ME/CFS as a hyper-regulated immune system driven by an interplay between regulatory T cells & chronic human herpesvirus infections (2019) Nacul et al.

[Cheshire]

Nuno Sepúlveda, Jorge Carneiro, Eliana M. Lacerda and Luis C. Nacul

Autoimmunity and chronic viral infections are recurrent clinical observations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a complex disease with an unknown cause. Given these observations, the regulatory CD4+ T cells (Tregs) show promise to be good candidates for the underlying pathology due to their known capacity to suppress the immune responses not only to body components but also against infections.

Here we discussed the overlooked role of these cells in the chronicity of Human Herpes Virus 6 (HHV6), Herpes Simplex 1 (HSV1) and Epstein-Barr virus (EBV), as often reported as triggers of ME/CFS. Using simulations of the Cross-regulation model for the dynamics of Tregs, we illustrated that mild infections might lead to a chronically activated immune responses under control of Tregs if the responding clone has a high autoimmune potential. Such infections promote persistent inflammation and possibly fatigue.

We then hypothesized that ME/CFS is a condition characterized by a predominance of this type of infections under control of Tregs. In contrast, healthy individuals are hypothesized to trigger immune responses of a virus-specific clone with a low autoimmune potential. According to this hypothesis, simple model simulations of the CD4+ T-cell repertoire could reproduce the increased density and percentages of Tregs observed in patients suffering from the disease when compared to healthy controls. A deeper analysis of Tregs in the pathogenesis of ME/CFS will help to assess the validity of this hypothesis.

https://www.frontiersin.org/articles/10.3389/fimmu.2019.02684/abstract

Study made with the UK ME/CFS Biobank
Full text not available yet, will be published soon.

 

[boolybooly]

Interesting, this appears to be more specifically about what I have which is comforting to see.

Makes me glad I backed the LSHTM biobank.

ME specialists from CureME, apparently working on an NIH project.

https://me-pedia.org/wiki/CureME

My thanks to them all.

 

[Hoopoe]

Are they saying my herpes simplex virus does more than occasionally give me cold sores in the face?

 

[Jonathan Edwards]

Autoimmunity and chronic viral infections are recurrent clinical observations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a complex disease with an unknown cause.

That statement seems a bad place to start. I am not aware of any basis for it.

 

[boolybooly]

Autoimmunity and chronic viral infections are recurrent clinical observations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a complex disease with an unknown cause.

That statement seems a bad place to start. I am not aware of any basis for it.

I am, that fits my CFIDS symptoms to a tee.

 

[FMMM1]

Autoimmunity and chronic viral infections are recurrent clinical observations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a complex disease with an unknown cause.

That statement seems a bad place to start. I am not aware of any basis for it.

Yes as you pointed out recently there's no strong evidence for B-cell autoimmunity (rituximab failure) and not much for T-cell autoimmunity. So that just leaves chronic viral infections and so far studies looking for virus's haven't been finding much (Ron Davis etc. however he's only really covered one class of virus's - viral DNA, or RNA, but I can't remember which).

 

[borko2100]

It might be autoimmunity after all. Then again, it might not be... At the end of the day we are still clueless after 40 years of research. I doubt that there's many other illnesses where research has been so incredibly unfruitful.

 

[adambeyoncelowe]

It'd be useful to see the final paper, I think. I presume/hope the hypothesis is based on actual findings at the Biobank, rather than wild guesses.

Then we'd be able to see what basis there is for this theory and how likely it is to be right. Only time will tell.

 

[boolybooly]

They must be aware of the Rituximab results, agree will be interested to see what the full paper is saying.

I am just "delighted" they are looking at chronic viral infection as a characteristic symptom of ME.

https://www.meassociation.org.uk/20...-to-improve-symptoms-in-me-cfs-03-april-2019/

In an accompanying editorial, Peter C. Rowe, MD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, notes,

“It is difficult to reconcile the phase 3 trial results with the earlier observations of clinical improvement. The earlier study participants may have differed from those in the phase 3 trial with regard to the presence of autoantibodies or other biological factors that influenced response rates to rituximab.”

I am pushed to understand how else I would get palindromic rheumatic pain in symmetrical patterns shifting through my joints over a number of years other than by an autoimmune reaction. If the people in the large Rituximab trial did not experience a relief of symptoms then it seems plausible to me we do not have the same illness.

Though the 150 patient Rituximab trial used Canadian Consensus Criteria, CCC cohorts can include people with zero immune deficits, potentially different subtypes if not diseases from CFIDS. I honestly think we may have an apples and oranges problem.

Besides which there is more to HHVs since they (egEBV) produce their own cytokines (IL10) which could do something similar in terms of turning down the immune response without invoking autoimmunity.

The lack of clinical effect of B-cell depletion in this trial weakens the case for an important role of B lymphocytes in ME/CFS but does not exclude an immunologic basis

 

[Mithriel]

It might be autoimmunity after all. Then again, it might not be... At the end of the day we are still clueless after 40 years of research. I doubt that there's many other illnesses where research has been so incredibly unfruitful.

Unfortunately, that 40 years of research has had about as much funding as 1 year of MS research (maybe more but definitely not much) and much of that research has not actually been on ME but on fatigue states which may not be relevant.

Also the patients being tested have been a rag tag bunch who may not have had ME in the first place because of the lax definitions used.

It is hopeful in the sense that the cause of ME may not be any harder to find than any other disease if money and attention are focused in the right places.

 

[Jonathan Edwards]

It'd be useful to see the final paper, I think. I presume/hope the hypothesis is based on actual findings at the Biobank, rather than wild guesses.

