Genes Highlight Inflammation and Mast Cells in Fibromyalgia

Cort

Founder of Health Rising and Phoenix Rising
Staff member
First the authors of this intriguing study went through the failed attempts to produce a diagnostic biomarker.
The 1990 criteria for FM (which included tender points) produced a moderately homogeneous group of quote "FM patients" which allows, they believe, for too little precision. (In fact a recent study suggested that a whopping 3/4's of people diagnosed with FM may not meet the criteria….)

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[/fright]Genetic studies indicating FM tends to run in families to a much greater degree than most other illnesses suggested a diagnostic biomarker might be found in the genes but gene studies, alas, have had mixed results. Nor have immune studies had consistent results. What's a poor researcher to do to get a handle on FM?

Then came the "M" word - molecular. The authors proposed that it's time to try and get at the molecular underpinnings of FM by determining which genes are active in the blood; i.e. by doing a gene expression study - the first apparently of its kind in FM.

The Study

Jones KD, Gelbart T, Whisenant TC, et al. Genome-wide expression profiling in the peripheral blood of patients with fibromyalgia. Clinical and experimental rheumatology. 2016;34(2 Suppl 96):89-98.

The nice thing about the gene expression study they did was its openness; they examined the entirety of the gene expression in the blood of 70 FM patients and 70 healthy controls. Anything could show up in a study like this. In a disease like FM or ME/CFS in which there are so many puzzles, that's a good approach to take. The researchers curiosity was indeed rewarded with a surprise.

Results
"Our hypothesis is that there is an upregulation of immune/inflammatory molecules in the blood of FM patients with a concomitant decrease in pathways related to hypersensitivity and the allergic responses." The authors
They found 428 significantly differentially expressed genes in FM and focused on the top twenty. A genetic network analysis found a trend towards an increased inflammatory response with the most significant group of genes associated with allergy and hypersensitivity. The inflammatory hub was centered on the IL-10 gene - a anti-inflammatory cytokine that has been highlighted in chronic fatigue syndrome several times. High IL-10 levels have been associated with attempts to turn down an overactive immune response.

That was intriguing given that the expression of genes associated with granulocytes (mast cells, neutrophils, eosinophils, basophils) was reduced in the FM patients. These granule containing immune cells are associated with mast cell activation and the allergic response. Some researchers believe they may also be tweaking the nerves and contributing to pain sensitization.

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[/fright]Does the reduced expression of allergic genes mean FM is an inflammatory disease which results in a reduced mast cell activation syndrome? Apparently the authors don't believe so. The evidence in FM trends towards mast cell activation not the opposite, and the authors emphasized three studies which have found an overexpression of mast cells in the skin of FM patients. One of the genes (CPA3) highlighted - a biomarker for local and systemic mast cell degranulation - suggested that mast cell activation (MCA) had occurred.

The increased expression of four genes associated with glutamate activity suggested that increased expression of the excitatory neurotransmitter glutamate, long suggested to play a role in FM, may be present.

Treatment?

A recent update on treatment options for FM patients found that little has changed on the treatment end for FM in the past ten years. (The update did not assess LDN or medical marijuana.) In fact, the only treatment it could give a 'strong' recommendation to was exercise; it reported that all other treatments had weak effects.

The 14 FM defining genes that popped up in this study lead the authors to suggest, if their findings are validated, some out of the box treatment options. Allergy and mast cell altering treatments were at the top of the list. They included
  • Omalizumab - an antibody used in moderate to severe allergic asthma.
  • Tesmilifene, triprolidine, buclizine -which inhibits histamine release in mast cells.
See the attachment for more of the drug possibilities.

One of the reasons these studies are difficult to interpret is that context is king in the immune system. If Broderick and Younger are others are right, then a gene doesn’t need to be expressed at high levels to make a difference if it's embedded in the right context. On the other hand, high expression of a gene does not necessarily mean that it's a key player.

This studies network analysis suggested something had gone awry in the immune system of FM patients is centered on IL-10 and inflammation and mast cell activation may be involved. That makes sense given what we know about ME/CFS and the hypersensitivity present in FM.

Variability

This is the second FM gene expression study to get published this year. The first, a study by Saligan - who is working on the ME/CFS Intramural study at the NIH - didn't highlight the same genes but did highlight immune genes in general. Interestingly, the study highlighted B-cells - a subject of interest in ME/CFS given the Rituximab results - but until now, not in FM.

