+100%-

Every once in a blue moon you come across a study that kind of stops you in its tracks. This is that one for me. (Thanks to Tim Vaughn for pointing it out.) If the findings hold up it could transform our understanding and approach to fibromyalgia (FM). Plus, it has interesting possible implications for chronic fatigue syndrome (ME/CFS).

Is fibromyalgia actually an immune disease? (Image of antibodies)

In 2019, the Goebel team behind this study replicated the symptoms of CRPS (Complex Regional Pain Syndrome) in mice simply by giving them IgG antibodies from people with CRPS. What they did in CRPS a couple of years ago, they did in fibromyalgia this year.

IgG antibodies are the most common type of antibody found in the blood. Their ability to bind to pathogens means they make up an important part of our immune defense. These powerful factors also neutralize toxins, activate the complement system, etc. When they go wrong, though, they can also trigger autoimmune attacks on human tissues.

That’s what the authors of this study believe has happened in fibromyalgia. The autoimmune attack, though, hasn’t targeted just any tissues. Their study suggests that an autoimmune attack has targeted the actual nerves in fibromyalgia…  No wonder it’s such a nasty disease.

Transformational Fibromyalgia Study (?)

“IgG is the principal pronociceptive, pathological serum component in FMS patients.” The authors

Goebel et. al started off their study by noting that along with the central nervous system problems found in FM, researchers have also found evidence of “peripheral” problems; i.e. problems affecting the body. These include hyperactive sensory nerves, disappearing small nerve fibers, and some immune issues. Those, plus the high rate of FM found in some autoimmune disorders, led the Goebel team to suspect an autoimmune basis for FM.

This is despite the lack of consistent and overt inflammation findings in fibromyalgia and ME/CFS. Researchers have looked for consistent evidence of the inflammation they’ve believed must be there almost since day 1. In 2016, Goebel proposed an alternative. While referencing chronic fatigue syndrome (ME/CFS), he proposed that autoantibodies may be causing pain without producing inflammation by binding tweaking receptors on the pain-producing nerves.

microglia

Activated microglial cells in the body play a key role in this hypothesis

One of the main culprits in this new scenario – our old “friend” – the glial cells. Presumably, to protect them, glial cells are wrapped around the nerve bodies found in the dorsal root ganglia (DRG). The DRG, which are found just outside the spinal cord, provide central processing gateways through which the sensory and autonomic signals from the body pass on their way to the spinal cord. The DRG determines which and how many pain, sensory and autonomic nervous system signals make it to the central nervous system.

Like glial cells everywhere, the glial cells surrounding the DRG can produce a wide range of substances (ATP, glutamate, TNF, other cytokines, fractalkine) that can activate the nerves, causing them to produce pain and other symptoms.

The Study

In fibromyalgia, Goebel had mostly concentrated on temperature and sensitivity issues, but in his 2021 study, “Passive transfer of fibromyalgia symptoms from patients to mice”, Goebel brought the autoimmunity issue in FM to the fore.

The study injected purified IgG from people with FM and healthy control subjects into mice. 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. (The mice given the healthy control IgG had no problems).

Dorsal Root Ganglia - from Wikimedia

The problems stopped at the dorsal root ganglia- found outside the central nervous system (Image from Wikimedia- Ganglia Category)

Further studies indicated that pain receptors on the nerves outside the spinal cord had become hyperactivated. Small fiber neuropathy cropped up in a couple of weeks. Goebel had swiftly created fibromyalgia mice simply by giving them immune factors found in his FM patients’ blood.

Importantly, 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.

Despite all the CNS (central nervous system) findings in FM, Goebel was able to push the small pain nerve fibers found outside the CNS into a state of hyperactivity without any central nervous system involvement at all.

At no time did systemic cytokine levels increase either. Whatever the IgG was doing, it was doing it very locally. Goebel’s findings could help explain one of the great mysteries in FM and ME/CFS – why the cytokines that are often associated with pain and fatigue haven’t been found to be consistently up-regulated in these diseases. The more Goebel dug, the more holes he was potentially blasting in the central dogma surrounding FM, and possibly ME/CFS.

Well aware of the implications of their findings, the authors wrote that they may

“transform future research and facilitate development of mechanism-based therapeutic interventions (in fibromyalgia)”.

In 2013, Goebel proposed the CRPS constitutes “a new kind of autoimmunity”, and that other ‘functional’ disorders may be autoimmune in nature. (Functional disorders like FM, ME/CFS, IBS, interstitial cystitis, chronic pelvic pain syndrome) occur when no trauma or structural abnormalities can be found that can explain reduced functioning.)

Autoimmune Research Opening Up New Options for Chronic Pain Sufferers

Similarly, in 2017 ME/CFS researchers including Shoenfeld, Scheibenbogen, and Martinez-Lavin proposed that chronic fatigue syndrome (ME/CFS), POTS, and complex regional pain syndrome (CRPS) belong to a new category of autoimmune diseases they called “autoimmune neurosensory dysautonomias“.

Could a Rare Autoimmune Disease Help Explain the Autonomic Issues in ME/CFS, POTS and Fibromyalgia?