I have a feeling that this is a theoretical modelling paper, not a data based paper.
I am not aware of any data to go with it.

 

[Hutan]

Using simulations of the Cross-regulation model for the dynamics of Tregs, we illustrated that mild infections might lead to a chronically activated immune responses under control of Tregs if the responding clone has a high autoimmune potential. Such infections promote persistent inflammation and possibly fatigue.

We then hypothesized that ME/CFS is a condition characterized by a predominance of this type of infections under control of Tregs. In contrast, healthy individuals are hypothesized to trigger immune responses of a virus-specific clone with a low autoimmune potential. According to this hypothesis, simple model simulations of the CD4+ T-cell repertoire could reproduce the increased density and percentages of Tregs observed in patients suffering from the disease when compared to healthy controls.

How solid is the statement that an increased density and percentage of Tregs is observed in ME/CFS? Perhaps this is something they have noted from the biobank data? Will be interesting to see.

For what it's worth, the one time my Tcells were checked, my number of Tregs (presumably the density) was above normal range. And CRP (one measure of inflammation) is always mildly above normal range. And 6 months after ME onset, I had constant cold sores (as in always had one) for about a year. These stopped with valacyclovir (and giving up work), although I still get one in each bad crash.

 

[Jonathan Edwards]

How solid is the statement that an increased density and percentage of Tregs is observed in ME/CFS? Perhaps this is something they have noted from the biobank data? Will be interesting to see.

My information is that the Biobank team have found some differences in mucosa-associated invariant T cells (MAIT) but not T regs.

 

[Hutan]

the Biobank team have found some differences in mucosa-associated invariant T cells (MAIT) but not T regs.

If that's the case, then their statement that it is observed that there are increased densities and percentages of Tregs in ME/CFS seems a bit odd.


Here's some background info on some T cell types for those of us still with lots to learn:
Development of unconventional T cells

T cells make up a central part of the adaptive immune system. Certain T cell populations, frequently referred to as unconventional T cells, share functional profiles of both innate and adaptive immunity. These innate-like T cells have the capacity to rapidly respond to non-cognate stimulation by releasing large amounts of cytokines on top of their characteristic T-cell receptor-mediated functions. In addition to direct anti-pathogenic actions, innate-like cells have also been implicated in stress responses and tissue homeostasis. Invariant Natural Killer T cells (iNKTs), certain γδT cell populations, Mucosal-Associated Invariant T (MAIT) cells and Intraepithelial Lymphocytes (IELs) constitute key variants of unconventional T cells (1–4). Thymus-derived regulatory T (tTreg) cells share at least some developmental features with unconventional innate-like T cells and are therefore discussed here as well (5, 6).

Broadly, unconventional T cells are generated through two major developmental pathways. The vast majority of γδT cells and a smaller percentage of IELs and iNKT cells are derived from CD4−CD8− co-receptor double negative (DN) thymocytes (7, 8). In contrast, most IELs, iNKT cells, MAIT cells, and tTreg cells are formed after passing through the more mature CD4+CD8+double-positive (DP) thymocyte stage in a process termed agonist selection (7, 9). In this review, we focus on the latter subset of cells.

 

[Jonathan Edwards]

If that's the case, then their statement that it is observed that there are increased densities and percentages of Tregs in ME/CFS seems a bit odd.

I agree.

 

[FMMM1]

It might be autoimmunity after all. Then again, it might not be... At the end of the day we are still clueless after 40 years of research. I doubt that there's many other illnesses where research has been so incredibly unfruitful.

Alzheimer's https://www.healthrising.org/blog/2019/09/16/alzheimers-chronic-fatigue-fibromyalgia/?

Lyme - http://simmaronresearch.com/2019/10/better-lyme-diagnostic-nih-strategic-plan/
A lot of money has been spent on a diagnostic test and it hasn't been delivered yet ---- post Lyme disease could be ME of course!

 

[Mij]

Also the patients being tested have been a rag tag bunch who may not have had ME in the first place because of the lax definitions used.

It would also be interesting to know the length of time these patients have been ill. My immune system has morphed over 30 years.

 

[Lisa108]

The full paper is out now (free access): Link

 

[Ravn]

I have a feeling that this is a theoretical modelling paper, not a data based paper.

The full paper is out now (free access): Link

Bump.
Looks like it's a mathematical modelling paper.
Above my head. What, in a nutshell and in plain English, does it say? And what relevance/implications does whatever it says have?

 

[FMMM1]

Bump.
Looks like it's a mathematical modelling paper.
Above my head. What, in a nutshell and in plain English, does it say? And what relevance/implications does whatever it says have?

All above my head too and I couldn't be bothered trying to understand it.

None of the following may be relevant to the theory presented in this paper!

I think one of the problems with the active virus theory is that Ron Davis etc. can't find viral DNA (not much done on RNA virus's yet). To be fair the same problem seems to occur in Lyme i.e. a lot of people considered to have with Lyme do not test positive http://simmaronresearch.com/2019/10/better-lyme-diagnostic-nih-strategic-plan/

So it seems we need a theory to explain these negative tests and a pathogen theory.

I think Bupesh Prusty is preparing a publication at the moment so here's hoping that this will help explain how we get from no detectable pathogen to ME.

There seemed to a reasonable model [of a post infection fatigue type illness] presented at the EMERGE Conference (Feb 2019?) re a disease which affects people living near intensive goat farms in the low countries (Neherlands?). From memory the idea is that bacteria persist in bone marrow for years - maintaining the immune response.