The 2nd International Conference on Clinical and Scientific Advances in ME/CFS and Long COVID (November 12th-13th) was held in Porto, Portugal, and ME Research UK attended remotely.
A highlight from Day 2 was a complex yet fascinating talk on autoimmunity in ME/CFS and long COVID by Prof. Dr Carmen Scheibenbogen, a clinical immunologist and former ME Research UK-funded researcher.
The question of whether autoimmunity – where the immune system mistakenly targets the body’s own cells – is involved in ME/CFS has been asked for many years. Studies have produced mixed results, but Prof. Dr Scheibenbogen firmly supports the “yes” side, drawing on extensive scientific and clinical experience.
A quick recap – The immune system can usually distinguish between “self” (your own body) and “non-self” (viruses, bacteria, etc.). In autoimmune disease, this distinction breaks down as the immune system produces high levels of autoantibodies which confuse “self” for “non-self” leading to damage to the body’s own cells.
Prof. Dr Scheibenbogen’s talk, Autoantibody treatments for ME/CFS and long COVID, described growing evidence that autoimmunity may play a role in at least a subset of people with ME/CFS and long COVID. General overview:
Autoimmunity as part of a larger disease picture
Referencing review findings [1, 2], Prof. Dr Scheibenbogen highlighted the complex disease mechanisms of ME/CFS involving interplay between immune dysregulation, autonomic dysfunction, and metabolic/mitochondrial dysfunction, which paints autoimmunity as part of a larger picture of disease.
Immune dysregulation
In relation to immune dysregulation, she highlighted that research shows ongoing, low-level inflammation, including neuroinflammation (inflammation primarily of brain and spinal cord). She also mentioned association with Epstein-Barr virus (EBV) reactivation (also after COVID) and “latent immune responses”, which likely refers immune activity triggered by pathogens, e.g. viruses, that remain dormant. Crucially, she noted there is “good evidence that autoantibodies do play a role in a subset at least of ME/CFS patients”.
Autoantibodies in ME/CFS and long COVID
Prof. Dr Scheibenbogen mentioned that long COVID is complex, both in its clinical picture and underlying pathophysiology (disease mechanisms). In a cohort trial she was involved in, 10-20% of long COVID patients met ME/CFS Canadian Consensus Criteria (CCC) for diagnosis. Even those who do not meet criteria often show a great deal of symptom and pathophysiological overlap, which includes the presence of several autoantibodies.
GPCR autoantibodies
G-protein coupled receptors (GPCRs) are a large family of proteins, found on cell surfaces, that receive signals from outside the cell and transmit them inside to trigger specific responses. Some autoantibodies against them naturally occur in healthy people and help regulate cell processes, but according to Prof. Dr Scheibenbogen in a subset of patients with long COVID and ME/CFS:
- GPCR autoantibody levels are higher
- Levels correlate with symptom severity and alterations in the central nervous system (brain and spinal cord)
The Beta-2 (β2) adrenergic receptor is a well-studied GPCR involved in many body functions. Beta-2 adrenergic receptor autoantibody function is impaired in ME/CFS and long COVID. Studies from Japan [3, 4] show Beta-1 (β1) and Beta-2 adrenergic receptor autoantibody levels correlate with changes on brain imaging, altered pain responses, and neuroinflammation.
Autoantibodies against nerves
Prof. Dr Scheibenbogen highlighted a preliminary study from the Ron Davis group that described antibodies against a protein within the myelin (fatty sheath) of nerve fibres in about half of the ME/CFS participants. The protein studied is otherwise implicated in multiple sclerosis – an autoimmune disorder.
EBV as a potential trigger of autoantibodies in ME/CFS
Prof. Dr Scheibenbogen and her team have looked into how antibodies related to EBV, a very common virus, might be implicated in ME/CFS.
Initial study findings:
- ME/CFS patients have more IgG (immunoglobulin G; the most abundant antibody in blood) responses to a specific EBV protein called EBNA6 than healthy controls.
- EBNA6 contains an interesting arginine-rich sequence (a type of amino acid pattern). Note: proteins are made up of amino acids, of which there are 20 types.
- Higher antibody responses in the post-infectious ME/CFS subsets.
Consecutive study findings:
- Arginine-rich sequences, similar to EBNA6, appear in human proteins. This suggests molecular mimicry: the immune system may accidentally target human proteins that look similar to EBV proteins.
- Elevated autoantibodies against several of these proteins and correlation with symptom severity in ME/CFS and long COVID.
