then found increases in antibody secreting cells or plasmablasts, which was associated with illness severity; i.e. the more severely ill the patient was, the more plasmablasts were present.

That suggested their B-cells might be flooding their systems with antibodies – another possible setup for an autoimmune disease. The more antibodies that are present, the better chance that something will go wrong and our tissues will get attacked.

Next, Sato used a gene expression study to see if the plasmablasts were “tuned” to producing an autoimmune reaction. The answer to that study was yes, the upregulated genes found have been associated with autoimmune reactions.

Finally, Sato reported that he’d found increased levels of the same adrenergic autoantibodies Loebel and Scheibenbogen reported they’d found in some patients back in 2016.

It’s certainly not clear that an autoimmune reaction involving these autoantibodies is happening, but this is the third or fourth study, I believe, to have found that. Sato and colleagues recently found that increased levels of beta adrenergic antibodies were associated with alterations in the prefrontal cortex of the brain.

Japanese studies have suggested that the failure of this center of “executive functioning” in the brain to rein in the limbic system may have profound implications for ME/CFS.

Sato hypothesized that plasmablast expansion in ME/CFS is producing antibodies that are whacking the adrenergic receptors in the brain. Given that, he believes that treatments which knock down B-cells may be helpful. Rituximab is one such treatment which didn’t work out, but others apparently exist.

Could Happiness Help? “Why Patients Improve. Why They Get Worse” 

Friedberg’s was more a coping or life situation study than a treatment study. It simply asked what, if any, activities in daily life made ME/CFS better or worse. One of the study’s strengths was that it included a physiological component: along with many questionnaires, etc. it actually measured heart rate variability (HRV).

Studies suggest that HRV in ME/CFS and FM tends to be low – which means the autonomic nervous system is kind of stuck and is not responding flexibly to stressors. Various wearables such as the Oura ring use HRV to advise the wearers whether to rest more, for instance. (It’s not clear how accurate devices like the Oura are …)

Check out how one person with ME/CFS utilized heart rate variability to improve her health.

Friedberg hypothesized that maladaptive activity patterns (such as engaging in a ‘push-crash’/ ‘boom and bust’ cycle or severely limiting activity), or higher levels of stressful events or major negative life events (loss of job, a death) would likely reduce HRV and increase symptoms.

Friedberg's study suggested that having more uplifting experiences might help.

Friedberg’s study suggested that having more uplifting experiences might help.

Likewise, things like pacing, uplifting pleasant events (such as positive social interactions or fun/joyful activities) or major positive life events (a marriage, a birth, a new job, a holiday) would increase HRV and reduce symptoms.

It was a large, 6-month study of 125 women, most with long-term ME/CFS (average illness – 16 years). Questionnaires, weekly diaries (charting fatigue, pain, activity levels, and negative or positive events), activity monitoring (using an accelerometer to measure steps) and HRV monitoring, and an interview at the end of 6 months were done.

The results were shocking. I expected pacing, push-crash problems, negative events to get highlighted but no … none of those things were different between the improved group and the non-improved or the worsened groups. Limiting activity didn’t improve symptoms and too much activity didn’t make one more likely to be in the non-improved group.

Instead it was the frequency and/or intensity of positive/ uplifting events that stood out (!). Those patients with a significantly higher frequency and/or intensity of positive or uplifting events tended to be the ones who said they were improved at the end of six months.

People who reported more “uplifts” – very positive activities in the day – tended to be the ones who improved the most. That’s one result I never saw coming …

Some people will undoubtedly be upset to find a study linking something like “uplifts” to improved health. It’s too emotional, too behavioral. Note, though, that Friedberg is not claiming he’s found a cure – the patients were just doing better. At the end of the study, they were still long-term ME/CFS patients.

This finding may make sense in a couple of ways. The hypotheses put forward regarding neuroinflammation and glial activation in ME/CFS suggest our immune systems are on a tripwire – responding to the slightest stressor by pumping out damaging cytokines that produce fatigue, pain, flu-like symptoms, etc. Andrew Miller has demonstrated how an infectious event can sensitize the neurons in parts of the brain that have been associated with ME/CFS.

Plus, many parts of the brain that are associated with ME/CFS and FM – the insula, basal ganglia, limbic system, amygdala and brainstem – regulate both the autonomic nervous and the emotions. It’s likely you don’t get a dysregulation in one without some problems in the other. We also know that the fight/flight system is jacked up in ME/CFS and that the other major stress response – the HPA axis – has problems in ME/CFS as well.

Plus, there’s the lived experience of ME/CFS. For me, having ME/CFS/FM has been associated with difficulty calming down, irritability, difficulty concentrating, lots of fear, etc. My version of ME/CFS/FM is also accompanied by quite a bit of pain – a sure fight/flight inducer.

This is a bear of a disease. Being occupied with it, thinking about it, worrying about it, etc. – that is a heavy load to put on any stress response system – let alone one that’s already been damaged.

Maybe finding ways to bring more joy or happiness or “uplifts” to our daily lives could be helpful. Friedberg’s study suggests that it’s worth a try. .

We have after all seen stuff like this work in autoimmunity.  Donna Jackson Nakazawa has severe autoimmune disease – one that twice left her paralyzed for periods of time. She was on heavy drugs, exhausted and miserable.

She was able to dramatically decrease her symptoms, increase her energy, and improve her immune results through a year of mindfulness, meditation, yoga, etc. She still had her autoimmune disease but she was much happier, more functional and healthier.

