“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.)
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.
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…)
Just this year, their findings were rewarded with a major grant: this finding is not going to die on the vine…
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 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.
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.
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.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.
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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Thanks as ever for a great article Cort- I’d be lost without this lifeline, and your summaries and explanations are always so accessible.
I had been really hopeful after the Goebel mice antibody FM study of 2021, so it is alarming that an attempt at replication has failed by another group. Do you know if the Goebels group have commented on why they got different results to this study (the antibody component I mean), or if these two groups are communicating? hopefully, as that would be best for research progresssion , and ultimately for patients, but not sure that’s always the primary driver …
Frustratingly it will take years to filter down to regular clinical practice, just listened to a lupus webinar tonight where the rheum said that fibro should under no circumstances be treated with immune drugs, yet I had a great response to high dose steroids given for something else….
Yes, that was really disappointing! They did suggest that differences in the way pain was measured or perhaps heterogeneity in FM could have played a role. I’m actually going to amend the blog because if I’m reading the supplement right the trial was very small – one FM patient and four mice. If that’s all they have I’m shocked they reported it at all. What if they got the wrong FM patient? I haven’t heard of any response from the Goebel group. This is what they said.
I must say this whole thing about FM possibly being an autoimmune disease is hilarious given the cold shoulder rheumatologists have given it for decades.
Cort, I think your interpretation is correct and it is possible as with a lot of research that a peer reviewer asked for this experiment to be done so they did it with only one sample they had laying around and it at best is inconclusive.
I have had low neutrophils since the day I got ME/CFS. It is one of the only blood test markers that I have that is abnormal.
I believe it is fairly common to have low neutrophils in CFS.
i was looking for the gist. maybe to ill to see it or it is not there?
It was me! I did it and somehow it ended up in the caption of one of the images. Second time in the last week or so I did it and didn’t get it in there (sigh). It’s in there now.
Thank you Cort, it could have happened to anyone!!! 🙂
And you write so much and are ill to…
May i ask, because could only read the gist, and there stood something “also in ME/cfs). Is ME/cfs as far on the road as FM. They have mousemodell, tested it, could turn healthy mouse in FM mouse and cure them again…? Sorry to ask, brain is worse and worse…
There are some things here – they created a FM-like mouse but it wasn’t quite FM. They created a chronic pain state but the mouse didn’t display some features of FM like poor sleep. They were able to significantly reduce the pain by removing the neutrophils using antibodies. My guess is that they’ve had this mouse model for a while.
ME/CFS is on a bit different track. Simmaron is using a mouse to explore the role impaired autophagy might be playing in ME/CFS and by doing so have created an ME/CFS-like mouse. A blog on this is coming up.
thank you verry much Cort!!!
This is SO interesting and promising – love seeing more and more studies pinpointing immune involvement and even if different cells are involved, it makes sense that there is a common target, the DRG. Also, not surprised if they couldn’t exactly replicate Goebel antibody findings, a lot of scientific research in mice is difficult to replicate and imagine how different FM patients are that you definitely can’t try it using just one patient sample. It also makes sense to me that there would not be just one immune mechanism gone awry in FM if it is more of an autoimmune-like state you are bound to see involvement of other cell types (so now we see neutrophils, NK cells). Maybe other cell type involvement will become clearer, too. I don’t think a neutrophil-depleting therapy will be the way to go because you never want to wipe out an entire cell type if you can help it, as that leads to worse consequences, and it is unlikely to be the only immune mediator at play in FM.
It was interesting to read this article. I have always believed that my FM started when I was in my mid twenties. When I was 21 I was in a very serious car accident. I had concussion and was in coma for a couple of days. When I recovered they found that I couldn’t use my right leg. I had to have physical therapy to be able to walk. Three years later my fibro started. I had extreme sensitivity just under the skin in my legs. Only bothered me when I would bang against something or it was squeezed. My husband grabbed my thigh as we were sitting on the couch. I screamed because it hurt so bad. This was the beginning of my life with FM. I am now 74 years old and I was fortunate to found a drug which really helped my pain and allowed me to work. I don’t know if doctors believe a traumatic event causes FM now or not, but something made my nerves become hyper sensitive. I believe that my immune system went haywire and caused my problem. Now I have numerous autoimmune problems. Any thoughts?