 

While we don’t know how the central nervous system ties into these findings, the findings suggested that one may not need to access the complex central nervous system to make an impact on FM. All that may be needed is to damp down the immune response and reduce the levels of those IgG autoantibodies.

Brief attempts to discover the suspected autoantigen – the protein the authors believed the FM patients’ IgG was binding to – were, however, fruitless. The authors did conclude, though, that it was probably not a common one.

The idea that something in plasma may be causing FM brings up, of course, the intriguing question, given the similar findings, whether the same process is occurring in ME/CFS. One wonders as well whether the adrenergic autoantibody findings from Scheibenbogen’s ME/CFS work could apply as well.

Threading the Needle: Nanoneedle Scores Big in First ME/CFS Test

The Gist

  • The study filtered IgG antibodies out of the blood of people with fibromyalgia and healthy control and then introduced them to mice.
  • The mice receiving the IgG antibodies from the FM patients quickly developed fibromyalgia-like symptoms; i.e. they became hypersensitive to pain, pressure, and heat, and their grip strength declined. The mice receiving the IgG antibodies from the healthy controls remained unchanged.
  • Further study indicated that the pain-sensing nerves have become hypersensitive and that the mice over time developed small fiber neuropathy.
  • No evidence of inflammation was found. Instead, it appeared that the IgG had activated the glial cells during the dorsal root ganglia or DRG. The DRG contains bundles of nerves that serve as the last sensory signal processing center before the signals reach the spinal cord and central nervous system.
  • While the study found a high uptake of fibromyalgia IgG in the DRB and microglial cells it found no IgG uptake in the spinal cord or central nervous system indicating that the pain hypersensitivity found in the mice was all produced outside the central nervous system.
  • The authors believe that a new kind of autoimmunity – one which does not produce inflammation – is present in fibromyalgia. Instead, the autoimmune processes directly target pain-producing nerves.
  • 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 from the FM patients. They suggest that therapies like plasmapheresis and immunoadsorption – which is being assessed in ME/CFS – could help. Other therapies which target the suspect autoantigens (when and if they are found), as well as therapies like IVIG, are possibilities.
  • Kevin Tracey lauded the study calling it a “tour de force” and “a shining example of how and why clinical translational research can and should be done”. He suggested it could provide insights that will lead to new and effective therapies for FM.

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THE ME/CFS and FM CORONAVIRUS VACCINATION SIDE EFFECTS POLL

Coronavirus vaccines

Tell us how your coronavirus vaccination went and find out how other people with ME/CFS and/or FM fared with their coronavirus vaccination in Health Rising’s Coronavirus Vaccine Side Effects Poll.

Next Up

The author’s next steps involve further delineating just how these “autoreactive” IgG levels are tweaking the glial cells and/or dorsal root ganglia. The authors didn’t downplay the central nervous system problems that have been found in FM but did state that future studies will determine if the process they’ve uncovered could be causing them.

Treatment Possibilities

As the authors note, the current treatment options for FM, which rely mainly “on lifestyle changes, physical exercise, and drug therapy with antidepressants and anticonvulsants”, leave “an enormous unmet clinical need”.

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 from the FM patients. They pointed to IgG reducing approaches such as plasmapheresis or immunoadsorption. Intriguingly, Scheibenbogen has found some success in small studies with immunoadsorption in ME/CFS. They also suggested that approaches that specifically target the autoreactive IgGs they believe must be present in FM could be effective.

Also, without naming them, they proposed that therapies which “interfere with the binding of autoreactive antibodies or prevent their functional consequences”. These therapies presumably include IVIG.

In his review, Kevin Tracey, MD, also proposed that therapies that interfere with IgG binding to the glial cells/DRG, or which stop those cells from reacting, will also be developed. One wonders if the “surge protectors” being developed might fit here.

Tracey’s review of the Goebel study, “From human to mouse and back offers hope for patients with fibromyalgia“, provided a nice validation of their work.

Tracey, the President, and CEO of the Feinstein Institutes has published hundreds of papers and is a leader in inflammation, vagus nerve, and bioelectronics research.

Check out Tracey’s stirring talk at the 2020 Dysautonomia International Conference about the bioelectronics revolution.

Good-bye to Drugs? Kevin Tracey MD on the Bioelectronics Revolution at the Dysautonomia International Conference

Tracey called the Goebel paper:

“a shining, impactful example of how and why clinical translational research can and should be done” and stated, “This tour de force study at once provides insight into a mysterious disease affecting millions of people and offers a solid and promising insight into just how to begin developing effective therapeutic strategies for a severe, chronic, uncurable illness.”

Let’s hope!

 

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Don't Miss Another Blog!

Like this blog? 

Make sure you don’t miss another one by registering for our free ME/CFS and Fibromyalgia blogs here...

THE ME/CFS and FM CORONAVIRUS VACCINATION SIDE EFFECTS POLL

Coronavirus vaccines

Tell us how your coronavirus vaccination went and find out how other people with ME/CFS and/or FM fared with their coronavirus vaccination in Health Rising’s Coronavirus Vaccine Side Effects Poll.

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