Post by Nadica (She/Her) on Oct 26, 2024 1:13:27 GMT
Something in the Blood in ME/CFS, Fibromyalgia and Long COVID III: Evidence Builds that Something in the Blood is Causing These Diseases - Published Oct 19, 2024
something in the blood of chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and long-COVID (LC) patients is causing these diseases is so enticing! Uncover it and bang – you potentially have a trifecta: – an arrow pointing at the cause, a biomarker, and a treatment target.
Recently two more studies suggested that the, or at least an answer for ME/CFS, FM, and long COVID may be hiding in plain sight.
Check out those studies and ones in the past that suggested that something lurking in the blood could tell us much about these diseases.
Muscle Mischief – the Serum Muscle Connection
The last blog covered a study, “571P Muscular metabolic plasticity in 3D in vitro models against systemic stress factors in ME/CFS and long COVID-19“, which exposed muscle tissues to serum from ME/CFS and long-COVID patients for 48 hours.
The muscle tissues were not happy to see the ME/CFS serum. First, though, note that the ME/CFS and long-COVID serum produced the same results, suggesting the two diseases share similar core abnormalities – a potentially critical finding for people with the much less well-studied ME/CFS.
Exposing the muscle to ME/CFS/long-COVID serum hampered the ability of the muscle to contract (i.e. produce force (muscles produce force by contracting)), leaving it “severely compromised”. Plus, the aerobic energy system pooped out, and fused mitochondrial networks indicated the mitochondria were under severe stress. The authors proposed that a “stress-induced hypermetabolic state” ultimately resulted in “severe deterioration of muscle function”.
All it took was some serum…
Tweaked Nerves – the Serum Nerve Connection
Muscle cells aren’t the only cells tweaked by serum from ME/CFS, FM, and/or long-COVID patients. Akiko Iwasaki’s Yale group and David Putrino of Mt. Sinai recently published a study, “A causal link between autoantibodies and neurological symptoms in long COVID“, suggesting that something in the serum of LC patients is impacting their central nervous system, resulting in brain fog, pain, sleep problems, etc.
Noting that 4 studies have found an increased incidence of autoimmune diseases in LC patients, the researchers took a deep dive into the autoantibodies that can cause autoimmune diseases. While doing so, they proposed that autoantibodies may be causing symptoms in LC even when patients do not meet the criteria for being diagnosed with a known autoimmune disease. (Thank you from all the ME/CFS patients who have fallen through the cracks
They took IgG antibodies from LC patients with neurological symptoms (brain fog (80.0%), headache (65.4%), loss of memory (64.4%), dizziness (58.2%), sleeping disturbance (58.2%), and confusion (54.5%)) and then determined if they reacted with human and mouse tissues and 21,000 proteins found in the human body. Then they gave the IgG serum to mice and watched what happened.
Nervous System Attack?
The first step was to determine if the LC patients’ antibodies were targeting antigens (pieces of proteins or sugars) found in nervous system tissues, and found that they were. That suggested antibodies found in the LC patients’ serum could be attacking nervous system tissues.
The study specifically identified two antigens – MED20 and USP5 – both of which have been associated with neurological disorders – as possible autoantibody targets in LC. USP5, which modifies calcium ion channels, has been shown to regulate the activity of nociceptive or pain-sensing neurons. The USP5 calcium channel connection was intriguing given the Griffiths team’s work and Klaus Wirth’s hypothesis that calcium channels are impaired in ME/CFS.
Creating Long-COVID Mice
The mice receiving the LC serum did not fare well. Almost all the mice that did so displayed enhanced pain sensitivity, as well as pins and needles and burning pain, and weakness and dysautonomia.
Half of the mice that received IgG from long-COVID patients with tinnitus ended up displaying muscle weakness (!). Ninety percent of the mice receiving IgG from patients with dysautonomia demonstrated a loss of balance and coordination. IgG staining indicated that parts of the spinal cord, meninges, cerebellum, and sciatic nerve appeared to have been targeted by the antibodies. Almost all the mice also developed small fiber neuropathy.
The authors concluded that:
“Collectively, our data illustrate the pivotal role of autoantibodies as a key driver of neurological disorders in LC and suggest their utility in the diagnosis of this LC endotype.”
Autoantibodies II: the Fibromyalgia Connection
Recently, Daniel Clauw MD, a fibromyalgia researcher and rheumatologist who has had a lot of experience with autoimmune diseases, asserted that fibromyalgia, ME/CFS and long COVID do not look or act like autoimmune diseases and, indeed, characterizing them as autoimmune diseases would stretch the definition of autoimmunity to ridiculous lengths.
