New video from Australia with research summary, etc

[Murph]

one can only conclude that ME must be an infectious disease and that all other findings are only secondary consequences of this infection.

I think this is totally possible, but your level of confidence is a bit too high. Once we have more evidence we can be confident but for now we need to stay open-minded to all possibilities. This disease shares attributes with certain autoimmune problems, for example (infectious onset, hits women more than men).

Ruling out disease models other than infection by pathogen at this early stage would mean these researchers weren't even looking for these TRPM3 issues they've found, Ron Davis mightn't have gone looking for the red blood cell deformities he's found, Naviaux mightn't have gone looking for the metabolic perturbations he's found, etc.

 

[Murph]

This site:

https://www.proteinatlas.org/ENSG00000083067-TRPM3/tissue

...shows the tissue expression of TRPM3.

It's in the brain a lot, but also the kidneys, the testes and the retina.

Those are not the tissues I'd say are most prone to failure in ME/CFS. Brain, yes, but why not muscles and gut and endothelium? I hear very little complaining about deteriorating eyesight on this website.

The distribution of TRPM3 makes me wonder if it is the main culprit. (assuming I've interpreted that website correctly). I'm pleased they're looking for other ion channel problems too.

 

[alex3619]

I hear very little complaining about deteriorating eyesight on this website.

I suddenly went blind in my left eye some years ago, overnight. Many of the long term patients have declining eyesight too, but its impossible to be sure why as there is almost no science on this in ME.

 

[Snow Leopard]

I hear very little complaining about deteriorating eyesight on this website.

Obviously I need to complain more often!!!!

Eyes are affected in many patients and although there haven't been much studies done on eye sight, those that have studied it have consistently shown substantially reduced accommodation compared to age matched control groups or population norms.

There is also this:
https://www.s4me.info/threads/restricted-spatial-windows-of-visibility-in-me.2006/

 

[FMMM1]

This is the view of Derya Unutmaz, a leading ME/CFS researcher-


LINK

Here is a study that also has the hypothesis that an infection could be a trigger for ME/CFS-

LINK

From the web [http://simmaronresearch.com/2018/05/montreal-ii-stopping-pem-antibody-subset-unutmazs-big-surprise/]:
"Unutmaz found that a high percentage of MAIT cells had been repeatedly activated in ME/CFS patients – suggesting a plethora of bad bacteria was present. In true ME/CFS fashion, Unutmaz also found that ME/CFS patients’ MAIT cells were activated — but “punked out” at the same time. (A wired and tired immune cell?). Seemingly exhausted by the continual stimulation, they (like their natural killer cell cousins) had problems killing infected cells.
Unutmaz is now trying to identify which bacteria are tweaking ME/CFS patients’ MAIT T-cells so much as to possibly burn them out. If he’s successful, he may have found a target that could quiet down a possibly overworked and burnt-out immune system and allow it to rejuvenate"

Well done to Dr Unutmaz and hopefully he will make more progress.

I assume that the pathogen exposure found by Dr Unutmaz could be the result of leaky gut. Search on the web [for "hla intestinal permeability"] and you'll notice a lot of studies i.e. HLA [& epigenetic changes to HLA] may be relevant in intestinal permeability. Ron Davis & Mike Snyder have received an NIH grant to study HLA genes in ME/CFS.

Ron Davis [my words/interpretation/emphasis] at the Invest In ME Conference (2018) said that the NIH approach to science was (with respect) wrong i.e. hypothesis testing then data gathering. He said the approach should be data gathering first not hypothesis first.

It's too early to say with confidence what causes ME/CFS but I welcome the funding of those like Dr Unutmaz/Ron Davis --- who are generating data to try to find the cause of ME/CFS and thereby diagnostic tests and treatments.

Can we help to increase funding? E.g. European Union science/health research fund (Horizon 2020) funded nothing for ME/CFS [http://www.europarl.europa.eu/sides/getAllAnswers.do?reference=E-2017-006901&language=EN]. What can we do to help change that?

