“These data demonstrate that neutrophils are fundamental for the development of chronic widespread pain through the infiltration of peripheral sensory ganglia.” The authors

There isn’t a lot of fibromyalgia research going on and the field has gone bonkers over exercise studies with efforts examining seemingly every kind of exercise imaginable. At some point, that effort has to run its course (doesn’t it?), but the field is also producing some fascinating studies that could have far-reaching impacts on pain but also on FM’s sister diseases.

First, there were the studies that put small fiber neuropathy on the map – and triggered similar investigations and findings in chronic fatigue syndrome (ME/CFS) and long COVID. (A big thanks to FM researchers for that.)

Is FibroCOVID a Real Thing? Plus Small Fiber Neuropathy Found in Long COVID

More recent studies have focused on mice. That’s a slant that, until the Simmaron research team got going on their mouse models, was completely missing in chronic fatigue syndrome (ME/CFS). It certainly appears to be paying dividends in FM.

Next came a jaw-dropping study demonstrating that the transfer of antibodies from FM patients into mice gave the poor mice FM – not anything anyone would wish on anyone – but suggesting that FM just might be an autoimmune disorder. Interestingly, the antibodies gathered around and seemed to trigger the activation of the microglial cells in the dorsal root ganglia.

Study Suggests Something in the Blood is Causing Fibromyalgia

For their next trick, the researchers demonstrated that the same thing appeared to be happening in long COVID. (ME/CFS can’t be far behind…)

Something in the Blood II: Long-COVID / Fibromyalgia Autoimmune Connection Found

Just this year, their findings were rewarded with a major grant: this finding is not going to die on the vine…

Signs of Change? Did Two ME/CFS and Fibromyalgia “Moments” Just Occur?

Then there was the gobsmacking finding from a Canadian research group that natural killer cells in fibromyalgia (not ME/CFS – fibromyalgia) were targeting sensory neurons.

Immune Cells May Be Killing the Small Nerve Fibers in Fibromyalgia

Immune Cells on the Attack

“Neutrophils play a critical role in the transition from acute to chronic pain in fibromyalgia.” The authors

Now comes another eye-opening mouse study. Once again we’re at the sensory ganglia! About a decade ago, Martinez-Lavin proposed these bundles of nerve bodies called the dorsal root ganglia (DRG), located just outside the spinal cord, were ground zero for FM. It made sense. These are the nerve bundles that the sensory signals from the body pass through to get to the spinal cord.

If you were to pick one place in the body to screw up the pain signaling process and cause pain hypersensitivity, this would probably be it. Let’s not forget that herpesviruses apparently love to hang out in the DRG.

Turning Stress into Pain: A Fibromyalgia Primer by Dr. Martinez-Lavin Pt I – Pain

The study, “Neutrophils infiltrate sensory ganglia and mediate chronic widespread pain in fibromyalgia widespread pain in fibromyalgia“, comes out, once again, from the U.K. (Where are you, NIH?). This is the third recent study to point a finger at immune cells associated with the early or innate immune response in ME/CFS, long COVID and/or fibromyalgia. Monocytes – another innate immune cell – have recently become a big thing in both ME/CFS and long COVID, natural killer cells popped up in FM, and now we have neutrophils. The native immune system is a primary driver of inflammation, so it makes sense it might be involved, but this is mostly new territory for these diseases and that’s a good thing.

Neutrophils may not have gotten much press in FM and ME/CFS, but they are the most abundant white blood cell in the body. The immune rapid responders are likely the first immune cell that any pathogen will encounter. Detecting signs of damage, they follow chemical signals in the blood to the site of injury, at which point they wiggle through the blood vessel walls and into the interstitial spaces. There, they will send out the alarm, and then if a bug is present, they will try to ingest it (phagocytose), and/or secrete anti-microbial proteins that damage it, nd/or create web-like traps that capture it.

Mouse studies

Mouse studies are opening new vistas on both fibromyalgia and ME/CFS.

First, these UK researchers created a fibromyalgia mouse model and transferred blood and serum from the FM mice into healthy mice. When the blood induced FM but the serum did not, they concluded that circulating cells in the blood were responsible.

They then filtered the blood into four immune subsets —T cells, B cells, neutrophils, and monocytes – and then injected each component into healthy mice. Only mice receiving the neutrophils displayed signs of ongoing and delayed pain hypersensitivity.

When they chemically removed the neutrophils from the mice, the mice responded to a pain stressor normally; that is, they temporarily demonstrated signs of pain but then returned to normal. Their chronic pain hypersensitivity was gone. Somehow, the neutrophils were creating a chronic pain state.

Encouragingly, when they removed the neutrophils after a chronic pain state had been produced, the mice showed significant reductions in pain; i.e. the chronic pain state was malleable.

They weren’t done yet. Next, they checked to see if the neutrophils had made it to the dorsal root ganglia and found that they had indeed infiltrated it. That was an unusual finding, as neutrophils only make it to nerve cells if they’ve been injured – yet these were healthy mice. Prior studies have shown that neutrophils can sensitize neurons – sending them into a kind of hissy fit in which they respond to inappropriate stimuli – which is exactly the situation we see in the pain hypersensitivity found in FM.

[types field="the-gist"][/types]Neutrophils are the most abundant white blood cell in the body. Highly sensitized neutrophils appear to be tweaking the nerves in the main signal processing center in the body – the dorsal root ganglion.