Andreas Goebel, however, believes a different kind of autoimmunity is present in many chronic pain diseases. A 2022 review, “The autoimmune aetiology of unexplained chronic pain“, reported that Goebel had uncovered “pain sensitizing autoantibodies” in no less than four chronic pain conditions, including fibromyalgia.
Goebel came to this conclusion in the same way Iwasaki did in long COVD – he injected purified IgG antibodies taken from the blood of people with FM and healthy control subjects into mice and watched what happened. Within two days, the mice given the IgG from the FM patients became hypersensitive to pressure, cold, and pain, and reduced their grip strength. The mice given the IgG from the healthy controls, on the other hand, remained fine.
Further digging indicated that the antibodies had apparently activated the pain receptors on the nerves outside the spinal cord in the dorsal root ganglia. The dorsal root ganglia are 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; i.e. they’re perfectly placed to bollix up the pain response.
The Dorsal Root Ganglia Long COVID Connection
Next Goebel 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.
Antibodies from both the long-COVID patients in pain and from the fibromyalgia patients attacked the glial cells in the dorsal root ganglia – throwing fibromyalgia into the long-COVID mix.
Even Sleep?
Thus far, studies suggest that something in the blood may be causing or contributing to two of the cardinal symptoms of these diseases – pain and cognition. San Diego researchers recently added sleep to the list.
This study took serum samples from ME/CFS patients with insomnia and healthy controls and injected them into connective tissue cells called fibroblasts from mice. The mice tissues injected with ME/CFS serum displayed disturbances in their circadian rhythms – suggesting that something in the serum was disrupting regular sleep schedules.
The Blood Vessels, Too?
How about the blood vessels? Problems with blood vessel functioning could, after all, conceivably produce just about any symptom. A 2019 Solve M.E. Ramsay Award produced an intriguing finding: endothelial cells exposed to ME/CFS patients’ plasma produced significantly less of a critical enzyme called eNOS that dilates or opens the blood vessels.
A follow-up ME Research UK-funded study added plasma from ME/CFS patients and healthy controls to the endothelial cells found in our blood vessels. To the researchers’ surprise, the MERUK study found across-the-board reductions in NO – even at rest – in people with ME/CFS.
That reduction in eNOS activity may not just effect blood vessel functioning. The authors pointed out that because nitric oxide (NO) also promotes mitochondrial production and fatty acid oxidation, reduced NO levels could impact energy production in the muscles during exercise and in other places. Plus, because it’s an anti-inflammatory, reduced NO production could result in more inflammation.
Solve M.E. is funding an extensive followup of this study.
Yes, the Blood Vessels (and the Mitochondria)
Speaking of the blood vessels and energy production, in 2023, Prusty found that IgG antibodies were taking out the blood vessels in ME/CFS. After purifying IgG antibodies from 30 healthy controls and ME/CFS patients, Prusty put them into a variety of different cells.
Most of the cells were not affected by the ME/CFS patient serum, but the mitochondria in the endothelial cells that line the blood vessels became fragmented. Prusty’s group was even able to link the mitochondrial fragmentation to a decrease in a mitochondrial protein that keeps the mitochondria intact – a nice sign suggesting that the finding is correct.
Interestingly, given Nath’s belief that B-cell dysfunction is the driving force in ME/CFS, Prusty implicated the B-cells in his findings.
Something Different in FM – the Neutrophil Question
Back to fibromyalgia. 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 – their chronic pain hypersensitivity was gone. Somehow, the neutrophils were creating a chronic pain state.
They then took neutrophils from people with fibromyalgia and 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.
The Beginning
From what I can tell, the “something in the blood scenario” in ME/CFS started, at least in the scientific literature, with Fluge and Mella’s mammoth 2016 paper, “Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome“.
The paper found that giving ME/CFS patients’ serum to progenitor muscle cells resulted in increased mitochondrial respiration (i.e. a state of hypermetabolism) that appeared to be driven, interestingly enough, by energy depletion. As other studies have found, the muscle cells transitioned from relying on clean-burning fatty acid derived energy to running mostly on a dirty source of energy – amino acids.
Treatment Possibilities
If autoantibodies are causing pain, headaches, sleep problems, etc., a possible remedy is intravenous immunoglobulin (IVIG). A review of IVIG case reports and studies in long COVID found “acceptable to great efficacy… with no or mild adverse effects.” IVIG is clearly not going to be the answer for everyone – hence the need for biomarkers that can guide clinical trials.
