ME/CFS: Untangling Cytokine Signature

[S-VV]

Hello everybody!

I thought I would share my research on cytokines and ME/CFS. My interest in this area was sparked by the recent transcriptome study that found the following genes over expressed:

We can take note of Il-8 a cytokine (and chemokine), TNF induced protein and Nf-kB Inhibitor A. This last gene seems to be unregulated by NF-kB as a negative feedback mechanism, [2] so high inhibitor of kB suggests high NF-kB.

IL-8

Now lets look at a recent paper by KDM looking for potential biomarkers:

"The best model included the sCD14, PGE2, IL-8"

Another point for IL-8, and we also note the Prostaglandin E2. Lets look at fibromyalgia research to see what we can learn:

Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain — Interleukin-8 in fibromyalgia and interleukin-1 β in rheumatoid arthritis

Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels.

So the importance of IL-8 seems to be clear.

TGF

Now lets turn to the Montoya Study:

"only two cytokines were found to be different (TGF-β higher and resistin lower) in ME/CFS patients"

What? No IL-8? KDM explains in his paper that due to the different IL-8 isoforms, and ELISA test used, results can vary dramatically. Are there any ME/CFS studies that can back up an elevated TGF level?

Increased neutrophil apoptosis in chronic fatigue syndrome
Patients with CFS had significantly higher levels of neutrophil annexing V and TNF-RI expression (37.4 vs 22.8%, p=0.001 [Mann-Whitney U-test]; and 12.5 vs 3.9%, p=0.004; respectively) and increased plasma levels of TGF-b1 (2.24 vs 1.89 pg/mL, p=0.005) when compared with controls

Up-regulation of TGF-β1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome.
The mean value of TGF-β1 mRNA expression in CFS patients was ΔΔCt=1.17±0.58, which was significantly higher than the disease controls (ΔΔCt=0.07±1.08, df=111, p < 0.01) and the healthy controls (ΔΔCt=0.00±1.63, df=111, p < 0.01)

Chronic fatigue syndrome and circulating cytokines: A systematic review
Cases of CFS had significantly elevated concentrations of transforming growth factor-beta (TGF-β) in five out of eight (63%) studies. No other cytokines were present in abnormal concentrations in the majority of studies

So IL-8 and TGF stand out as being predictors of ME/CFS, with the possible addition of PGE2 and TNF, all of them probably mediated by NF-kB. Now comes the interesting part. In what diseases are these cytokines upregulated?

The effects of Ang-1, IL-8 and TGF-β1 on the pathogenesis of COPD
We found statistically significant differences in the expression levels of Ang-1, IL-8 and TGF-β1 between the stable and acute phases

Exhaled leukotrienes and prostaglandins in COPD
There is a selective increase in exhaled LTB4 and PGE2 in patients with COPD which may be relatively resistant to inhaled corticosteroid therapy

Bare with me, I'm not crazy. Let's look at the recent FM transcriptome study

Thats right. Just after Liver and OXPHOS sits COPD. What could this mean? I don't know yet. But - eosinophils have been associated both with asthma and COPD. What is there to learn about eosinophils and ME/CFS? Lipkin to the rescue

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome
Group-specific differences were found for the majority of analytes with an increase in cases of CCL11 (eotaxin), a chemokine involved in eosinophil recruitment

COPD in the brain? God only knows. But, studies may give us some hints:

Transforming growth factor-β stimulates the expression of eotaxin/CC chemokine ligand 11 and its promoter activity through binding site for nuclear factor-κβ in airway smooth muscle cells.

TGF-beta1 stimulates IL-8 release, COX-2 expression, and PGE(2) release in human airway smooth muscle cells.
(cox catalyzes PGE2 formation)

Finally, assuming eosinophils are a problem, some druggable targets:

Regulation of Serotonin-Induced Trafficking and Migration of Eosinophils
Association of the neurotransmitter serotonin (5-HT) with the pathogenesis of allergic asthma is well recognized and its role as a chemoattractant for eosinophils (Eos) in vitro and in vivo has been previously demonstrated

Eosinophilic gastroenteritis in a young girl--long term remission under Montelukast

Montelukast reduces peripheral blood eosinophilia but not tissue eosinophilia or symptoms in a patient with eosinophilic gastroenteritis and esophageal stricture
During treatment with montelukast, the mean peripheral blood eosinophil count fell from 5,064 cells/microL to 1,195 cells/microL

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This is as far as I have gotten. I hope someone can take this info and connect it to other pieces of the puzzle. Lets do this!

(@mariovitali We need your algorithms. Perhaps a new run taking into consideration these findings?)

 

[Belbyr]

Impressive!

 

[S-VV]

Thanks!

 

[pattismith]

Great painting too, thank you!

 

[S-VV]

Thanks!!

I see you are more of the late-reinnasance aesthetic. I usually prefer it, but lately I've been attracted to early reinnasance paintings.

