A causal link between autoantibodies and neurological symptoms in long COVID, 2024, Santos Guedes de Sa, Iwasaki et al

A causal link between autoantibodies and neurological symptoms in long COVID

Abstract
Acute SARS-CoV-2 infection triggers the generation of diverse and functional autoantibodies (AABs), even after mild cases. Persistently elevated autoantibodies have been found in some individuals with long COVID (LC). Using a >21,000 human protein array, we identified diverse AAB targets in LC patients that correlated with their symptoms. Elevated AABs to proteins in the nervous system were found in LC patients with neurocognitive and neurological symptoms. Purified Immunoglobulin G (IgG) samples from these individuals reacted with human pons tissue and were cross-reactive with mouse sciatic nerves, spinal cord, and meninges. Antibody reactivity to sciatic nerves and meninges correlated with patient-reported headache and disorientation. Passive transfer of IgG from patients to mice led to increased sensitivity and pain, mirroring patient-reported symptoms. Similarly, mice injected with IgG showed loss of balance and coordination, reflecting donor-reported dizziness. Our findings suggest that targeting AABs could benefit some LC patients.

https://www.medrxiv.org/content/10.1101/2024.06.18.24309100v1?rss=1&utm_source=dlvr.it&utm_medium=twitter

 

I would like to see how well controlled this study is.
I am a bit leery of antibodies that react both to meninges and sciatica nerves being related to headache. It would also be more convincing if they mentioned a bit about what they didn't find too.

 

It seems "causal" is used somewhat vaguely here.

The data on the cohort seems to be lacking. I can't see any information on illness duration, last known infection, BMI, comorbidities, etc. Furthermore whilst they started of with a large cohort in later experiments they are using various different subsets of this cohort and I can't see any details on these subsets or how these subsets were selected.

Other than that they did a lot of IgG transfer mice experiment. Hard to tell if anything is a signal there or rather noise and some results seem to contradict those of den Dunnen. For example I don't think there's much evidence to suggest that grip strength test tells us much in humans with neurological LC (there's some evidence by Scheibenbogen but also different results from various other studies for general LC or ME), I think such experiments on mice are even more speculative especially if grip strength is supposed to be correlated with tinnitus.

 

I think the pain aspect with impact on SFN is fascinating and important.

Really that's the stand out piece for me.

They took IgG from patients that experienced pain and put them in mice, which then created increased pain in the mice. They took a cohort from these mice to look at small fibers and find enhanced SFN in those that got the IgG from patients experiencing SFN. That's pretty convincing to me from first read.

We might be seeing IgG as an initiator of autonomic dysfunction. That's the potentially causal aspect I think they refer in the title.

 

I'm quite taken by this paper. I like the way they've not just hunted for auto-antibodies but tried to see what effects those autoantibodies might have on tissues and whole organisms.

I don't think they're claiming definitive proof that AABs are the cause of long covid, but they do provide a solid link from some of the AABs to symptom load in some patients.

The happy thing about pointing the finger at AABs is we have a mechansim to attack them, via ivig/plasmapheresis. So the paper leads naturally to an interventional trial where they define a subset with high neurological symptom load (and/or high measured AABs) and see if they feel different after ivig. I'm very keen on adding definition to the subset of people ivig/plasmapheresis might help, since we know it does seem to help some.

The paper will make a splash since it's from Yale, and so it's pleasing to see it is fairly solid paper.

 

Have you ever done experiments on pain sensitivity in mice, Chris?
To me this is far too good ever to be true. And it doesn't really add up if you look at detail as ever.

To get a meaningful result with a system like this you would need a drug company unit running fresh experiments every fortnight for eighteen months to get the quality control you need.

 

Can you give us an example for the kind of mistaken procedure that would lead to SFNP in 4 mice but not in the other 4? How would that happen?

Personally, I don't think ME/CFS is a B-cell mediated disease, but it might be for some, maybe the mistake that we keep on making is not to subgroup patients. Injecting ABs in mice (until we know more) could be a way to subgroup patients?

Additionally, is it not conceiveable that various (differing from patient A to patient B) ABs lead to the same or similar enough downstream pathology? Maybe our mistake has been thinking that we will find one AB that explains it all?

We already kind of know from the NIH intramural study that 40% of pwME are misdiagnosed, which means nothing other than 'we have a better explanation' for these patients. Maybe patients with ABs eliciting such responses in mice will be another group of patients for which there are better explanations, at least for parts of what they individually consider 'their version of ME'.

Not all ME/CFS paients have SFNP and suffer from pain; both aren't necessary for an ME/CFS diagnosis, they are real issues nevertheless, and they need solutions.

Thank you!

 

Just that the method of measurement may be unreliable - for a hundred different reasons.

We have seen how consistent.y poor methodology is in the psychiatric sector. I am afraid to say that it tends to be almost as bad in this sort of biomedical area. Everyone wants to report a positive result and most of the time not enough standardisation has been done to ensure the experiments mean anything.

If there are problems with choosing the right patients it becomes even more improbable that you would get a significant result that is meaningful. Post hoc rationalisation of why experiments did not quite do what you expected are what bad science feeds off for ever.

 

The way forward then would be better standardisation.

 

Akiko Iwasaki is at Yale & Yale researchers have been working on a technique to identify autoantibodies*. However, I do still wonder if this is a reliable technique - you'd like to think that the proposed +ve result [autoantibodies] has been tested using a number of techniques.

*https://www.s4me.info/threads/reap-...eome-2021-wang-et-al.20747/page-2#post-372083