Even better would be more specifically targeted treatments. Iwasaki et al. asserted that identifying the specific autoantibodies at play in LC “will open the door to the development of novel treatments, such as next-generation target-specific immunotherapies.”
One reason we don’t have answers may be the need to identify the specific autoantibodies—which may or may not have been described yet—at work in different subsets of patients.
The fact that the mice in Goebel’s study 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. Indeed, in a recent Unraveled podcast, Dr. Ruhoy and Kaufman report that they’ve found that plasmapheresis can be quite helpful. (A blog on that is coming up.)
Conclusions
Nine studies over the past 9 years have found that adding purified IgG, serum, plasma, or blood from people with ME/CFS, fibromyalgia, and/or long COVID to either mice or tissues has caused things to go haywire – and in ways (weakened muscles, cognitive problems, increased pain, mitochondrial dysfunction, blood vessel problems, sleep issues) that one might expect.
The big question, of course, is what in the blood could be causing these problems. Hopefully, enough evidence has accrued that a real hunt for the mystery substance is underway. Currently, it appears that IgG autoantibodies are the lead candidate – and they are getting some attention.
In October 2022, Andersson and Goebel (and Schofield) argued in, “The Biology of Symptom-based Disorders – Time to Act“, that “symptom-based disorders are… very common, including pain and fatigue disorders, functional gastrointestinal and respiratory disorders” and “cause far greater disability than diseases where signs are prominent.” They urged funders to pour “resources into exploring the role of ‘invisible’, functional, non-inflammatory autoantibodies in symptom-based disorders”.
Andersson hit pay dirt when he won the Sir Jules Thorn Award for Biomedical Research, giving him and his co-investigators (including Goebel) £1,699,572 ($2,100,000) over five years. Stating that, “These insights will fundamentally change future research and clinical management of FMS“, the funders appeared confident that they were onto something.
Let’s not forget the neutrophils that quickly turned healthy mice into fibromyalgia mice. A new (and rather timely) ME/CFS study funded by the Open Medicine Foundation at Ron Davis’s Genome Center is producing new technology that will allow researchers to provoke them and assess their functioning more deeply than has every been done before – in any disease.
Time will tell. As Ron Davis says sometimes about difficult projects “This is not a trivial problem”
, and finding the X factor in the blood is apparently not an easy task. The payoff, though, (biomarker, potential treatment target) could be enormous.
something in the blood of chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and long-COVID (LC) patients is causing these diseases is so enticing! Uncover it and bang – you potentially have a trifecta: – an arrow pointing at the cause, a biomarker, and a treatment target.
Recently two more studies suggested that the, or at least an answer for ME/CFS, FM, and long COVID may be hiding in plain sight.
Check out those studies and ones in the past that suggested that something lurking in the blood could tell us much about these diseases.
Muscle Mischief – the Serum Muscle Connection
The last blog covered a study, “571P Muscular metabolic plasticity in 3D in vitro models against systemic stress factors in ME/CFS and long COVID-19“, which exposed muscle tissues to serum from ME/CFS and long-COVID patients for 48 hours.
The muscle tissues were not happy to see the ME/CFS serum. First, though, note that the ME/CFS and long-COVID serum produced the same results, suggesting the two diseases share similar core abnormalities – a potentially critical finding for people with the much less well-studied ME/CFS.
Exposing the muscle to ME/CFS/long-COVID serum hampered the ability of the muscle to contract (i.e. produce force (muscles produce force by contracting)), leaving it “severely compromised”. Plus, the aerobic energy system pooped out, and fused mitochondrial networks indicated the mitochondria were under severe stress. The authors proposed that a “stress-induced hypermetabolic state” ultimately resulted in “severe deterioration of muscle function”.
All it took was some serum…
Tweaked Nerves – the Serum Nerve Connection
Muscle cells aren’t the only cells tweaked by serum from ME/CFS, FM, and/or long-COVID patients. Akiko Iwasaki’s Yale group and David Putrino of Mt. Sinai recently published a study, “A causal link between autoantibodies and neurological symptoms in long COVID“, suggesting that something in the serum of LC patients is impacting their central nervous system, resulting in brain fog, pain, sleep problems, etc.