 

[wastwater]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420261/

Cilia and diseases
Chlamydomonas and African sleeping sickness and worms mentioned

Bardet-biedl syndrome mentioned

I have progressive bilateral iris atrophy

 

[Murph]

This paper is now out and I've set up a separate thread for discussion on it:

https://forums.phoenixrising.me/ind...cells-from-cfs-me-patients.61238/#post-995819

Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients.
Cabanas H1,2, Muraki K3, Eaton N4,5, Balinas C4,5, Staines D4,5, Marshall-Gradisnik S4,5.
Author information
Abstract
BACKGROUND:
Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME) is a debilitating disorder that is accompanied by reduced cytotoxic activity in natural killer (NK) cells. NK cells are an essential innate immune cell, responsible for recognising and inducing apoptosis of tumour and virus infected cells. Calcium is an essential component in mediating this cellular function. Transient Receptor Potential Melastatin 3 (TRPM3) cation channels have an important regulatory role in mediating calcium influx to help maintain cellular homeostasis. Several single nucleotide polymorphisms have been reported in TRPM3 genes from isolated peripheral blood mononuclear cells, NK and B cells in patients with CFS/ME and have been proposed to correlate with illness presentation. Moreover, a significant reduction in both TRPM3 surface expression and intracellular calcium mobilisation in NK cells has been found in CFS/ME patients compared with healthy controls. Despite the functional importance of TRPM3, little is known about the ion channel function in NK cells and the epiphenomenon of CFS/ME. The objective of the present study was to characterise the TRPM3 ion channel function in NK cells from CFS/ME patients in comparison with healthy controls using whole cell patch-clamp techniques.

METHODS:
NK cells were isolated from 12 age- and sex-matched healthy controls and CFS patients. Whole cell electrophysiology recording has been used to assess TRPM3 ion channel activity after modulation with pregnenolone sulfate and ononetin.

RESULTS:
We report a significant reduction in amplitude of TRPM3 current after pregnenolone sulfate stimulation in isolated NK cells from CFS/ME patients compared with healthy controls. In addition, we found pregnenolone sulfate-evoked ionic currents through TRPM3 channels were significantly modulated by ononetin in isolated NK cells from healthy controls compared with CFS/ME patients.

CONCLUSIONS:
TRPM3 activity is impaired in CFS/ME patients suggesting changes in intracellular Ca2+ concentration, which may impact NK cellular functions. This investigation further helps to understand the intracellular-mediated roles in NK cells and confirm the potential role of TRPM3 ion channels in the aetiology and pathomechanism of CFS/ME.

 

[S-VV]

This may be interesting:

Transient receptor potential melastatin 2 protects mice against polymicrobial sepsis by enhancing bacterial clearance

https://www.ncbi.nlm.nih.gov/m/pubmed/24781495/

So trpm2 helps with bacterial (lps) clearance. Maybe trpm3 plays a similar role and impaired trmp3 expression leads to lower lps clearance.

This would play very well with the microbiome/leaky gut theory, and the elevated levels of lps seen in CFS patients.

 

[FMMM1]

This may be interesting:

Transient receptor potential melastatin 2 protects mice against polymicrobial sepsis by enhancing bacterial clearance

https://www.ncbi.nlm.nih.gov/m/pubmed/24781495/

So trpm2 helps with bacterial (lps) clearance. Maybe trpm3 plays a similar role and impaired trmp3 expression leads to lower lps clearance.

This would play very well with the microbiome/leaky gut theory, and the elevated levels of lps seen in CFS patients.

Thanks for this. I've arrived at a similar place i.e. ME/CFS may be leaky gut. However, I've used more words.

Wenzhong Xiao presented data from a gene expression study (OMF Conference September 2017) which indicated that ME/CFS was most strongly correlated with SEPSIS [

.

MAIT T-cells (Mucosal associated invariant T cells) found in our gut lining --- defending against microbial activity and infection [https://en.wikipedia.org/wiki/Mucosal_associated_invariant_T_cell].
Unutmaz found that a high percentage of MAIT cells had been repeatedly activated in ME/CFS patients – suggesting a plethora of bad bacteria was present [http://simmaronresearch.com/2018/05/montreal-ii-stopping-pem-antibody-subset-unutmazs-big-surprise/].

I think I read/heard somewhere (possibly from Donald Staines) that TRP ion channels are poorly understood. I assume therefore that it's possible that TRPM3 channels could have a role in SEPSIS.

I think the Griffith's group originally worked with Bernd Nilius, KU Leuven, Belgium. Horizon 2020 (European Union Science Fund) hasn't funded any ME/CFS research. If TRP ion channels take off then it might be worth lobbying the European Union to fund Bernd Nilius.

 

[Murph]

@alex3619 I too haven't thought about that and like you find it very interesting!