I find their simplicity very soothing

 

[wigglethemouse]

Gordon Broderick also had this paper with IL8 highlighted
Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue (2012)

Abstract/Results
Standard comparative analysis indicated significant differences in IL-8 and 23 across subject groups. In constructing a linear classification model IL-6, 8 and 23 were selected by two different statistical approaches as discriminating features, with IL-1a, IL-2 and IFN-? also selected in one model or the other. This supported an assignment accuracy of better than 80% at a confidence level of 0.95 into PI-CFS versus recovered controls.

@S-VV Did you see this recent paper from Michael VanElzakker - urges caution on Cytokine studies due to difficulty of repeatable measurements, local to tissues, etc
Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods

 

[alex3619]

I have been warning people about a potential link with PGE2 for decades. Its the primary inflammatory hormone at the tissue level. Indeed I have been saying that our drive to more series 2 prostaglandin synthesis is likely to create deficiency (think salicylate sensitivity) and excess (think alcohol poisoning). This is because I suspect a high release rate for arachidonic acid, which will drain omega-6 essential fat supply, and lead to more inflammatory eicosanoids. However which eicosanoids are synthesised might be tricky to investigate.

All of this needs more confirmation, but we have lots of paths for investigation now.

 

[alex3619]

COPD signalling is interesting as I have an undiagnosed breathing problem that can totally shut my breathing down for up to a few minutes. Its either on, or off, though the intensity can be low enough sometimes that I am just struggling to breathe, similar to asthma. The primary risk, for me, is wheat. The exact mechanisms still eludes me, but it can be inhibited with the PDE4 inhibitor Resveratrol.

 

[wigglethemouse]

@alex3619 Here is a plot of arachidonic from the Hanson metabolite data. Not sure it shows anything........

I would love to see data for Prostaglandins as I think they are interesting too, but some of those have a very short half life and don't seem to be in the Metabolon scan yet.

Regarding series 2, both my PGF2alpha and PGD2 were both high (MCAS). Is there a blood test for PGE2 that the doctor can order?

 

[Belbyr]

Gordon Broderick also had this paper with IL8 highlighted
Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue (2012)


@S-VV Did you see this recent paper from Michael VanElzakker - urges caution on Cytokine studies due to difficulty of repeatable measurements, local to tissues, etc
Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods

I remember reading something like this too. Something like the things we eat or do can change them from day to day.

 

[Archie]

The ever so wonderfull World of genes , after i watched this presentation i have looked things on different angle, or at least wonder how much researchers really know what the heck is going on and why

https://www.brucelipton.com/what-epigenetics

 

[alex3619]

I would love to see data for Prostaglandins as I think they are interesting too, but some of those have a very short half life and don't seem to be in the Metabolon scan yet.

Some of them last only seconds. I do not expect to see the interesting stuff in arachidonic acid, I expect we need to look for stable eicosanoid breakdown products if we can identify them.

I know nothing about current clinical tests. I was involved in this stuff about 26 years ago.

 

[mariovitali]

I think that Tgf-β1 is definitely involved, given the fact that it is related to hepatic fibrosis :


https://jvi.asm.org/content/90/6/3044

If you can give me a set of targets, be it function, disease or gene name i can add it and i will get back to you

 

[pattismith]

PG2 also got my interest, as I suffer severe dysmenorrhea with worsening of all my symptoms at that time

https://forums.phoenixrising.me/ind...-uterus-cramp-pg-crashing.62085/#post-1010112

 

[mariovitali]

COPD signalling is interesting as I have an undiagnosed breathing problem that can totally shut my breathing down for up to a few minutes. Its either on, or off, though the intensity can be low enough sometimes that I am just struggling to breathe, similar to asthma. The primary risk, for me, is wheat. The exact mechanisms still eludes me, but it can be inhibited with the PDE4 inhibitor Resveratrol.

count one more here. I was not able to breathe at times which was also associated with me not able to walk up on stairs and hence also being fatigued.

 

[pattismith]

let's go back to this IL8 elevation…

This study about auto antibodies against G Protein Coupled Receptors says:

"Considering the central role of interleukin-8 (IL-8) as an important chemokine that regulates neutrophil migration29, we were able to show that HealthyDonors-IgG triggered IL-8 production by peripheral blood mononuclear cells (PBMCs) (Fig. 8d), which also express EDNRA32.
The spontaneous IL-8 synthesis by PBMCs strongly correlated with EDNRA expression (Fig. 8e).
These findings suggest that HD-IgG controls the trafficking of neutrophils directly via chemotactic mechanisms and indirectly by triggering IL-8 production."

They showed that Ab anti-EDNRA (endothelin receptor type A) are activator of neutrophil migration via IL8 production (this is the result of agonist effect of these auto-antibodies against EDNRA also called ETA-R in other studies and in the celltrend panel)

These auto antibodies are natural part of the immune regulation, but the equilibrium can be disrupted in some auto-immune diseases, with too much or too little of these Ab.

In ME/CFS we have too much IL8, so we may have too much of these ETA auto-antibodies.

I had the test from celltrend and I am strongly positive for this one.