Noting that 4 studies have found an increased incidence of autoimmune diseases in LC patients, the researchers took a deep dive into the autoantibodies that can cause autoimmune diseases. While doing so, they proposed that autoantibodies may be causing symptoms in LC even when patients do not meet the criteria for being diagnosed with a known autoimmune disease. (Thank you from all the ME/CFS patients who have fallen through the cracks
They took IgG antibodies from LC patients with neurological symptoms (brain fog (80.0%), headache (65.4%), loss of memory (64.4%), dizziness (58.2%), sleeping disturbance (58.2%), and confusion (54.5%)) and then determined if they reacted with human and mouse tissues and 21,000 proteins found in the human body. Then they gave the IgG serum to mice and watched what happened.
Nervous System Attack?
The first step was to determine if the LC patients’ antibodies were targeting antigens (pieces of proteins or sugars) found in nervous system tissues, and found that they were. That suggested antibodies found in the LC patients’ serum could be attacking nervous system tissues.
The study specifically identified two antigens – MED20 and USP5 – both of which have been associated with neurological disorders – as possible autoantibody targets in LC. USP5, which modifies calcium ion channels, has been shown to regulate the activity of nociceptive or pain-sensing neurons. The USP5 calcium channel connection was intriguing given the Griffiths team’s work and Klaus Wirth’s hypothesis that calcium channels are impaired in ME/CFS.
Creating Long-COVID Mice
The mice receiving the LC serum did not fare well. Almost all the mice that did so displayed enhanced pain sensitivity, as well as pins and needles and burning pain, and weakness and dysautonomia.
Half of the mice that received IgG from long-COVID patients with tinnitus ended up displaying muscle weakness (!). Ninety percent of the mice receiving IgG from patients with dysautonomia demonstrated a loss of balance and coordination. IgG staining indicated that parts of the spinal cord, meninges, cerebellum, and sciatic nerve appeared to have been targeted by the antibodies. Almost all the mice also developed small fiber neuropathy.
The authors concluded that:
“Collectively, our data illustrate the pivotal role of autoantibodies as a key driver of neurological disorders in LC and suggest their utility in the diagnosis of this LC endotype.”
Autoantibodies II: the Fibromyalgia Connection
Recently, Daniel Clauw MD, a fibromyalgia researcher and rheumatologist who has had a lot of experience with autoimmune diseases, asserted that fibromyalgia, ME/CFS and long COVID do not look or act like autoimmune diseases and, indeed, characterizing them as autoimmune diseases would stretch the definition of autoimmunity to ridiculous lengths.
Andreas Goebel, however, believes a different kind of autoimmunity is present in many chronic pain diseases. A 2022 review, “The autoimmune aetiology of unexplained chronic pain“, reported that Goebel had uncovered “pain sensitizing autoantibodies” in no less than four chronic pain conditions, including fibromyalgia.
Goebel came to this conclusion in the same way Iwasaki did in long COVD – he injected purified IgG antibodies taken from the blood of people with FM and healthy control subjects into mice and watched what happened. Within two days, the mice given the IgG from the FM patients became hypersensitive to pressure, cold, and pain, and reduced their grip strength. The mice given the IgG from the healthy controls, on the other hand, remained fine.
Further digging indicated that the antibodies had apparently activated the pain receptors on the nerves outside the spinal cord in the dorsal root ganglia. The dorsal root ganglia are 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; i.e. they’re perfectly placed to bollix up the pain response.
The Dorsal Root Ganglia Long COVID Connection
Next Goebel 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.
Antibodies from both the long-COVID patients in pain and from the fibromyalgia patients attacked the glial cells in the dorsal root ganglia – throwing fibromyalgia into the long-COVID mix.
Even Sleep?
Thus far, studies suggest that something in the blood may be causing or contributing to two of the cardinal symptoms of these diseases – pain and cognition. San Diego researchers recently added sleep to the list.
This study took serum samples from ME/CFS patients with insomnia and healthy controls and injected them into connective tissue cells called fibroblasts from mice. The mice tissues injected with ME/CFS serum displayed disturbances in their circadian rhythms – suggesting that something in the serum was disrupting regular sleep schedules.
The Blood Vessels, Too?
How about the blood vessels? Problems with blood vessel functioning could, after all, conceivably produce just about any symptom. A 2019 Solve M.E. Ramsay Award produced an intriguing finding: endothelial cells exposed to ME/CFS patients’ plasma produced significantly less of a critical enzyme called eNOS that dilates or opens the blood vessels.
A follow-up ME Research UK-funded study added plasma from ME/CFS patients and healthy controls to the endothelial cells found in our blood vessels. To the researchers’ surprise, the MERUK study found across-the-board reductions in NO – even at rest – in people with ME/CFS.
