HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity, 2025, Gimenez-Orenga, Oltra

Now published - link here


Preprint
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia (FM) are chronic diseases with poorly understood pathophysiology and diagnosis based on clinical assessment of unspecific symptoms. The recent post-COVID-19 condition, which shares similarities with ME/CFS and FM, has raised concerns about viral-induced transcriptome changes in post-viral syndromes. Viral infections, and other types of stress, are known to unleash human endogenous retroviruses (HERV) repression that if maintained could lead to symptom chronicity.

This study evaluated this possibility for ME/CFS and FM on a selected cohort of female patients complying with diagnosis criteria for ME/CFS, FM, or both, and matched healthy controls (n=43). The results show specific HERV fingerprints for each disease, confirming biological differences between ME/CFS and FM. Unexpectedly, HERV profiles segregated patients that met both ME/CFS and FM clinical criteria from patients complying only with ME or FM criteria, while clearly differentiating patients from healthy subjects, supporting that the highly prevalent comorbidity condition must constitute a different nosological entity. Moreover, HERV profiles exposed significant quantitative differences within the ME/CFS group that correlated with differences in immune gene expression and patient symptomatology, supporting ME/CFS patient subtyping and confirming immunological disturbances in this disease.

Pending issues include validation of HERV profiles as disease biomarkers of post-viral syndromes and understanding the role of HERV during infection and beyond.

https://www.biorxiv.org/content/10.1101/2023.10.05.561025v1

 

Similar to a previous study HERV-W and HERV-K again don’t seem to play a major role in ME/CFS (here they even seem to be downregulated in ME/CFS, FM and other comobidities). On the other hand a larger role was suggested in Covid and Long Covid https://autoimmunhighlights.biomedcentral.com/articles/10.1186/s13317-019-0122-8, https://www.frontiersin.org/articles/10.3389/fimmu.2022.1020064/full (allegedly the W-ENV positivity rate in LC is even above 30% https://www.businesswire.com/news/h...lf-Year-Results-and-Provides-Corporate-Update).

As such it seems relevant to me to know whether some of these ME/CFS case are due to Covid or at least consider the disease duration and whether participants in the study recently had a Covid infection (or possibly a different stressor?) if the testing can heavily depend on a viral infection.

How much of all this is just pure noise is not possible for me to tell. But I'm sure the smart people on this forum can provide some answers.

 

p. 2 of the pdf--https://www.biorxiv.org/content/10.1101/2023.10.05.561025v1.full.pdf

"Previous studies found overexpression of some HERV families in immune cells of ME/CFS
(33) and FM (34) at the transcript level. However, the study and comprehension of HERV in
ME/CFS and FM are still at infancy. In this study, we hypothesized that genome-wide HERV
profiling of ME/CFS and FM could reveal distinct underlying pathomechanisms that justify
their separate classification, and/or common fingerprints explaining their high comorbid
prevalence."

 

Preprint - revised
Abstract
Research of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia (FM), two acquired chronic illnesses affecting mainly females, has failed to ascertain their frequent co-appearance and etiology. Despite prior detection of human endogenous retrovirus (HERV) activation in these diseases, the potential biomarker value of HERV expression profiles for their diagnosis, and the relationship of HERV expression profiles with patient immune systems and symptoms had remained unexplored.

By using HERV-V3 high-density microarrays (including over 350k HERV elements and more than 1500 immune related genes) to interrogate the transcriptomes of peripheral blood mononuclear cells from female patients diagnosed with ME/CFS, FM or both, and matched healthy controls (n=43), this study fills this gap of knowledge. Hierarchical clustering of HERV expression profiles strikingly allowed perfect participant assignment into four distinct groups: ME/CFS, FM, co diagnosed, or healthy, pointing at a potent biomarker value of HERV expression profiles to differentiate between these hard-to-diagnose chronic syndromes. Differentially expressed HERV-immune-gene modules revealed unique profiles for each of the four study groups and highlighting decreased γδ T cells, and increased plasma and resting CD4 memory T cells, correlating with patient symptom severity in ME/CFS.

Moreover, activation of HERV sequences coincided with enrichment of binding sequences targeted by transcription factors which recruit SETDB1 and TRIM28, two known epigenetic silencers of HERV, in ME/CFS, offering a mechanistic explanation for the findings.

Unexpectedly, HERV expression profiles appeared minimally affected in co-diagnosed patients denoting a new nosological entity with low epigenetic impact, a seemingly relevant aspect for the diagnosis and treatment of this prevalent group of patients
LINK

 

I'd also like to hear from someone who understands this better than me, but from a quick skim figure 1D certainly looks interesting.

Demographics

 

Peer reviews and authors' responses have been added.

Link

 

Merged thread

Abstract
Research of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia (FM), two acquired chronic illnesses affecting mainly females, has failed to ascertain their frequent co-appearance and etiology.

Despite prior detection of human endogenous retrovirus (HERV) activation in these diseases, the potential biomarker value of HERV expression profiles for their diagnosis, and the relationship of HERV expression profiles with patient immune systems and symptoms had remained unexplored.

