It’s like a sapling putting out roots. Will it grow into a big tree or will it die on the vine? However, it turns out, Andreas Goebel Ph.D. has certainly planted some fascinating and possibly game-changing ideas about how fibromyalgia, ME/CFS, and long COVID occurs.
This blog focuses on a poster presented at the World Congress on Pain that recently took place in Toronto. (Thanks to Herbert for the tip :)).
Andreas Goebel has been on the hunt for a new way to explain pain ever since he found that his patients at the pain clinic at Würzburg University typically had low-level increases in post-infectious antibodies. (Hmm). He also knew that the current pain paradigms couldn’t explain a large group of chronic pain sufferers. How large? Potentially billions of people, large:
“In other words, symptoms that profoundly affect billions of people across the globe have remained unexplained. New approaches to their understanding are needed.” Goebel et. Al. 2022
A Different Kind of Pain
Chronic pain has long been believed to be the result of either tissue damage/inflammation (nociceptive pain) or damage to the nerves (neuropathic pain). In diseases like fibromyalgia, however, no evidence of tissue damage or widespread inflammation has been found, and the small fiber neuropathy damage thus far found can’t explain the disease.
Recently a new term, ‘nociplastic pain’, was developed to define people in chronic pain who have “structurally intact, but abnormally functioning” pain networks. Fibromyalgia is considered a classic example of this kind of disease. While this new characterization helped, it couldn’t explain how these “abnormally functioning” pain networks came about.
Enter Andreas Goebel – a German pain researcher working at the University of Liverpool. The Director of the Pain Research Institute in London, Goebel has been focused on understanding the role the adaptive immune system plays in causing severe ‘unexplained’ chronic pain, for the past 15 years.
A Different Kind of Autoimmunity
In March of this year, Goebel and colleagues penned a review, “The autoimmune aetiology of unexplained chronic pain“, that explained that they’d uncovered “pain sensitizing autoantibodies” in no less than four chronic pain conditions (complex regional pain syndrome, fibromyalgia, chronic post-traumatic limb pain, and rheumatoid arthritis). Interestingly, the autoantibodies bound themselves to different sites in the 4 diseases – indicating that each appeared to be a different type of autoimmune disease. Goebel et al. stated that they showed that “functional, non-destructive biological processes can cause exquisite pain which severely affects daily living.”¹
Seven years ago Littlejohn proposed that CRPS, fibromyalgia, IBS, and migraine are all neuroinflammatory diseases driven by inflammation of the sensory and central nervous system nerves.
With fibromyalgia, Goebel injected purified IgG from people with FM and healthy control subjects into mice and then watched. Within two days, the mice given the IgG from the FM patients had become hypersensitive to pressure, cold, and pain, and reduced their grip strength while the mice given the IgG from the healthy controls remained fine. Goebel had apparently swiftly given mice fibromyalgia simply by giving them immune factors found in his FM patients’ blood.
Further digging indicated that the pain receptors on the nerves outside the spinal cord in the dorsal root ganglia had become hyperactivated in the FM mice. The dorsal root ganglia are like a way station that sensory and autonomic signals from the body pass through in order to enter the spinal cord and reach the central nervous system.
Fibromyalgia researchers have mapped out all sorts of central nervous system abnormalities, but it’s never been clear if they were the result of central nervous system problems or if they were simply the result of central nervous system overload from an unrelenting barrage of signals that were hitting it.
Goebel’s findings suggest the second: the IgG from the FM patients never made it to the spinal cord or the brain; instead, it mostly accumulated in the glial cells surrounding the dorsal root ganglia. While the glial cells just outside the spinal cord became hyperactive, the activity of the glial cells inside the spinal cord remained at normal levels.
That meant that after all the focus on the central nervous system in FM, Goebel was able to reproduce a fibromyalgia-like condition in mice without ever directly impacting the central nervous system at all. Nor did evidence of systemic inflammation crop up. Whatever the antibodies were doing, they were doing it very locally.
Goebel’s findings are potentially so exciting because they could explain one of the great mysteries in FM and ME/CFS – why we don’t see enormous spikes of inflammation. Goebel’s findings suggest that small amounts of inflammation are probably occurring very close to nerves. (Van Elzakker, in his Vagus Nerve Hypothesis, proposed something similar for ME/CFS.)