You really have some big triggering factors. Post-concussion syndrome can mimc ME/CFS/FM. Trauma can easily dysregulate your system as well. Just being in pain increases the risk of coming down with fibromyalgia.
Can you say what drug helped?
I’ve experienced a similar progression into FM and ME. I was involved in two bad accidents but also had Epstein Barr, hhv6 and c-pneumonia so it’s complicated.
I’d also like to know what medication helped. I’ve been in ridiculous pain. Thanks
Evidently, they should try exactly the same thing with blood from ME/CFS patients, but then also examine what happens in different regions of the whole CNS (brain).
I would have hoped after the first Goebel report that this would have happended long since, it´s such an evident approach.
Thanks Cort, that’s really interesting! Does anyone know Ron Davis’ take on neutrophils – I think he’s studying them from the bone marrow (apologies if that’s wrong) – or when he’s likely to publish? Thanks!
I’d forgotten about that! Thanks for the reminder. I added something on that in the blog. I don’t know anything about the status of the study though. I’m really excited to see all this innate immune stuff popping up though. Its a big driver of inflammation.
Thanks Cort – hopefully it won’t be too long to wait! 🙂
This post is interesting since I am someone that has had FM over thirty years. I have noticed whenever I am ill from a cold or even digestive upset, the surrounding area is inflamed, and the pain magnified as well. It well may be the result of traveling neutrophils. In the morning my spine is always stiff and painful, particularly the base of the spine. I have found that a couple of sprays from magnesium oil eases the pain and stiffness. I don’t know if other FM sufferers have a similar experience or not.
I had mono in early twenties so I had Epstein-Barr in my system. I asked doctors if that could be the cause of my fibro. They didn’t know. Really depressing how that is not high on the list for research. Plus, how docs put that low on the list when treating someone who has pretty severe fibro issues. It’s like they just blow it off. I have had enlarged lymph nodes in my body for years. I keep being told it has nothing to do with the fibro. I was even sent to MD Anderson for complete workup to make sure I didn’t have lymphoma. I finally started seeing that in lists of issues from fibro. I’ve even been told I have “autoimmune issues.” When I had a major surgery after a really bad resp. Infection that had hung on for months is when they found the lymph nodes. That’s when my body started falling apart even worse than it already was and finally got the right dx of fibro. Since then I have had more surgeries, a new problem added every 6 mths to a year to the point I am now on 24 meds.
I was an RN for 20 years and finally had to quit on go on disability because I couldn’t stand the pain anymore and started noticing I wasn’t as sharp as I use to be and thought I was getting early Alzheimer’s. I got to wear I couldn’t even hold a conversation with anybody because my memory was gone. Thank God for a new Alzheimer med at the time that brought back some of my long-term memories. There is so much more I could say here but getting long winded.🙂
Magnisium oil spay sounds interesting. Not messy, is it? Tell me about it, please. Which firm of magnisium? Thank you, Javen morell
Neutrophil, monocyte and microglia are all native immune cells. Maybe the native immune cells go berserk after an infection in some people? I wonder if they can deplete microglia and see if ME/CFS symptoms go away, the same way FMS pain went away with the depletion of neutrophil. There is a drug to do that, I think. Not sure about ethics of doing that to people though. Maybe they can do that to mice.
It appears things are falling into place. Grimson study found that the severity long COVID symptoms are predicted by the number of “diseased” monocytes. Now neutrophil is implicated in FMS pain while microglia has been long suspected in ME/CFS.
This is a fascinating post, Cort! Do you know whether neutrophils cross the BBB?
I wonder whether they get the microglia excited. There is definitely inflammation in the brain and spinal cord of FM patients, as Karolinska and Harvard have demonstrated. Dr. Jarred Younger at U of Alabama is endeavoring to prove that autoimmunity may be one cause of central sensitization. They need to try replicating it again. What a relief it would be it they could stop or at least diminish the pain based on this research.
This link is quite interesting in light of the above-cited research.
Love you, cort. I don’t know how you do it with your own ME/CFS…But, you do. The NIH is just abysmal even after all these decades. We are always playing musical chairs. We all feel bad. I thought when Francis Collins left, it would change but it has not. This article is really interesting and it sounds so plausible. I think all of us would be so grateful to not be in pain so much, so hard. This sounds like it’s possible. Ring around the ROSEY. I’m just infuriated today as I hurt so bad and it’s a bad bad thing. Sincerely, Javen