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Time to take a deep dive into AI.
Getting Up to Speed with AI – To be honest, I was floored by how controversial the ChatGPT brainstorming treatment post was. The fact that it happened in a post with pretty moderate treatment suggestions only amplified what a hot button issue AI is.
With that post I stepped into a minefield I didn’t know existed. That’s my mistake – I’ve been tooling along so well with AI search engines both personally and with blogs that I honestly missed the controversy.
So I will do what should have been done earlier: take a deep dive into the pros and cons of ChatGPT, make sure it’s being used as safely as possible, produce a page on how that’s going to be done, and from time to time demonstrate how it responds to the queries. Thanks to the support of a Health Rising supporter, last week I’ve also enrolled in a class on AI.
The Catalyst
If anyone has been a catalyst in ME/CFS and long COVID, it’s been Yale immunologist Akiko Iwasaki PhD. She and her team came out with one of the first really major COVID studies in 2023, and since then, she’s been driving the field forward.
Over the past couple of years, she’s received the Keio Medical Science Prize in 2025, Forbes 50 over 50 Innovation 2024, TIME 100 Most Influential People 2024, TIME 100 HEALTH Most Influential People Affecting Global Health 2024, and the Else Kröner Fresenius Prize for Medical Research 2023 (!).
My favorite thing about Dr. Iwasaki, though, has been her constant advocacy for more research, not just into long COVID but into ME/CFS and other post-infectious diseases. Iwasaki first came up on many ME/CFS patients’ radars in 2022 when she was the keynote speaker for the IACFS/ME conference.
In 2023, she received $3 million to study ME/CFS, long COVID, and post-treatment Lyme disease in tandem. Noting the decades of distress caused by puny funding, she stated, “The wind is shifting. The pandemic has opened the world’s eyes to the fact that many chronic illnesses have been largely ignored, dismissed, and ridiculed. Long COVID has taught the world that these diseases are real, there.”
Floating All Boats… Iwasaki’s ME/CFS, Long COVID and Lyme Disease Awards Promises New Insights into Post-Infectious Diseases
‘My favorite quote from her has been: ‘We need to get beyond the spike protein” i.e. we need to stop focusing so much on the specific virus-body impacts of the coronavirus and looking more at the multisystemic effects that are taking place in all of these post infectious diseases. That was a bold statement in a field that has mostly been focused of understanding viral persistence.
Both she and David Putrino at Mt. Sinai are really members of a new generation of researchers who are emphasizing studying these post-infectious diseases in tandem. Dr. Iwasaki began her presentation by noting the many types of post-infectious diseases.
Dr. Iwasaki presented her work on functional autoantibodies at a Solve M.E. webinar.
THE GIST
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Solve M.E.’s Catalyst award will allow Dr. Iwasaki to bring her autoantibody work to ME/CFS.
AI Controversy – The controversy over the ChatGPT brainstorming treatment session has made it clear that it’s past time to take a deep dive into the pros and cons of ChatGPT, make sure it’s being used as safely as possible, produce a page on how that’s being be done, and from time to time, demonstrate how these AI engines respond to the queries.
- Yale immunologist Akiko Iwasaki PhD is right in the thick of things regarding long COVID and ME/CFS. The winner of many awards and a strong advocate for ME/CFS as well as long COVID, Iwasaki recently appeared on a Solve ME/CFS webinar (see the blog), and received the first “Catalyst Award” for her work on functional autoantibodies.
- The Catalyst award provides funding to deepen work that’s shown it’s on the right track with ME/CFS.
- By binding to receptors on the cell surface, functional autoantibodies alter cell function. While it’s not necessarily in a pathological way, they often produce pathological results.
- These autoantibodies often appear quickly after an infection but then usually subside. In long COVID, however, many of them appear to remain. They’re not necessarily the result of an infection. Numerous other factors, including stress, trauma, toxins, and drugs, can trigger a burst of autoantibody production.
- Dr. Iwasaki and de Sa’s recent preprint, “A causal link between autoantibodies and neurological symptoms in long COVID,” emphasized the role that neuroimmune interactions may play in long COVID-19. It found, for instance, that the antibodies seen in long-COVID patients reacted almost entirely with central nervous system proteins and tissues.
- This follows a rather startling recent trend of studies that have pointed an arrow not at the muscles, cardiovascular system, or immune system in the periphery (the body), but directly, and almost wholly, at the brain.
- When these researchers gave purified IgG from long-COVID patients to mice, the mice, as we’ve seen in ME/CFS, fibromyalgia, and long-COVID studies, recapitulated many of the symptoms in long COVID.
- Interestingly, antibodies from long-COVID patients with high rates of pain tended to produce high rates of pain in the mice.
- The increased reactivity to common autoantigens seen – proteins often implicated in autoimmune diseases – provided another link to autoimmunity.