Well aware of the implications of their findings, the authors wrote their results may “transform future research and facilitate development of mechanism-based therapeutic interventions (in fibromyalgia)”.
A Different Look at Long COVID
Recently, Goebel reached outside of the chronic pain arena when he did a different experiment on long-COVID patients. He and his team took purified IgG antibodies from-long COVID patients experiencing widespread pain, from people who’d recovered from COVID-19, and from an FM patient, and then planted them in cultures of glial cells from the dorsal root ganglia of mice.
They then did an inflorescence study to see if the antibodies from the patients or healthy controls were binding to or attacking those glial cells – thus activating them and causing them to begin spewing out pro-inflammatory factors that were tweaking the nerves and causing increased pain.
- About ten years ago, Andreas Goebel saw that some of his chronic pain patients had high levels of post-infectious antibodie,s and began searching for an autoimmune cause of it.
- Since then, he’s shown that putting IgG antibodies from people with fibromyalgia, rheumatoid arthritis, chronic regional pain syndrome, or post-traumatic limb pain into mice appeared to cause the mice to come down with similar conditions. Interestingly, the IgG antibodies appeared to attack different parts of the body in each condition.
- Goebel found that the antibodies from the fibromyalgia patients had gathered in the glial cells covering the dorsal root ganglia (DRG). The DRG are the last way station for the sensory signals before they enter the spinal cord. The glial cells are immune cells that, when activated, spew out proinflammatory cytokines that could cause the DRG to become hypersensitized to pain signals.
- Goebel believes that the reason that systemic inflammation is not found in FM or ME/CFS is because the autoimmune attack is very localized and is focused on these nerve bodies found just outside the spinal cord. (Herpesviruses are known to infect these nerve bodies.)
- Goebel has said he plans to test ME/CFS and included ME/CFS in a list of autoimmune chronic pain conditions but moved forward first with long-COVID patients who were experiencing significant pain.
- Using a culture experiment, Goebel found that the IgG from the long-COVID patients attacked the glial cells covering the dorsal root ganglia – suggesting that the same process occurring in fibromyalgia is occurring in long COVID.
- Goebel proposed that long COVID is a subtype of ME/CFS and fibromyalgia.
- He also noted that, at least in mice, the condition is reversible if one can mop up the autoantibodies. Plasmapheresis, the BC007 aptamer, or a drug that blocks the autoantibodies in question could do that.
- Much more work clearly needs to be done, but if Goebel is right, he would clear up several problems in these diseases – why not a lot of inflammation or evidence of trauma or injury is found.
These findings were clearly preliminary, and more work needs to be done, but they suggest – as some other studies have – that an abnormal antibody (e.g. autoimmune) response is present in long COVID and that it may be an autoimmune disease. Importantly, fibromyalgia – which, for some reason, has been almost totally outside of the long-COVID discussion – now becomes the third leg of a possible ME/CFS/FM/Long-COVID triad.
The fact that the mice returned to normal when the FM IgG levels declined suggested that the illness is not permanent and could be reversed by removing the autoantibodies. Goebel suggested that IgG-reducing therapies such as plasmapheresis or immunoadsorption could be helpful. Of course, some success has been found in small studies with immunoadsorption in ME/CFS, and the BC 007 aptamer is another candidate. Approaches that block the autoreactive IgGs could be effective as well.
Lastly – in my favorite part of the poster – they suggested – rightly in my opinion – that long COVID is not a separate condition but is a subtype of FM and chronic fatigue syndrome (ME/CFS).
“Our results lend credence to the hypothesis that long-COVID is an infection-triggered subtype of FMS and chronic fatigue syndrome.”
And there you have it – a possible infection-triggered autoimmune response that sends the glial cells that are wrapped around the main sensory processing neurons at the spinal cord into a tizzy.
Time will tell if Goebel’s sapling grows into a mighty tree and redefines how we understand fibromyalgia, long COVID, ME/CFS, and others. His autoimmune hypothesis, though, seems to me, at least, like just the thing the NIH RECOVER Initiative would be interested in. Let’s hope they give it some water and fertilizer and see if it can grow.
Update! – FM researchers score major grant to continue this antibody work.
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