Correlation is not causation
She emphasised that the presence of autoantibodies is not proof of causation. Stronger evidence comes from:
- IgG transfer models (transferring patient antibodies into mice)
- Autoantibody-targeting treatments
- Clinical trials
She evidenced two IgG transfer models [4,5] demonstrating that if you take the IgG from individuals with long COVID and transfer it into mice then several known symptoms of long COVID are induced in the mice e.g. latent pain response, reduced grip force.
Note: Both studies referenced are pre-prints, meaning they have not yet been peer-reviewed. The peer-review process aims to assess the validity and quality of articles for publication.
Clinical trials
Although clinical trials in ME/CFS are not frequent, Prof. Dr Scheibenbogen described several approaches that showed promise.
1. Rituximab
Rituximab is a synthetic antibody, used to treat autoimmune disease, that reduces B cells – the cells that produce antibodies.
- Norwegian randomised control trials [6,7] suggested that rituximab helped a subset of individuals with ME/CFS, demonstrating efficacy and long-term clinical remission. Unfortunately, phase III trial failed to reach an end point.
- A new phase II trial with rituximab is underway in Japan.
2. IgG therapy
Prof. Dr Scheibenbogen and her team conducted a proof of concept study which involved giving IgG to 17 ME/CFS patients who had recurrent infections and mild IgG (or IgG subclass) deficiency. They found:
- A subset of 5 patients had meaningful improvements in fatigue and physical function.
- Some patients did not tolerate the treatment (side effects included headaches, skin reactions, flu-like symptoms, and liver toxicity).
3. Immunoadsorption (removing IgG)
Immunoadsorption removes IgG antibodies directly from the bloodstream. According to Prof. Dr Scheibenbogen – it is a well established treatment in Germany in autoantibody-mediated disease. Her team did two small trials [8,9] pre-pandemic and got some evidence that in a subset of patients with ME/CFS immunoadsorption results in “rapid symptom improvement”.
With government funding, they conducted an immunoadsorption trial with 20 post-COVID ME/CFS patients (individuals with long COVID meeting ME/CFS criteria). They found:
- Improvement in physical function according to the SF-36 measure.
- Before treatment the patients were housebound, whereas afterwards 14 patients had an increase in average to 60 points on the measure, which meant according to Prof. Dr Scheibenbogen that they were “back in life”. Note: they did still have symptoms which she states is not surprising because they did not not get rid of the autoantibody-producing B cells, rather only reduced autoantibodies.
- Similar improvements in pain and markers of neurocognition
- Improvements in hand grip strength
Importantly, they also identified a B-cell marker that could distinguish responders to immunoadsorption therapy vs non-responders. This has future potential as a marker that will help predict who will respond to autoantibody-depleting therapies.
4. Targeting autoantibody-producing cells with Daratumumab
A small Norwegian pilot study, involving 10 individuals moderate to severe ME/CFS, evaluated the effects of daratumumab, a synthetic antibody that targets plasma cells (the cells that make antibodies). Prof. Dr Scheibenbogen highlighted that the study showed:
- “Impressive clinical response” in six of 10 patients, demonstrating “rapid improvement” in SF-36 physical function. Those who received several repeat treatments were “back to normal”.
- Those not responding well were those with lowest levels of natural killer (NK) cells. She suggested that the lack of treatment response could be due to low NK cells or that these individuals did not have autoantibody-mediated disease at all.
Conclusion
Prof. Dr Scheibenbogen confidently stated: “We do have evidence for a role of autoantibodies in long COVID and ME/CFS.” Furthermore, there is evidence that antibody targeting therapies have efficacy (in a subset) and there is potentially a specific B cell signature which can predict response to treatment. Therefore, she believes autoantibody targeting therapies hold promise as effective treatment for the autoimmune subset of long COVID and ME/CFS
Important considerations
Whilst the research on autoimmunity in ME/CFS and long COVID is encouraging, it is still early days. Many studies are small, and two of the antibody-transfer studies discussed are still pre-prints, which means interpretation of their findings needs extra caution. It seems not all individuals with ME/CFS and/or long COVID have autoantibody-mediated disease, and it is not yet clear whether autoantibodies directly cause symptoms or are a consequence of disease. Promising biomarkers and therapies will require larger, long-term trials before they can be used routinely. Nevertheless, the growing number of consistent findings and improvements seen in some individuals offer cautious but genuine hope for more targeted treatments ahead.