I listened to Prof. Pete Smith make his comment [about 36.28 on the video] and checked PubMed for two mast cell papers he might have been referring to, but that wasn't too clear on the video:

https://www.ncbi.nlm.nih.gov/pubmed/27362406
https://www.ncbi.nlm.nih.gov/pubmed/29223146

Papers seem to say mast cells circulate in immature form in the circulation and ordinarily not in mature form. Their researchers found activated mast cells in patients and more mast cell progenitor cells circulating in the blood than in controls.

Interestingly, doing a quick internet search I see that large-scale mast cell degranulation-- cells burst and spill their contents-- can cause "hypovolemia" (low blood volume), hypotension, vascular permeability, and other symptoms. Also "exercise" can trigger mast cell activation. Astronauts get hypovolemia in space which resolves when they return to the gravity on earth; perhaps this is how it occurs in those of us earth-bound!

So now I'm wondering (1) as you point out Alex whether any mast cell contents might be in the plasma getting through the filter @ljimbo423 indicates Ron Davis used; and (2) whether cytokines Dr. Montoya measured after exercise might have come from mast cell activation due to the exercise.

Also be nice to know if Maureen Hanson's planned exercise research will include mast cells (she said at the London Conference she'd be looking at immune cells by type) and that Dr. Chia would be collaborating. Could that be to examine the tissue microenvironment where one might find viruses and mature mast cells?

So many questions and excellent research going on!

I asked Smith about the Mast cell research and he says it is from these two papers:


Asian Pac J Allergy Immunol.2017 Dec 10. doi: 10.12932/AP-200517-0086. [Epub ahead of print]
Investigation of mast cell toll-like receptor 3 in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Systemic Mastocytosis participants using the novel application of autoMACS magnetic separation and flow cytometry.
Balinas C1,2,Nguyen T1,2,Johnston S1,2,Smith P2,Staines D1,2,Marshall-Gradisnik S1,2.
Author information
Abstract
BACKGROUND:
Viral infections and hypersensitivities are commonly reported by Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients. Mast Cells (MC) uniquely mediate type 1 hypersensitivities and resolve viral infections via toll-like receptor 3 (TLR3).

OBJECTIVE:
To characterise and compare mast cell progenitors (MCPs) in CFS/ME participants with a known MC disorder, Systemic mastocytosis (SM), and secondly, to investigate the role of MC TLR3 in CFS/ME participants following Polyinosinicolycytidylic acid (Poly I:C) stimulation.

METHODS:
A total of 11 International Consensus Criteria defined CFS/ME participants (40.42 ± 10.31), 9 World Health Organisation defined systemic mastocytosis (SM) participants (47.00 ± 10.37) and 12 healthy controls (HC) (36.36 ± 9.88) were included. Following autoMACS magnetic separation, CD117+/Lin-MCPs were stimulated with Poly I:C for 24hr. MCP purity (CD117 and Lin2), maturity (CD34 and FcεRI), interaction receptors and ligands (CD154 and HLA-DR), and SM-specific (CD2 and CD25) markers were measured using flow cytometry.

RESULTS:
There was a significant decrease in HLA-DR+/CD154- expression between CFS/ME and SM groups pre and post Poly I:C stimulation. There were no significant differences in maturity MCPs, CD154, and CD2/CD25 expression between groups pre and post Poly I:C stimulation.

CONCLUSION:
This pilot investigation provides a novel methodology to characterise MCPs in a rapid, inexpensive and less invasive fashion. We report a significant decrease in HLA-DR+/CD154- expression between CFS/ME and SM participants, and an observed increase in HLA-DR-/CD154+ expression post Poly I:C stimulation in CFS/ME participants. Peripheral MCPs may be present in CFS/ME pathophysiology, however further investigation is required to determine their immunological role.
PMID: 29223146
DOI: 10.12932/AP-200517-0086

--

Asian Pac J Allergy Immunol.2017 Jun;35(2):75-81. doi: 10.12932/AP0771.
Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients.
Nguyen T1,2,Johnston S1,2,Chacko A1,2,Gibson D1,2,Cepon J1,2,Smith P1,2,Staines D1,2,Marshall-Gradisnik S1,2.
Author information
Abstract
BACKGROUND:
Mast cells (MCs) mediate inflammation through neuropeptides and cytokines, along with histamine and reactive oxygen species (ROS). Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is an illness characterized by an unexplained disabling fatigue with multiple physiological impairments as well as dysregulated cytokine profiles.