The most statistically significant gene found in FM patients appears to play a role in genomic instability - something that has not been tested in FM before. This gene has been associated with infertility, mental disorder, aging, degenerative disease, cancer, and autoimmune disease in humans. This time a heat shock protein (HSP90AA1) occupied the main hub gene in the genetic network produced.

Inconsistent results in large gene expression studies have dogged the field in ME/CFS and FM. (More targeted gene expression studies have had better success). Which study to trust, if any? I would go with the study that makes the most biological sense at the moment - the first one.
 

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Issie

Well-Known Member
Cool..... I've been saying for at least 7 years - autoimmune and inflammation is the core and that glutamate and dopamine dysregulation has something to do with it. Glad it's starting to be proven.

And as for mast cell the connection could be with the glutamate connection - NMDR dysfunction. Can cause one to be in sympathetic mode. But.... with me taking GABA has a paradox reaction. (It should modify glutamate.) Instead it hypes my sympathetic overdrive. It has been said that if one has a response to GABA (in either direction - good or bad) the blood brain barrier has been breeched. This isn't a good thing. Because harmful substances can go to your brain. I have found Tramadol to help with all my autonomic nervous system issues. It affects all the neurotransmitters and NMDA. (Not everyone has a positive response to Tramadol.) I stay very low on my dose and stop taking it when it quits working. Stay off a week or two and then go back on it. It somehow reboots and starts working at low doses again. I find using Bentyl - a mild muscle relaxer - helps in combination. Those two meds along with GastroCrom for mast cell have been my best RXs to date.
Issie
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
Cool..... I've been saying for at least 7 years - autoimmune and inflammation is the core and that glutamate and dopamine dysregulation has something to do with it. Glad it's starting to be proven.

And as for mast cell the connection could be with the glutamate connection - NMDR dysfunction. Can cause one to be in sympathetic mode. But.... with me taking GABA has a paradox reaction. (It should modify glutamate.) Instead it hypes my sympathetic overdrive. It has been said that if one has a response to GABA (in either direction - good or bad) the blood brain barrier has been breeched. This isn't a good thing. Because harmful substances can go to your brain. I have found Tramadol to help with all my autonomic nervous system issues. It affects all the neurotransmitters and NMDA. (Not everyone has a positive response to Tramadol.) I stay very low on my dose and stop taking it when it quits working. Stay off a week or two and then go back on it. It somehow reboots and starts working at low doses again. I find using Bentyl - a mild muscle relaxer - helps in combination. Those two meds along with GastroCrom for mast cell have been my best RXs to date.
Issie
Glad to see that there is a potential glutamate/mast cell connection.

That is a weird response to GABA - and interesting about the Tramadol. Maybe your ANS is responding to the drop in pain? I imagine that it could get set off pretty good by pain (?)
 

Issie

Well-Known Member
You may find these interesting :

Affect of mast cell and CNS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282993/

This person wrote a blog with research on connections to MTHFR mutations and mast cell issues
http://mthfrliving.com/health-conditions/mast-cell-activation-disorder-histamine-intolerance/

I have another article, I can't find. I'll keep looking.

I found the connection between glutamate and mast cells the hard way. I chewed way to much sugar free gum. It triggered a severe mast cell response that went into Kounis Syndrome that affected my heart. ICU in cardiac unit over night and lots of research later, connection made. You could say, I was the lab rat who got my own data - the hard way.

Issie
 
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Issie

Well-Known Member
And to make even more connections to glutamate dysfunction - there is a strong connection with foods. This article shows a connection with autism, vaccines and foods. Read the comments.... someone listed all the foods. For MCAS people - do you notice trigger foods?
http://www.ageofautism.com/2011/03/autism-and-glutamate-dysfunction-avoid-the-cause-race-to-the-cure.html

There is a close connection to the autoimmune system and mast cell function. Some of us have found good response to low dose antibiotics.

Issie
 

Issie

Well-Known Member
Just a quick search and here are some articles backing up what I'm saying. There are so many more. There is one other one on aspartame that I want to find. We are friends with one of the cardio docs who did the initial research before the stuff came out. I've heard all about the research and how horrible it is. I'll try to find that article too. But for now. ....you may find it more challenging to get better until you get it out of your diet.

http://www.naturodoc.com/library/nutrition/aspartame.htm

https://chronicdiseaserecovery.wordpress.com/2013/03/13/glutamate-and-gaba-balance/

http://www.holistichelp.net/blog/how-to-increase-gaba-and-balance-glutamate/
Additionally, glutamate receptors also pull in other excitatory substances into the cell besides glutamate, including all of the following:

  • Aspartate (can also be converted into glutamate)
  • Aspartame
  • Aspartic acid
  • Glutamate
  • Glutamic acid
  • Glutamine
  • Monosodium glutamate (MSG)
  • Cysteine (But not n-acetyl-cysteine. However, does contain sulfur and too much sulfur can be counterproductive as well, so should be used mindfully.)
  • Homocysteine
Therefore, each of these can bind with glutamate receptors, which also results in excessive stimulation and contributes to the imbalance in GABA and glutamate and the wide array of symptoms that are generated.