By using HERV-V3 high-density microarrays (including over 350k HERV elements and more than 1500 immune related genes) to interrogate the transcriptomes of peripheral blood mononuclear cells from female patients diagnosed with ME/CFS, FM or both, and matched healthy controls (n=43), this study fills this gap of knowledge. Hierarchical clustering of HERV expression profiles strikingly allowed perfect participant assignment into four distinct groups: ME/CFS, FM, co diagnosed, or healthy, pointing at a potent biomarker value of HERV expression profiles to differentiate between these hard-to-diagnose chronic syndromes.

Differentially expressed HERV-immune-gene modules revealed unique profiles for each of the four study groups and highlighting decreased γδ T cells, and increased plasma and resting CD4 memory T cells, correlating with patient symptom severity in ME/CFS.

Moreover, activation of HERV sequences coincided with enrichment of binding sequences targeted by transcription factors which recruit SETDB1 and TRIM28, two known epigenetic silencers of HERV, in ME/CFS, offering a mechanistic explanation for the findings.

Unexpectedly, HERV expression profiles appeared minimally affected in co-diagnosed patients denoting a new nosological entity with low epigenetic impact, a seemingly relevant aspect for the diagnosis and treatment of this prevalent group of patients.
LINK

 

What’s the significance of having three separate groups?

1. ME/CFS
2. FM
3. ME/CFS + FM

Wouldn’t you expect there to be some overlap between 1 and 3, and 2 and 3?

 

I think this is still a preprint actually.

 

@Utsikt

Possibly because a subgroup of pwME don't experience pain?

 

Does pain equal FM though? I’m not very familiar with the criteria.

 

Chronic widespread pain in muscles and soft tissue is the main criteria for FM that r/o other disorders that could explain pain.

 

I’m assuming ME/CFS is an acceptable comorbidity for FM then, given that ME/CFS often, but not always presents with pain?

But FM is essentially ‘unexplained pain’, as in ‘not yet understood’?

 

The ME doctor I saw in the 90s didn't give an ME/CFS diagnosis to my friend who was later diagnosed with FM only. She does not experience PEM and has no idea what I'm talking about when I explained delayed PEM in my case.

It wasn't until over a decade ago that FM was considered a neurological disorder/disease. Many years ago pwFM used FM and ME/CFS interchangeably but that is no longer the case.

That is my understanding.

 

My take on the difference between FM and ME is personal. I was diagnosed with FM and the rheumatologist added a CFS diagnosis to my chart because I had to take a rest at work by 830am, back when I was struggling to stay employed.

Pain in several body regions at once is the key finding in FM. However, exhaustion and cognitive problems, as well as sleep problems (typically fragmented sleep) are also common symptoms.

FM patients don't have orthostatic problems and the disease onset isn't post-viral. And the degree of exhaustion from physical movement is not as severe as ME. FM patients can be more active and upright during the day, for sure.

Also, the degree of cognitive function is not as severe. FM patients get their own type of pem, I believe. However no sore throat or swollen glands with it.

However, when I am having a poor functioning day, it's due to exhaustion and pain can be low or high.

But FM doesn't fluctuate to severe as ME does. Whether the two are related I don't know.

 

Thank you @shak8 - that was a very useful personal anecdote!

 

Now published:

HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity

Karen Giménez-Orenga, Eva Martín-Martínez, Lubov Nathanson, Elisa Oltra

[Line breaks added]

Abstract
Research of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM), two acquired chronic illnesses affecting mainly females, has failed to ascertain their frequent co-appearance and etiology.

Despite prior detection of human endogenous retrovirus (HERV) activation in these diseases, the potential biomarker value of HERV expression profiles for their diagnosis, and the relationship of HERV expression profiles with patient immune systems and symptoms had remained unexplored. By using HERV-V3 high-density microarrays (including over 350k HERV elements and more than 1500 immune-related genes) to interrogate the transcriptomes of peripheral blood mononuclear cells from female patients diagnosed with ME/CFS, FM, or both, and matched healthy controls (n = 43), this study fills this gap of knowledge.

Hierarchical clustering of HERV expression profiles strikingly allowed perfect participant assignment into four distinct groups: ME/CFS, FM, co-diagnosed, or healthy, pointing at a potent biomarker value of HERV expression profiles to differentiate between these hard-to-diagnose chronic syndromes. Differentially expressed HERV–immune–gene modules revealed unique profiles for each of the four study groups and highlighting decreased γδ T cells, and increased plasma and resting CD4 memory T cells, correlating with patient symptom severity in ME/CFS.

Moreover, activation of HERV sequences coincided with enrichment of binding sequences targeted by transcription factors which recruit SETDB1 and TRIM28, two known epigenetic silencers of HERV, in ME/CFS, offering a mechanistic explanation for the findings.

Unexpectedly, HERV expression profiles appeared minimally affected in co-diagnosed patients denoting a new nosological entity with low epigenetic impact, a seemingly relevant aspect for the diagnosis and treatment of this prevalent group of patients.

Link | PDF (eLife) [Open Access]

 

I thought this quote in response to Reviewer 2 was interesting.