- The antibodies also showed high reactivity against the pons tissues in the brain. While other kinds of brain tissues were not assessed, the pons finding was fascinating. For one, it’s part of the brainstem. For another, it’s located in the locus coeruleus – the seat of norepinephrine production in the brain. Because the locus coeruleus was recently implicated in ME/CFS, it’s possible that these autoantibodies could impair norepinephrine production.
- It’s all speculation at this point. While this study did show that long-COVID autoantibodies were making their way into the brains of the mice, it’s not clear that they’re attacking the pons, and if they are, if they’re actually damaging it.
- It’s worth noting, though, that problems with arousal, vigilance, attention, brain fog, the wired-and-tired symptom, sleep, and pain could all stem from damage to this part of the brain.
- The same mice that were in pain also demonstrated small nerve fiber neuropathy – a reduction in the small nerve fibers in their skin – that’s been seen in fibromyalgia, ME/CFS, and long COVID.
- They concluded that their data “illustrate(s) the pivotal role of autoantibodies as a key driver of neurological disorders in LC”.
- Next, they will attempt to identify the exact autoantibodies that increase pain sensitivity and will extend the IgG-to-mouse transfer study to ME/CFS, Lyme Disease, POTS, etc.
- When asked if the findings indicate that long COVID is an autoimmune disease, Dr. Iwasaki replied that at least with regard to a subset of long-COVID patients, the mouse transfer findings constitute “a causal finding”.
- Once they can target specific subsets, they hope to test autoantibody therapies (IVIG, FcRn inhibitors, BC 007, plasmapheresis, and anti-CD20 monoclonal antibodies) which Dr. Iwasaki said are having “incredible results” in autoimmune diseases in long COVID, ME/CFS, and other diseases.
- Specifically, subsetting long-COVID (or ME/CFS) patients that might benefit from these powerful immune drugs would constitute a giant leap forward for the long-COVID field.
- Thus far, the IVIG clinical trials in long COVID and ME/CFS have been small and have had mixed results. Two large, rigorously done trials are underway in long COVID. The results, which should appear over the next year, should tell us much about IVIG effectiveness in long COVID.
- They still won’t, however, achieve what Dr. Iwasaki is attempting to do: study IVIG-responsive subsets by targeting patients with autoantibody-driven neurological symptoms. Being able to biologically identify patient subsets who are likely to respond to specific drugs is the cat’s meow in these complex diseases.
- The good news for people with ME/CFS is that SOLVE M.E.’s new Catalyst award will allow Dr Iwasaki to replicate her work in ME/CFS and prepare the path for similar trials. It’s a great way to start off this new grant award.
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The Catalyst Award
Solve M.E.’s new Catalyst Award seeks to take already successful projects to the next level.
Solve M.E. didn’t give Iwasaki their inaugural Catalyst award for all she’s done for the ME/CFS and long-COVID fields (although she deserves one); it gave her the award for her current work on autoantibodies in long COVID.
Solve M.E.’s Catalyst Awards help fund research projects that have made progress and are on the right track, and could use a boost to deepen and expand their findings. As we’ll see, Dr. Iwasaki’s functional autoantibody work fits that description like a glove.
The Functional Autoantibody Study
Functional autoantibodies are strange creatures indeed. Unlike autoantibodies, which bind to a target and mark it for destruction by immune complexes and cells, functional autoantibodies bind to a receptor on a cell and block it from activating, or enhance its functioning, or change how it signals the cell; i.e., they change how a cell functions. They’re not automatically harmful, but in practice, they often are.
By latching onto receptors on cells, autoantibodies change their functioning.
Iwasaki noted in her Solve M.E. talk that a (the?) critical need for this field is to be able to subset patients according to the particular biological drivers of their diseases, and then target them in treatment trials. We’ll see by the end of the blog that that’s exactly what she hopes to do with her autoantibody work.
She’s not alone. PrecisionLife’s entire focus has been to create a streamlined pathway in these diseases that biologically defines patient subsets and finds treatments that can help.
Iwasaki’s 2023 paper found high levels of autoantibodies in long-COVID patients. In 2024, things really got going on the autoantibody front, though, with her and de Sa’s recent preprint, “A causal link between autoantibodies and neurological symptoms in long COVID“.
The Hugely Predictive Factor for Long COVID…is also found in ME/CFS and Fibromyalgia: the IACFS/ME Conference II
Central Nervous System Emphasis Pt. I – Protein Reactivities
The Huprot human protein array system enables researchers to determine whether antibodies bind to an extremely large number of proteins (22,000). Once again, the nervous system stood out in spades.
Once again, the brain showed up big time.
In what Dr. Iwasaki called “a very robust response”, the antibodies from the long-COVID patients targeted central nervous system tissues (and left the immune, cardiovascular, muscle, etc. tissues alone). This suggests that, if autoantibodies play a major role in long COVID, they do so by attacking the central nervous system.