That reduction in eNOS activity may not just effect blood vessel functioning. The authors pointed out that because nitric oxide (NO) also promotes mitochondrial production and fatty acid oxidation, reduced NO levels could impact energy production in the muscles during exercise and in other places. Plus, because it’s an anti-inflammatory, reduced NO production could result in more inflammation.
Solve M.E. is funding an extensive followup of this study.
Yes, the Blood Vessels (and the Mitochondria)
Speaking of the blood vessels and energy production, in 2023, Prusty found that IgG antibodies were taking out the blood vessels in ME/CFS. After purifying IgG antibodies from 30 healthy controls and ME/CFS patients, Prusty put them into a variety of different cells.
Most of the cells were not affected by the ME/CFS patient serum, but the mitochondria in the endothelial cells that line the blood vessels became fragmented. Prusty’s group was even able to link the mitochondrial fragmentation to a decrease in a mitochondrial protein that keeps the mitochondria intact – a nice sign suggesting that the finding is correct.
Interestingly, given Nath’s belief that B-cell dysfunction is the driving force in ME/CFS, Prusty implicated the B-cells in his findings.
Something Different in FM – the Neutrophil Question
Back to fibromyalgia. 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 – their chronic pain hypersensitivity was gone. Somehow, the neutrophils were creating a chronic pain state.
They then took neutrophils from people with fibromyalgia and 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.
The Beginning
From what I can tell, the “something in the blood scenario” in ME/CFS started, at least in the scientific literature, with Fluge and Mella’s mammoth 2016 paper, “Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome“.
The paper found that giving ME/CFS patients’ serum to progenitor muscle cells resulted in increased mitochondrial respiration (i.e. a state of hypermetabolism) that appeared to be driven, interestingly enough, by energy depletion. As other studies have found, the muscle cells transitioned from relying on clean-burning fatty acid derived energy to running mostly on a dirty source of energy – amino acids.
Treatment Possibilities
If autoantibodies are causing pain, headaches, sleep problems, etc., a possible remedy is intravenous immunoglobulin (IVIG). A review of IVIG case reports and studies in long COVID found “acceptable to great efficacy… with no or mild adverse effects.” IVIG is clearly not going to be the answer for everyone – hence the need for biomarkers that can guide clinical trials.
Even better would be more specifically targeted treatments. Iwasaki et al. asserted that identifying the specific autoantibodies at play in LC “will open the door to the development of novel treatments, such as next-generation target-specific immunotherapies.”
One reason we don’t have answers may be the need to identify the specific autoantibodies—which may or may not have been described yet—at work in different subsets of patients.
The fact that the mice in Goebel’s study 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. Indeed, in a recent Unraveled podcast, Dr. Ruhoy and Kaufman report that they’ve found that plasmapheresis can be quite helpful. (A blog on that is coming up.)
Conclusions
Nine studies over the past 9 years have found that adding purified IgG, serum, plasma, or blood from people with ME/CFS, fibromyalgia, and/or long COVID to either mice or tissues has caused things to go haywire – and in ways (weakened muscles, cognitive problems, increased pain, mitochondrial dysfunction, blood vessel problems, sleep issues) that one might expect.
The big question, of course, is what in the blood could be causing these problems. Hopefully, enough evidence has accrued that a real hunt for the mystery substance is underway. Currently, it appears that IgG autoantibodies are the lead candidate – and they are getting some attention.
In October 2022, Andersson and Goebel (and Schofield) argued in, “The Biology of Symptom-based Disorders – Time to Act“, that “symptom-based disorders are… very common, including pain and fatigue disorders, functional gastrointestinal and respiratory disorders” and “cause far greater disability than diseases where signs are prominent.” They urged funders to pour “resources into exploring the role of ‘invisible’, functional, non-inflammatory autoantibodies in symptom-based disorders”.
Andersson hit pay dirt when he won the Sir Jules Thorn Award for Biomedical Research, giving him and his co-investigators (including Goebel) £1,699,572 ($2,100,000) over five years. Stating that, “These insights will fundamentally change future research and clinical management of FMS“, the funders appeared confident that they were onto something.
Let’s not forget the neutrophils that quickly turned healthy mice into fibromyalgia mice. A new (and rather timely) ME/CFS study funded by the Open Medicine Foundation at Ron Davis’s Genome Center is producing new technology that will allow researchers to provoke them and assess their functioning more deeply than has every been done before – in any disease.
Time will tell. As Ron Davis says sometimes about difficult projects “This is not a trivial problem”
, and finding the X factor in the blood is apparently not an easy task. The payoff, though, (biomarker, potential treatment target) could be enormous.