Exosome-associated Mitochondrial DNA is Elevated in Patients with ME/CFS and Stimulates Human Cultured Microglia to Secrete IL-1β, 2021, Theoharides

[John Mac]

Abstract

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease that presents with fatigue, sleep disturbances, malaise and cognitive problems. The pathogenesis of ME/CFS is presently unknown and serum levels of potential biomarkers have been inconsistent.

Methods: Exosomes were purified from serum obtained from patients with ME/CFS before and after exercise and their content of mitochondrial DNA (mtDNA) was determined by quantitative PCR. Exosomes from both patients and controls were incubated with cultured human microglia and release of interleukin-1beta (IL-1β) was measured by ELISA.

Results: Here we show that serum mtDNA, associated with exosomes, is increased in ME/CFS after exercise. Moreover, exosomes isolated from patients with ME/CFS stimulate significant secretion of IL-1β from cultured human microglia.

Conclusion: These results provide evidence for a potential novel pathogenetic factor and target for treatment of ME/CFS.

https://www.researchsquare.com/article/rs-154011/v1

 

[Ravn]

The serum level of mtDNA (7S) was increased only after exercise in ME/CFS patients

They looked at ME patients both before and after exercise but for the controls there only seems to be one time point?

Also, the numbers of dots in each figure are different. Missing data? Not very clear what sort of cohort this was. They only say:

We isolated total exosomes (30–100 nm fin diameter) from serum samples obtained from ME/CFS patients and controls as we reported previously. 28

Reference 28 goes to a study about children with autism?!
Tsilioni I, Theoharides TC. Extracellular vesicles are increased in the serum of children with autism spectrum disorder, contain mitochondrial DNA, and stimulate human microglia to secrete IL-1beta. J Neuroinflammation. 2018;15(1):239

Maybe that reference just relates to the method of isolating the exosomes, not to the ME/CFS cohort selection?
It's all very confusing. Version 1 of a preprint but still...

 

[Sly Saint]

Now published in the European Journal of Neuroscience. Has link to Peer-review history.

https://onlinelibrary.wiley.com/doi/abs/10.1111/ejn.15828

 

[RedFox]

Hmm. I can't say this study is very rigorous. They compared several parameters among healthy controls, pwME before exercise, and pwME after exercise. So we don't know if the post-exercise results are unique to people with ME, or if healthy people have similar changes when they work out. In another experiment, they added exosomes from the blood of pwME to microglial cells in a Petri dish, and observed that the microglial cells produced more of a pro-inflammatory cytokine called IL-1β. (They don't specify the container; I'm saying Petri dish simply to illustrate that these were cells grown in a lab.) Once again, we lack a good control here. They used more of the solution the cells grew in as a control, rather than exosomes from healthy controls. Thus, not much can be concluded from this paper. It's a pilot study if anything.

Regardless, it's interesting to see further research into microglia and ME, as several researchers hold this hypothesis. The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure got me interested in the hypothesis that low-grade neuroinflammation is the cause of ME, and Jarred Younger's work in the same area heightened it. It's my favorite hypothesis because pro-inflammatory communication between the brain and rest of the body might explain both physical and neurocognitive symptoms, and the time it takes microglia to activate might explain the delayed onset of PEM.

They also mention that exosomes from autistic children have the same effect. If this is a difference from neurotypical controls, then maybe autism could be a risk factor for ME? This reasoning is extremely tenuous but I'm interested in any potential connections between ME and autism given that I have both.