Issie
 
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Remy

Administrator
image.png
Just a quick search and here are some articles backing up what I'm saying. There are so many more. There is one other one on aspartame that I want to find. We are friends with one of the cardio docs who did the initial research before the stuff came out. I've heard all about the research and how horrible the stuff is. I'll try to find that article too. But for now. ....you may find it more challenging to get better until you get it out of your diet.

http://www.naturodoc.com/library/nutrition/aspartame.htm

https://chronicdiseaserecovery.wordpress.com/2013/03/13/glutamate-and-gaba-balance/

http://www.holistichelp.net/blog/how-to-increase-gaba-and-balance-glutamate/
Additionally, glutamate receptors also pull in other excitatory substances into the cell besides glutamate, including all of the following:

  • Aspartate (can also be converted into glutamate)
  • Aspartame
  • Aspartic acid
  • Glutamate
  • Glutamic acid
  • Glutamine
  • Monosodium glutamate (MSG)
  • Cysteine (But not n-acetyl-cysteine. However, does contain sulfur and too much sulfur can be counterproductive as well, so should be used mindfully.)
  • Homocysteine
Therefore, each of these can bind with glutamate receptors, which also results in excessive stimulation and contributes to the imbalance in GABA and glutamate and the wide array of symptoms that are generated.

Issie
None of those are actual studies like I posted. Those are just opinions and I think most people get aspartame very very wrong. The risks are so overblown and the inaccuracies around this topic on blogs etc are rampant and blatant.

From the American Chemical Society:


Glutamine converts to glutamate and then can *use* aspartate to convert to a-ketoglutarate. None of that adds up to aspartame increases glutamate.

image.png


I gave up all drinks but water for almost five years. It made no difference. Actually it was a negative result because I do well with caffeine.
 
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Issie

Well-Known Member
Here is some of the history findings while they did research. I know one of the docs who helped with the research.....he is a personal friend. He said he wouldn't give it to his worst enemy.
http://rense.com/general33/legal.htm

Alot of companies benefit from the sell of aspartame.

I was a legal and medical secretary and one of our clients was DXd with dementia - it was Aspartame related. She got off it and her memory function came back.

We have the right to make our own choices. I know what it did to me. It was an expensive and could have been a death experience. It does affect and create a neuroexcitatory response. People can crave the high it gives. It has phenylalanine in it and that mixes with other neurotransmitters and ramps up that system of the body. That combination causes a sort of neurotoxin response when over ingested. I initially felt really energized until the mast cell attack came and then......the rest is history. They thought I was having a heart attack. Yet no heart muscle damage. The treatment was massive antihistamines and nitroglycerin. And a night in Intensive care.
www.mpwhi.com › ijc_atrial_fibrillation
Just passing on what may benefit others.

Issie
 
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Remy

Administrator
Here is some of the history findings while they did research. I know one of the docs who helped with the research.....he is a personal friend. He said he wouldn't give it to his worst enemy.
http://rense.com/general33/legal.htm

Alot of companies benefit from the sell of aspartame.

I was a legal secretary and one of our clients was DXd with dementia - it was Aspartame related. She got off it and her memory function came back.

It's not good for you. We have the right to make our own choices. I know what it did to me. It was an expensive and could have been a death experience. It does affect and create a neuroexcitatory response. People can crave the high it gives. It has phenylalanine in it and that mixes with other neurotransmitters and ramps up that system of the body. I initially felt really energized until the mast cell attack came and then......the rest is history. They thought I was having a heart attack. Yet no heart muscle damage. The treatment was massive antihistamines and nitroglycerin. And a night in Intensive care. Just passing on what may benefit others. Up to you if you heed my advice or not.

Issie
The problem is that aspartame is one of the most extensively studied substances and none of what you have said regarding excitotoxins is supported by the vast amount of scientific findings. In fact, it's all exactly the opposite. No effect at all.

