Passive transfer of fibromyalgia symptoms from patients to mice, 2021, Goebel et al

Two expert opinions on this study (press release by the New Zealand Science Media Centre):

One is from Dr Bronwyn Lennox Thompson, Senior Lecturer, Academic Coordinator Postgraduate Programmes in Pain & Pain Management, University of Otago, Christchurch:

"The major caution about this study is that it’s conducted in mice, and humans are not mice. Mice can’t describe their experiences so we’re inferring from their behavioural responses to short-term stimulation to humans who may be experiencing fibromyalgia for many years. We also may know a great deal about the possible mechanisms associated with developing fibromyalgia or long Covid, but treatments may be quite a long way off.​

The other is from Emeritus Professor Warren Tate, biochemist and molecular biologist, Brain Health Research Centre, University of Otago:

"Does this mean Fibromyalgia is a condition of the immune system and not the brain, as this Guardian headline reviewing the research suggests? It seems more likely the wider array of symptoms similar to Chronic Fatigue Syndrome are brain related, but the autoantibodies are an important secondary feature of the disease, just as they are in Chronic Fatigue Syndrome."​

Full article: https://www.scoop.co.nz/stories/GE2...-not-be-only-in-the-brain-expert-reaction.htm

 

I am puzzled by this quote. Science doesn’t know much at all about fibromyalgia and i am not confident the majority of physicians or researchers out there know a great deal about Long-Covid.

 

Two opinions. Neither is an immunologist and this is immunology.

I don't think we have reason to think autoantibodies are of any importance in ME, whether primary or secondary whatever that might mean.

 

I'm a fan of Warren Tate (the second "expert") i.e. since his daughter suffered from ME/CFS - I think her health has improved.

Speculation -
Perhaps Warren's thinking of the tryptophan ("trap") theory i.e. (I assume) lower kynurenine production would lead to increased susceptibility to autoimmune disease.

Not saying I'm sold on these theories, by the way.

 

We literally know nothing, what is "known" is at best speculation. Quotes like this are so annoying when you see how common they are. What is even the point of pretending? Maybe just so as not to admit to total failure, given that it's the product of an obsessive ongoing effort going back decades and that would imply a complete paradigm shift? Well, that's partly why no progress happens.

 

I don't know why it should though.

 

That quote shocked me too. Since nothing is known about mechanisms of FM and Long Covid I wonder if he meant to say that even in the hypothetical future when we know a lot, the treatments could still be far off. It’s understandable that they are trying to dampen patient enthusiasm. It’s an unreplicated mouse study.

 

If this can be replicated this could be huge. But history has taught me to be careful jumping to conclusions, so waiting for the replication before I get too excited.

 

Here is a paper discussing the next research step by the same group of researchers.

https://academic.oup.com/painmedicine/advance-article/doi/10.1093/pm/pnab338/6443164

Research Recommendations Following the Discovery of Pain Sensitizing IgG Autoantibodies in Fibromyalgia Syndrome: Goebel, Anderson, et al. Pain Medicine, Nov 2021



…an excerpt (I broke up the text for readability):

Suggestions for Clinical Trials in FMS

This topic was discussed extensively, and good agreement was found for only one recommendation.

Stakeholders agreed that a three-arm experimental trial including immunoglobulin G (IgG) immunoadsorption versus plasma exchange should be considered to improve understanding of the clinical relevance of pain-sensitizing Aab in FMS. Patients would need to be told before enrol- ment that even if that trial was successful these interven- tions may not become available in clinical practice.

Plasma exchange (removal of serum and all solutes from the blood) and immunoadsorption (removal of IgG or IgG subclasses through specific columns) are often effective in Aab-mediated autoimmune conditions [19]. However, these interventions are cumbersome given they require venous access and are generally considered less suited for long-term treatment. They are frequently being used to interrupt disease flares or to rapidly bring an immune disorder under control until the effect of disease modifying treatments set in.

There was agreement that FMS patients enrolled in interventional trials aiming to address Aab or their downstream mechanisms should be tested for the presence of such antibodies; serum tests are yet to be developed—passive transfer bioassay testing of each screened patient is unlikely feasible or ethically acceptable.

 

I fear that this is a committee discussing how to find more cases of Piltdown Man.

I had a look at the original paper immunochemistry. Two things are seriously worrying.

Firstly the staining of mouse dorsal root ganglion does not appear to stain nerve cells or even glia. The brightest staining is round the edges and entirely consistent with a non-specific binding to tissue stroma. Moreover, the pattern does not look anything like the pattern obtained with human tissue.

