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Genes Highlight Inflammation and Mast Cells in Fibromyalgia

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Reprinted with the kind permission
of Cort Johnson and Health Rising.

Lamenting the lack of a diagnostic biomarker for FM, U.S. researchers turned to measuring the expression of the genes in FM patients’ blood. Their findings suggested FM was a neuro-immune disease with a twist.
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 of people diagnosed with FM may not meet the criteria….)
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.

"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."  

They found 428 significantly differentially expressed genes in FM and focused on the top 20. 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 – an 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.
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.
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. 

One of the reasons these studies are difficult to interpret is that context is king in the immune system. If Broderick and Younger and 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 study’s 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.
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.

About the Author: ProHealth is pleased to share information from Cort Johnson.  Cort has had myalgic encephalomyelitis /chronic fatigue syndrome for over 30 years. The founder of Phoenix Rising and Health Rising, he has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort's and other bloggers' work at Health Rising.

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