When the neutrophils moved, they moved quickly – it took just an hour for them to invade the dorsal root ganglia after the pain state had been invoked using a carrageenan injection into the calf muscle. Note that the dorsal root ganglia are a long, long way from the calf!

Next, seeking to identify which types of neutrophils might be involved, they identified 11 different subpopulations, one of which was characterized by decreased levels of immune factors (CXCR2, CD62L, CD11b, Ly6G, and Ly6C) and was found nestled in the dorsal root ganglia.


  • The fibromyalgia (FM) field has gone bonkers over exercise but it’s also producing some fascinating studies. First FM researchers uncovered small fiber neuropathy, then a study found that giving mice antibodies from FM patients gave them FM, then – in a stunning finding – natural killer cells were found to attacking pain-producing nerves, and now we have neutrophils/ 
  • The common thread – cells from the innate immune system e.g. the early immune response that plays a major role in inflammation – are popping up big time in both FM and ME/CFS (monocytes). This is a change and given the difficulties understanding these diseases a good one.
  • This study methodically chased down their leads. They turned healthy mice into FM-like mice by giving blood and serum from FM patients. Noting that only the blood did that they divided the blood up into different sets of immune cells  (monocytes, T-cells, B-cells, neutrophils) and then gave them to the mice. This time, only the neutrophils produced a chronic pain state.
  • Neutrophils, the most common white cell in the body, move quickly to get to any areas of damage. They also ingest pathogens, knock them out with antimicrobial factors, and cast nets to capture them. They have, however, been implicated in the pain production process and unusually high levels of neutrophils have been found in FM.
  • Next, they chemically removed the neutrophils from the blood of the mice, and voila! – their pain receded. A closer examination revealed that the neutrophils had invaded the primary sensory processing center of the body – the dorsal root ganglia. That was unusual – neutrophils usually find their way inside the DRG when it’s been damaged – but these mice were healthy.
  • Further work indicated that neutrophils which were unusually sensitized to chemical signals that lead them to sites of inflammation were implicated.
  • The big test came next: they took neutrophils from FM patients and healthy controls and injected them into the mice…Only the mice receiving FM neutrophils lapsed into a chronic pain state.
  • The authors did not explore the treatment ramifications of their study, but they did find that an anti-neutrophil antibody tamped down the pain in the mice, and one anti-neutrophil antibody drug – Avacopan, or Tavneos – the first in its class – has been FDA approved to treat a form of vasculitis.
  • In it’s one sour note, the authors reported they had been unable to replicate the antibody transfer results of the Goebel team. The Goebel team gave mice FM by injecting IgG antibodies from FM patients into them
  • For decades, FM was thought of as a purely central nervous system neurotransmitter-driven disease – a conception that gave us lifestyle changes, antidepressants, and anticonvulsants – not exactly a winning formula. These new findings, though, provide a new angle on FM – one, which if it’s validated, should open many new treatment options.

This subpopulation of neutrophils may be acting too aggressively because they’re carrying unusually high levels of receptors that respond to “chemoattractants” – chemical signals that lead neutrophils to the site of injury. These neutrophils, then, appear to be hypersensitized to any evidence of injury. As we know, the immune system has the power to heal and to destroy.

Next came the make-or-break moment. They then took neutrophils from people with fibromyalgia and from healthy people and injected them into the mice. The mice receiving the neutrophils from the healthy people remained fine, but the mice receiving neutrophils from the FM patients developed FM-like symptoms.

Testing the hypersensitivity of the mice, they found that the mice receiving the neutrophils from the FM patients exhibited hypersensitization at both the level of the spinal cord and the dorsal root ganglia.

The authors reached back to a 2007 study that suggested that “an enhanced adhesion and recruitment of leukocytes to inflammatory sites” was occurring in FM.

A fairly rich literature has demonstrated that neutrophils play a role in acute pain and pain hypersensitivity, but this was the first time that they’ve been linked with the transition to the chronic pain state we see in fibromyalgia. Neutrophils are short-living – surviving at most 4 or 5 days – but some studies suggest their lifespan may be extended in pathological states.

The authors did not explore the treatment ramifications of their study, but they were able to use an anti-neutrophil antibody to tamp down the pain in the mice. One anti-neutrophil antibody drug – Avacopan, or Tavneos – has been FDA-approved to treat neutrophil-associated vasculitis. It’s a “first-in-class” drug; i.e. it’s the first drug of its kind to be produced.

Noting that immune cells have been associated with pain in fibromyalgia, the authors reported they had been unable to replicate antibody transfer results of the Goebel team. However, if I’m reading the supplement correctly, the test involved only 1 fibromyalgia patient and four mice; i.e. its hardly conclusive.

For decades, FM was thought of as a purely central nervous system neurotransmitter-driven disease – a conception that gave us lifestyle changes, antidepressants, and anticonvulsants – not exactly a winning formula.

These recent findings are suggesting that whatever else, the immune system and the peripheral nervous system are involved – and that ultimately could, if validated, lead to a whole new array of treatment choices for a disease that desperately needs them.

Neutrophils, interestingly, are the subject of a new ME/CFS study funded by the Open Medicine Foundation. This study is going to use new testing technology that will take them out of ME/CFS patients, provoke them with an inflammation stressor, and assess them more deeply than has been done before.


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