OBJECTIVE:
To determine mast cell phenotypes in isolated human PBMCs, in healthy controls and in CFS/ME patients. Second, determine receptor expression of RAGE and its ligand high mobility group box 1 protein (HMGB1).

METHOD:
Moderately severe CFS/ME patients (n=12, mean age 39.25 ± SD3.52 years), severe CFS/ME patients (n=6, mean age 43.00 ± SD4.02 years) and healthy controls (n=13, mean age 42.69 ± SD3.87 years) were included in this study. CFS/ME patients were classified according to the 2011 International Consensus Criteria. LSRFortessa X-20 Flow cytometry was used for the identification of phenotypic peripheral mast cell population in PBMCs using an exclusion marker Lin2 cocktail (anti-CD3, anti-CD14, anti-CD19, anti-CD20 and anti-CD56) and inclusion markers (CD117, CD34, FCεRI, chymase, HLA-DR and CD154) following comparative investigation. HMGB1 and soluble RAGE expression in plasma was measured by sandwich ELISA assay.

RESULTS:
There was a significant increase in CD117⁺CD34⁺FCεRI-chymase- mast cell populations in moderate and severe CFS/ME patients compared with healthy controls. There was a significant increase in CD40 ligand and MHC-II receptors on differentiated mast cell populations in the severe CFS/ME compared with healthy controls and moderate CFS/ME. There were no significant differences between groups for HMGB1 and sRAGE.

CONCLUSIONS:
This preliminary study investigates mast cell phenotypes from PBMCs in healthy controls. We report significant increase of naïve MCs in moderate and severe CFS/ME patients compared with healthy controls. Moreover, a significant increase in CD40 ligand and MHC-II receptors on differentiated mast cells in severe CFS/ME patients. Peripheral MCs may be present in CFS/ME pathology however, further investigation to determine their role is required.
PMID: 27362406
DOI: 10.12932/AP0711

 

[FMMM1]

So now I'm wondering (1) as you point out Alex whether any mast cell contents might be in the plasma getting through the filter @@ljimbo423 indicates Ron Davis used;

Off the top of my head: you could take mast cells, mash them (so to speak) i.e. to extract there contents, and run this through the filter. One you'd collected the correct fraction then you'd check it i.e. to see if it convert normal cells to ME cells.
Alternately, if it's something the mast cells are secreting, (chemical messenger) then you could take mast cells and stimulate then; then run the fluid which surrounds the cells through the filter i.e. to see if they convert normal cells to ME cells.

 

[Murph]

Obviously I need to complain more often!!!!

Eyes are affected in many patients and although there haven't been much studies done on eye sight, those that have studied it have consistently shown substantially reduced accommodation compared to age matched control groups or population norms.

There is also this:
https://www.s4me.info/threads/restricted-spatial-windows-of-visibility-in-me.2006/

baader meinhoff: just found this paper:
Visual Aspects of Reading Performance in Myalgic Encephalomyelitis (ME)
https://www.frontiersin.org/articles/10.3389/fpsyg.2018.01468/full

 

[Gemini]

Visual Aspects of Reading Performance in Myalgic Encephalomyelitis (ME)
https://www.frontiersin.org/articles/10.3389/fpsyg.2018.01468/full

Very nice catch @Murph! It's new, can someone create a thread for it in "Latest ME/CFS Research" as well?

 

[FMMM1]

Very nice catch @Murph! It's new, can someone create a thread for it in "Latest ME/CFS Research" as well?

I think this group published a previous paper:
https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=24187048
Vision-related symptoms as a clinical feature of chronic fatigue syndrome/myalgic encephalomyelitis? Evidence from the DePaul Symptom Questionnaire.

I seems to recall a review of a previous publication by this group by Cort Johnson.

 

[Gemini]

I asked Smith about the Mast cell research and he says it is from these two papers... Peripheral MCs may be present in CFS/ME pathology however, further investigation to determine their role is required.

Thanks for verifying the papers @Murph.

By any chance did Smith indicate if they'll be following up with further mast cell research?

Reason for asking, two clinicians, Dr. Susan Levine and one other longtime physician indicated 60% of their patients had MCAS during a clinicians meeting several months ago.

@FMMM1 offers steps Smith could take working future research into Ron Davis' findings.