Mitochondria Maladies: “The Dysregulation of Mitochondrial Function and Fuel Preference in ME/CFS Lymphoblasts” 

Talking about stress – Daniel Missailidis’s Australian study suggested that “a persistent mitochondrial stress response” was present. Missailidis is a young, obviously whip smart PhD candidate in Paul Fisher’s group at the University of La Trobe. Still a candidate, he’s already been the lead author in two ME/CFS studies and one review. Let’s hope he sticks around ME/CFS.

At the last EMERGE conference, Paul Fisher, a longtime mitochondrial researcher, reported that he’s been wanting to study ME/CFS for ten years. When he finally got the funds, he made the most of it.

In February of this year, Missailidis and Fisher published a complex study, “An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients“, that will be covered further.

Missailidis and his team put cell lines from 65 ME/CFS patients and 37 healthy controls through the Seahorse metabolic torture chamber. (Beside measuring the oxygen consumption and other metabolic parameters of the cells, one of the things the Seahorse does is metabolically stress cells in different ways to uncover where, metabolically, they don’t measure up.)

As has been seen in other studies, they didn’t find any differences in ATP production when the cells were unstressed.

Among other things Missailidis found that Complex V was inhibited in ME/CFS - and Complex I were trying to compensate. The end result - a likely inability to respond to energy demands.

Among other things Missailidis found was that Complex V was inhibited in ME/CFS – and Complex I were trying to compensate. The end result – a likely inability to respond to energy demands.

The Gist

  • A B-cell study from Japan produced several findings (oligoclonal expansion, increased plasmablasts, altered gene expression) which could be associated with autoimmunity. Plus, the study author also recently linked a possible autoimmunity (adrenergic autoantibodies) to prefrontal cortex problems in the brain.
  • Fred Friedberg’s large heart rate variability and “life situations” study suggested that having more positive life events might play a larger role than pacing in determining who improves or doesn’t.
  • An Australian study found more evidence of problems in mitochondrial energy production. Complex V of the energy production pathway in the mitochondria was inhibited, plus, in what was apparently a compensatory reaction driven by the TORC-1 pathway, activity in Complex 1 was upregulated. Several other problems (non-mitochondrial oxygen consumption, overall oxygen consumption, and proton leaks were found).
  • The Australian study also found evidence – as other studies have – that ME/CFS patients’ cells are turning to amino acids for fuel rather than glucose – thus adding another inefficiency to the energy metabolism equation in this disease.
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Five “complexes” make up ATP production in the mitochondria. Complexes 1-4 were functionally normal; i.e. they responded well to tests. A 25% drop in efficiency, however, was found in Complex V, and my notes say that proteomics revealed elevated activity in Complex I.

That suggested that Complex I was racheting up its activity – flooding the next complexes with electrons – in order make up for poor performance of Complex V.  Plus, non-mitochondrial sources of oxygen consumption were elevated as well – suggesting that the cells were trying to metabolize oxygen in any way they could. All told, the cells were actually using more oxygen than normal (as a proportion of basal oxygen consumption rate) – another sign of inefficiency and stress. Plus, the ME/CFS patients cells were leaking protons.

Further analyses pinned the TORC-1 pathway – one of the regulators of cellular respiration – as the source of the Complex I upregulation.

A look at glycolysis – the part of the ATP production cycle which does not depend on oxygen – found everything normal. However, a shift towards fatty acid utilization (instead of glucose) as a source of energy was found. This was highlighted by the increased degradation of branched chain amino acids or BCAAs. Because BCAAs break down ammonia, one of the potential consequences of increased degradation of the amino acids could be increased ammonia levels.

This metabolic shift – from glucose to amino acids – as a source of “food” appears to be pretty consistently found in ME/CFS. That shift, plus the problems with Complex V, could leave ME/CFS patients’ cells less able to respond to demands for more energy – resulting in the mitochondria being in a state of post-exertional malaise.

Conclusion

In the third in a series of blogs from the IACFS/ME Zoom conference we find more evidence of immune dysregulation and problems with energy production.

In what looks to be a strong B-cell study from Japan produced several findings (oligoclonal expansion, increased plasmablasts, altered gene expression) which could be associated with autoimmunity. Plus Dr. Sato recently co-authored a study suggested that autoantibodies to adrenergic receptors was impacted the prefrontal cortex of the brain. We might keep in mind as well a recent study which possibly linked B-cell problems with impaired energy metabolism

Fred Friedberg’s large heart rate variability and life situation study suggested – probably to everyone’s surprise – that it wasn’t a pacing (or the lack of it), or the number of negative life events that differentiated people who didn’t improve over 6 months from those who did – it was the frequency of positive or uplifting life events that did.

Daniel Missailidis and Paul Fisher’s study from Australia found more evidence that energy metabolism is off. In fact, using cultured cells the Fisher group may have come closer to figuring out what that is than anyone else.

Missailidis found significant inhibitions in Complex V of the mitochondria and other problems and -in an apparently compensatory reaction – Complex 1 was upregulated. (Complex 1 is one of the complexes that CoQ10 (ubiquinone) plays a role in.)The TORC-1 pathway was determined to be the source of the Complex I upregulation.

While glycolysis was normal, Missailidis found, as others have before, evidence of an increased use of amino acids for fuel. All in all his findings suggested that cells in people with ME/CFS are more likely to became exhausted quickly when presented with increased demands for energy.

More blogs from the 2020 IACFS/ME Zoom conference

Congratulations to Lily Chu, Fred Friedberg and the others at the IACFS/ME who adjusted to the coronavirus pandemic, moved the conference (at least part of it) online, and provided some intriguing findings for us to chew on.

 

Other Conference Reviews

How one person with ME/CFS used HRV to improve her health: 

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