Notably, though, a wide range of autoantibodies were found in the long-COVID group – demonstrating, as expected, that even at the autoantibody level, the disease is quite heterogeneous.
Pt. II – Brain Tissues
Next, they collected antibody (IgG) samples from long-COVID patients and exposed them to various mouse and human tissues. The only tissues that the long-COVID autoantibodies attached to or interacted with were found in the central nervous system.
The IgG antibodies reacted with human pons tissues and the sciatic nerve, meninges, and cerebellum in mouse tissues. Not everyone exhibited them, but a significant subset did, and the IgG from some people also reacted to mouse spinal cord, thalamus and hypothalamus, hindbrain, cerebral nuclei, cerebral cortex, and hippocampus tissues.
The wide range of reactivities may provide a possible explanation for the wide range of neurological symptoms observed in long COVID (and similar diseases). A person with autoantibodies that react to the hypothalamus might have different symptoms than a person whose antibodies react to the cerebral cortex.
An Interesting Finding
The locus coeruleus sits in the pons, which is part of the brainstem.
Because the authors only exposed the antibodies to the pons tissues, we don’t know if they might be cross-reacting with other kinds of brain tissues or other tissues. But what an interesting part of the brain the pons is.
The locus coeruleus, which we’ve heard so much about lately, sits in the pons, which is part of that other major brain organ of great interest – the brainstem.
Role Reversal: Could a WEAKENED Fight/Flight Response Be Causing ME/CFS and Long COVID? The 2025 IACFS/ME Conference Pt. I
We don’t know where in the pons these autoantibodies might be attacking, if indeed they are attacking it. They could be attacking the nerves associated with the locus coeruleus, nuclei that affect sensory/balance/autonomic nervous system functioning, and/or the glial cells and blood vessels associated with it.
Damage to locus coeruleus neurons, if it occurs, could conceivably inhibit mitochondrial function, introduce more “noise” into the system, and produce sensory problems that ramp up the stress machinery. Problems with arousal, vigilance, attention, brain fog, the wired and tired symptom, sleep, and pain could all emanate from damage to this part of the brain.
In other words, the pons autoantibody finding could help explain why the low NE levels may be present. This is the latest of several studies that have put the emphasis firmly on the nervous system.
Note that we don’t know whether long-COVID autoantibodies are actually reaching the pons, or, if so, whether they’re damaging it. Those findings await us. We simply know that if they can reach the pons, the potential for damage is there.
They were able to show, though, that a small percentage of the long-COVID IgG antibodies were making their way into the brains of the mice. Because the blood-brain barrier (BBB) should be stopping them, that suggests something in the IgG antibodies may be damaging it. That’s potentially a key finding as it provides a way for infection-associated autoantibodies to affect the brain.
This was one of several recent studies that not only highlighted but also focused solely on the role the brain may be playing in these diseases.
The Brain Disease: Huge Fibromyalgia Genetic Study Highlights the Brain and Offers New Treatment Possibilities
Autoimmune Emphasis
The IgG autoantibodies from long-COVID patients also showed increased reactivity to common autoantigens. Because these proteins commonly come under assault in autoimmune diseases, this finding constitutes another possible link to autoimmunity in at least a subset of long-COVID patients.
ANOTHER Positive Passive Transfer Mice Study
Then, using “passive transfer,” they took purified IgG antibodies from the long-COVID patients and transferred them into mice. Once again, we saw mice with IgG antibodies from long-COVID patients (but not those with IgG antibodies from healthy controls) develop the characteristics of long COVID. They experienced chronic pain, pain sensitivity, weakness, and dysautonomia, a trend towards reduced handgrip strength, loss of balance, and small fiber neuropathy.
Interestingly, IgG antibodies from long-COVID patients with chronic pain tended to increase pain sensitivity in the mice. Eighty-five percent of the mice given IgG from long-COVID patients with pain (burning pain and/or pins and needles sensations) ended up displaying increased heat sensitivity.
After receiving antibodies from long-COVID patients, mice began looking very long-COVID-like.
The same mice that were in pain also demonstrated small nerve fiber neuropathy – a reduction in the small nerve fibers in their skin – which could have accounted for those pain symptoms (pins and needles, burning pain). (Increased levels of small fiber neuropathy have been found in fibromyalgia, ME/CFS, and long COVID.)
In a new finding, they suggested that the small nerve fiber neuropathy might be associated with the tinnitus that so many people with these diseases exhibit. An elevated marker of neuronal damage buttressed the small nerve fiber finding.
They concluded that their data “illustrate(s) the pivotal role of autoantibodies as a key driver of neurological disorders in LC”.