I love a good conspiracy theory as much as the next person but the actual chemistry *has* to override that at some point. Anyone who knows me, knows that I have a high tolerance for woo but this vendetta against aspartame is totally off the mark.

Are you going to stop drinking milk because it has 8x the phenylalanine as a can of diet soda? Is anyone out there claiming milk is a toxic substance that should be banned (without a dairy allergy, of course)? No, of course not.

Phenylalanine is fantastic for pain and I'd suggest anyone with chronic issues to give the supplement a try. Julia Ross writes about this use extensively.

I don't doubt that you had a terrible experience and fully support your personal decision to avoid aspartame. But I do have a problem with making statements like "aspartame increases glutamate" that are just not true. There's way too much unjust prejudice against aspartame as it is. It shifts focus off finding the real problems.
 
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Issie

Well-Known Member
The problem is that aspartame is one of the most extensively studied substances and none of what you have said regarding excitotoxins is supported by the vast amount of scientific findings. In fact, it's all exactly the opposite. No effect at all.

I love a good conspiracy theory as much as the next person but the actual chemistry *has* to override that at some point. Anyone who knows me, knows that I have a high tolerance for woo but this vendetta against aspartame is totally off the mark.

Are you going to stop drinking milk because it has 8x the phenylalanine as a can of diet soda? Is anyone out there claiming milk is a toxic substance that should be banned (without a dairy allergy, of course)? No, of course not.

Phenylalanine is fantastic for pain and I'd suggest anyone with chronic issues to give the supplement a try. Julia Ross writes about this use extensively.

I don't doubt that you had a terrible experience and fully support your personal decision to avoid aspartame. But I do have a problem with making statements like "aspartame increases glutamate" that are just not true. There's way too much unjust prejudice against aspartame as it is. It shifts focus off finding the real problems.
It's an excitotoxin and affects the body adversely. It can be a serious problem and one piece of the puzzle.

Point of discussion is excitotoxins can trigger a glutamate over response/reaction and cause mast cell activation degranulation. (From whatever source, and can be diet related.)

Issie
 

Issie

Well-Known Member
MSG is also a glutamate and a neurotoxin. Here is a doc talking of his findings about MSG and the glutamate affects on the body.

He says why few docs will write about it and warn people. And why he decided he had to write a book and talk about his findings and the cover ups. He has several videos on his findings with neurotoxins.

One point I found interesting that glutamate causes a release of calcium through an opening that is supposed to allow a small release. But if there is too much glutamate it doesn't close and too much calcium is released. That can cause an inflammatory response that can affect the mitochondria and cause the cells to kill themselves because of being to damaged. It's around the 35 minute mark. (GastroCrom moderates calcium and is a mild calcium channel blocker. My best med for MCAS.)

I'm about half way through it, really interesting.

Here's a written interview he did.
http://www.bibliotecapleyades.net/salud/esp_salud23k.htm
Issie
 
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Snow Leopard

Active Member
Heatshock proteins being the most significant finding is interesting... There is a potential for more than a few interesting hypotheses there, I hope someone follows it up.
 

Issie

Well-Known Member
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Issie

Well-Known Member

This was the best explanation I could find describing what heat shock proteins are. They regulate and fold proteins that have become irregular due to stressors - heat being only one. He list the stressor that would cause a need for heat shock proteins.
I'm always saying - 'stress is going to kill us all' .
Issie
 

Remy

Administrator
New research study in April 2016 linking issues to MSG and Aspartame -
www.academicjournals.org › journal › AJB
http://www.academicjournals.org/journal/AJB/article-abstract/AACECC858074

Authors suggest more study. Especially found connections to behavior and biochemical analysis. (Again in mice.)
http://www.ncbi.nlm.nih.gov/pubmed/24556450
I know one thing - I intend to read labels more carefully.

Now Snow Leopard to look into heat shock proteins.
Issie
Unfortunately, @Issie, I don't find Blaylock or his conspiracy theories credible. I'm not particularly impressed with the African Journal of Biotechnology either, which describes its mission as to publish exciting news as quickly as possible.

The final article actually says that aspartame did not affect neurotransmitters or oxidative stress alone.

The science just doesn't support the theory that aspartame is a toxin in normal human amounts of consumption.

If that were true, people would be falling over with brain damage from juice and milk too and they simply aren't.

We can agree to disagree.
 
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madie

Well-Known Member
For what it's worth, my son lost bladder control the 2 times he had aspartame as a child. Nobody else in the family reacted in visible ways, but we choose to keep it out of our diets.
 

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