The staining of human tissue (DRG) in figure 11 is described as 'FMS IgG bound human DRG tissue sections more intensely than HC IgG'. Indeed, what we see is the same pattern of staining with healthy controls and (brighter) for fibromyalgia.

This is not specific staining. When we get specific staining with an antibody the staining pattern is completely unrelated to the pattern with negative control. As an analogy a positive signal pattern might look like highlighting all the 'a's on a page of text when the control just slightly highlighted all letters or all words of more than four letters or all the uprights. It is a bit like comparing a Mondrian with a Botticelli.

What is most worrying is that the original paper was considered suitable for J Clin Invest and as a result has gathered up a committee of worthies to consider what to do next.

 

Thank you @Jonathan Edwards for that.

 

Here is an apparently follow on preprint paper by some of these Swedish researchers plus a group of researchers from McGill University.


Fibromyalgia patients with high levels of anti-satellite glia cell IgG antibodies present with more severe symptoms

https://www.biorxiv.org/content/10.1101/2022.07.06.498940v1.article-info

 

@voner At first glance, this seems to be a well conducted and promising study. There was a replication cohort (McGill), a relevant diseased control group (osteoarthritis) and healthy controls (HC). Importantly total levels of IgG were similar between FM and HC and anti-neuron IgG levels were similar between FM, OA and HC.

Perhaps the most interesting finding is that the amount of anti-SGC antibodies and antibody binding correlated with pain severity — so this would be a biomarker for people with severe FM more than mild FM. The same might be true of a biomarker for ME.

 

This is going to be slow read for me… Perhaps better educated readers will chime in. I know this Swedish group has been wanting to find a test for Fibromyalgia. From the previously cited Guardian article:

The next step will be to identify what factors the symptom-inducing antibodies bind to, said Svensson: “This will help us not only in terms of developing novel treatment strategies for fibromyalgia, but also of blood-based tests for diagnosis, which are missing today.”

From the Results section of this paper:

Anti-SGC IgG levels were not associated with fibromyalgia duration.

from the Conclusion:

A subset of fibromyalgia patients have elevated levels of anti-SGC antibodies, and the antibodies are associated with more severe fibromyalgia severity.

 

For anyone who, like me, wants to learn about satellite glial cells (SGC) here is a good review paper:


Emerging importance of satellite glia in nervous system function and dysfunction

https://www.nature.com/articles/s41583-020-0333-z

 

here they clearly state this is work that continues on from their previous paper.

We previously used single patient IgG preparations from eight individuals or pooled IgG preparations from several individuals. Thus, the frequency of FM patients with autoantibodies, and their association with disease severity, remains unclear. To further establish the clinical relevance of our findings, the aim of the current study was to determine the frequency of SGC autoantibodies in FM patients and the relation between FM autoantibodies and FM symptom severity.

 

the image analysis involves using AI. ..

Individual cells were identified using Cellpose, a deep-learning neural network (27). Cellpose was run with Python v3.7.9 and the region of interest of each cell were imported into FIJI. Human IgG binding to SGCs and neurons was then assessed in FIJI and the percentage of cells bound and the average integrated density of IgG binding was determined. Human DRG images were analyzed using the drgquant pipeline as described previously (28). Experimenters were blinded to the serum type that cells or tissue were incubated with.

 

Antibodies are in the correct size range I think, but its peripheral evidence. All with me on the mantra? - we need more research! Having an hypothesis to test is good though, as if its wrong it will fail a study somewhere along the line.

 

in the discussion they talk about the pooled samples used in the previous paper (as noted by @Jonathan Edwards, @Simon M, @Hutan ,…):

In the current study we did not find a difference between FM IgG and HC IgG binding to neurons in culture. We had previously reported elevated IgG binding to sensory neurons in vitro (9), but these experiments were done using pooled IgG preparations. When looking at the data points from single individuals in the current study, many individuals have no or low levels of neuron binding IgG, but there are also individuals that have higher levels of IgG binding to neurons. It remains possible that a rare subset of FM patients has anti-neuron antibodies.

 

Their final statement in the discussion section:

We found that anti-SGC IgG levels are elevated in two distinct FM cohorts. The level of these antibodies correlated with a more severe clinical presentation, while being unrelated to FM duration. Moreover, the level of anti-SGC antibodies detected in culture is correlated with binding to human SGCs. These results, combined with our previous findings that FM IgG induces pain-like behaviour in mice, provide a possible answer to one mechanism of nociplastic pain in FM. Taken together, the data suggest that testing FM patients for elevated levels of anti-SGC IgG may be a relevant strategy to stratify patients for therapies that interfere with antibody function such as abatacept, anti-FcRn antibodies, IVIg or plasmapheresis.