Next, they will attempt to identify the exact autoantibodies that increase pain sensitivity and will extend the IgG-to-mouse transfer study to ME/CFS, Lyme Disease, POTS, etc.
Once they can target specific subsets, they hope to test autoantibody therapies (IVIG, FcRn inhibitors, BC 007, plasmapheresis and anti-CD20 monoclonal antibodies) which Dr. Iwasaki said are having “incredible results” in autoimmune diseases in long COVID, ME/CFS, and other diseases.
Specifically, subsetting long-COVID (or ME/CFS) patients that might benefit from these powerful immune drugs would constitute a giant leap forward for the long-COVID field. That has been done only rarely, and then on a very small scale.
As the PrecisionLife blog noted, being able to target patients by isolating their biological drivers, then using biomarkers that can assess those drivers in clinical trials, and targeting those patients with those drives (which they call “super-responders”) is a potential game-changer, not just for patients but for pharmaceutical companies that continue to neglect these diseases (and the enormous potential they represent).
PrecisionLife’s Bold Attempt to Break the Code on and Beat ME/CFS and Long COVID
IVIG
Thus far, IVIG results in long COVID have come from small, retrospective, or uncontrolled (non-placebo-controlled) trials. In other words, the results are preliminary.
In a small, uncontrolled, open-label trial, six long-COVID patients were reported to receive “significant to remarkable” benefits in fatigue, brain fog, pulmonary, and cardiologic symptoms. In a retrospective RECOVER Initiative study, all nine long-COVID patients with small fiber neuropathy demonstrated “significant improvement” in their neuropathic symptoms.
A small study (n=7) using plasmapheresis plus IVIG in long-COVID patients with ME/CFS with high levels of adrenergic autoantibodies had decidedly mixed results. Three of the seven were so debilitated by the first round of plasmapheresis that they left the study. Although the rest experienced gradual improvements, no significant changes in symptom scores were observed. The adrenergic antibody situation in ME/CFS remains confusing, with both positive and negative results.
A COVID-19 Long Hauler Case Report Points To ME/CFS, Autoimmunity – and IVIG Treatment
IVIG long-COVID results have been sketchy. Over the next year or so, we will know much more.
Our understanding of the effect of long COVID and IVIG are about to dramatically change. We are awaiting the results of two rigorously produced, larger (one very large) long-COVID trials. (Note, though, that both of the studies are filtering their patients by symptoms – not by the biological markers Akiko Iwasaki hopes to uncover.)
The 380-person RECOVER Initiative long-COVID autonomic trial underway is the big one. It’s an interesting adjunct to the small fiber neuropathy study, as RECOVER believes that damage to autonomic nerves may be causing dizziness, increased heart rate, and fatigue. Besides symptoms, this study will assess viral, autonomic function, immune, inflammatory, and endothelial biomarkers. It’s an excellent study that should tell us much. Results should be available by the end of 2026. Since blood samples are being stored, if Iwasaki finds an autoantibody signature, she should be able to use it to assess its effectiveness in ferreting out IVIG-responsive patients.
Avindra Nath is conducting a smaller (n=45) placebo-controlled, triple-blinded long-COVID IVIG trial in patients with neurological symptoms. Each person is receiving IVIG for five days and they are being followed for up to four months. The study, which began in 2022, is expected to wind up next month.
Catalyzing Research
Catalyst: “a person or thing that provokes or speeds significant change or action” Merriam Webster Dictionary
Solve M.E.’s Catalyst award will allow Dr. Iwasaki to bring her autoantibody work to ME/CFS.
Solve M.E.’s $100,000 Catalyst award will help Iwasaki reach a point where she can apply the same process to people with ME/CFS.
She will be identifying autoantibody targets (the proteins the autoantibodies are targeting in ME/CFS), the tissues they may be attacking, and will be doing a mouse passive transfer trial (giving antibodies from ME/CFS patients to mice). Similar results to those found in long COVID would further cement the relationship between the two, help researchers “get beyond the spike”, and focus more on understanding the post-infectious aspect.
Question Period
Finally….An Autoimmune Subset?
“That’s a causal relationship.” Akiko Iwasaki
In the question section, Solve M.E. President Emily Taylor asked a great (and it seems perennial) question. If Dr. Iwasaki finds the same results in ME/CFS, would she conclude that it’s an autoimmune disease?
Noting that these antibody findings applied to a subset of LC patients, she stated that if you take IgG antibodies from ME/CFS patients, inject them into mice, and they end up looking like long-COVID or ME/CFS patients, to her, “that’s a causal relationship.”
Once that happens, the next critical step would be coming up with a panel to determine who has the particular pathological autoantibodies that are causing symptoms, and they were exploring how to do that.
What about ME/CFS patients who didn’t have an infectious onset? Not to worry – you’re potentially in this group, too. Dr. Iwasaki stated that these autoreactive antibodies can be triggered in many ways.
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