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

[Tyler Hulett]

Curious what the explanation might be that antibodies from LC are more likely to cause pain sensitivity in mice compared to antibodies from convalescent controls. Several groups have reported this now.

Looks like this group did in-depth measurements to figure out what causes this but that they didn't fully manage to figure it out.

I think this is why it took so long to publish they were unable to isolate the ultimate smoking gun ab like more profound papers (Lanz Robinson 2022 Nature on EBNA1 and GlialCAM in MS). Isolated the monoclonal from a patient; induced same symptoms and simultaneous T cell immune infiltration in mice with tolerance breaking vaccines vs the molecular mimic peptide. That paper did full mechanism round trip and imagine Iwasaki was shooting for that and they never quite accomplished it. Still a great paper.

 

[Tyler Hulett]

Then they aren’t the «same» autoantibodies, just part of the same over-arching measurement category, like you said.

So «normal» would have to be defined based on more accurate measurements.

Exactly. An antibody “sticking” is not an antibody “doing.” You cannot tell from larger antigens what a titer vs something means. Some autoabs are agonists. Some are antagonists. Some are even catalytic? Some are protein clearing. Some are paradoxically protein lifetime and signal extending. Some are cytotoxic; some are more protective. And sadly each individual ab sort of needs its own bespoke functional assays to see what it’s doing. I’m hopeful someday we can have a catalogue sort of like OMIM of known site/isotype specific pathogenic autoabs - ie minimal sites you can trust likely cause functional changes by antibody sticking alone. There are some that behave like this - the anti transcolbalamin B12 blocking minimal epitope seems to mostly mean the same thing each time. But you couldn’t guess that from the whole protein you need to specifically assay the pathogenic binding site.

 

[Utsikt]

I think this is why it took so long to publish they were unable to isolate the ultimate smoking gun ab like more profound papers (Lanz Robinson 2022 Nature on EBNA1 and GlialCAM in MS). Isolated the monoclonal from a patient; induced same symptoms and simultaneous T cell immune infiltration in mice with tolerance breaking vaccines vs the molecular mimic peptide. That paper did full mechanism round trip and imagine Iwasaki was shooting for that and they never quite accomplished it. Still a great paper.

I made a thread for the MS paper.