Stress-Induced Transcriptomic Changes in Females with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveal Disrupted Immune Signatures

[SWAlexander]

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM), which is defined as a worsening of symptoms following even minor physical or mental exertion. Our study aimed to evaluate transcriptomic changes in ME/CFS female patients undergoing an exercise challenge intended to precipitate PEM. Our time points (baseline before exercise challenge, the point of maximal exertion, and after an exercise challenge) allowed for the exploration of the transcriptomic response to exercise and recovery in female patients with ME/CFS, as compared to healthy controls (HCs). Under maximal exertion, ME/CFS patients did not show significant changes in gene expression, while HCs demonstrated altered functional gene networks related to signaling and integral functions of their immune cells. During the recovery period (commonly during onset of PEM), female ME/CFS patients showed dysregulated immune signaling pathways and dysfunctional cellular responses to stress. The unique functional pathways identified provide a foundation for future research efforts into the disease, as well as for potential targeted treatment options.
https://www.mdpi.com/1422-0067/24/3/2698

 

[Wishful]

That's the most promising research paper on ME I've read yet. I'd like to see the study improved, not only by more participants, but also by using not-healthy controls who suffer similarly limited lifestyles, and testing at longer times (at least 24 hrs, when PEM typically starts). More difficult, but important: they should test fluid from within the brain, not just the spine, since there may be significant changes localized in the brain.

This is quite timely, since just last night I had thought of a new hypothesis about why physical exertion triggers PEM, and this study supports that. I'll post that as a separate thread about what triggers PEM.

 

[Consul]

That's the most promising research paper on ME I've read yet.

True


Some quotes from the discussion section:

In order to recover from a physical stressor, HCs may be able to inactivate their immune cells and reduce inflammation, whereas these pathways are dysregulated in patients with ME/CFS leading to constant low-grade inflammation.

Previously, our group analyzed the differential expression of microRNAs in ME/CFS patients during and after an exercise challenge [13]. We found that hsa-miR-146a-5p was overexpressed in female ME/CFS patients but not in HC between 4 h after maximal exertion (T2) and maximal exertion (T1). This microRNA has been shown to regulate the expression of the gene TRAF6 [62]. It is noteworthy to mention that in the current study, TRAF6 was significantly downregulated in ME/CFS patients (but not HC) at 4 h post-exercise challenge, as compared to maximal exertion (Supplementary Table S3). TRAF6 has been identified as a signal transducer important for the regulation of inflammation and immunity [63].

Why is that miRNA overexpressed.

I think this stuff is getting to the core of the disease.

 

[SWAlexander]

I think this is somewhat important too:
I wondered for a long time why "nearly" all meds must fit males and females.

 

[Murph]

I really like this paper.

1. This is the study design they must use, and which we are starting to see: exercise provocation. There's no point measuring mecfs patients lying flat on their back trying their hardest to feel fine.
2. It is also smart to limit it to females. The differences between men and women are big, if money is limited, just measure the ladies, you'll get cleaner results.
3. The details are fascinating. Healthy controls got a lot of immune system activity during maximal exertion. Us: none. But after maximal exertion (they only measure 4 hours later, a weakness of the study imo), our immune systems suddenly do things differently. The problems they find are about the innate immune system(i.e. not the learning part of the immune system, where b-cells make targeted antibodies). This is a Nancy Klimas paper so it talks a lot about NK cells, but there are other parts of the innate immune system. One came up the other day in the discussion by robert phair, his theory being that interferon alpha signalling is stuck on.
4. there's also a fascinating tidbit where they see a gene for responding to herpesviruses get turned on in patients but not controls. If replicated, this could be a sign that we have a virus lingering in a part of our body and it is reactivated or shaken out into the bloodstream by exercise (they cite work by Prusty, who finds mitochondria get fragmented by exposure to herpesviruses.)

This paper doesn't lead straight to treatment but I think it does a lot to reveal where scientists should be looking for issues.

last point: this paper is part of a special journal issue on me/cfs, so we should see some more papers coming out soon.

 

[Murph]

Cool bonus fact from the study: if you look at all the genes that act differently between maximal exertion and 4 hours later, the biggest change is in something called syndecan-2. In healthy controls it doesn't change but in patients the expression of this gene plummets.

Sydnecan 2 has to do with vascular permeability, as this 2022 study shows.

Syndecan-2 selectively regulates VEGF-induced vascular permeability

Vascular endothelial growth factor (VEGF)- driven increase in vascular permeability is a key feature of many disease states associated with inflammation and ischemic injury, contributing significantly to morbidity and mortality in these settings. Despite its importance, no specific regulators that preferentially control VEGF-dependent increase in permeability versus its other biological activities, have been identified. Here we report that a proteoglycan Syndecan-2 (Sdc2) regulates the interaction between a transmembrane phosphatase DEP1 and VEGFR2 by controlling cell surface levels of DEP1. In the absence of Sdc2 or the presence of an antibody that blocks Sdc2-DEP1 interaction, increased plasma membrane DEP1 levels promote selective dephosphorylation of the VEGFR2 Y951 site that is involved in permeability control. Either an endothelial-specific Sdc2 deletion or a treatment with an anti-Sdc2 antibody result in a highly significant reduction in stroke size due to a decrease in intracerebral edema

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9544384/


if your blood vessels are leaking, it could explain why crap is getting into your brain. could also explain why blood volume is not maintained. blood vessel permeability in mecfs is addressed more in this hypothesis paper: https://www.sciencedirect.com/science/article/pii/S1568997220300823

 

[Wishful]

This paper doesn't lead straight to treatment but I think it does a lot to reveal where scientists should be looking for issues.

Reducing the amount of the limited funding wasted on low-probability-of-useful-results studies would be helpful. So far they don't know what is unlikely to lead to success (well, maybe just ignore requests from psychologists).

 

[Mary]

The differences between men and women are big, if money is limited, just measure the ladies, you'll get cleaner results.

Why would just measuring "the ladies" give cleaner results?

 

[Murph]

Why would just measuring "the ladies" give cleaner results?

example: If male patients have normal levels of a metabolite compared to controls, and female patients have reduced levels, and you decide to have a sample of 30 patients, you will find the mean result in your patients is closer to the controls if you use both sexes. The data will be muddied, and even though there is a difference, it miht not be measurable / statistically significant. In this scenario if you measure only females you get a clearer picture of the differences between female patients and controls.

 

[Mary]

Thank you @Murph!

 

[ruben]

In a post on Twitter, Prusty in Germany has got what apparently seems some significant announcements coming in the next couple of months!