Thanks for this lengthy idea collection
@Jonathan Edwards. I cannot claim to have understood much of it yet, but I wonder how one could begin to examine the above ideas.
Regarding the analogy to pregnancy and autoimmune disease: Do we have any (anecdotal) evidence on the role of pregnancy in ME/CFS? My impression from a few internet stories had been that some people had reported symptomatic improvement during pregnancy and I hadn't heard anything about worsening of symptoms which is probably what one be more likely to expect as a pregnany seems to come with a lot of "PEM-inducing" efforts, but I cannot say anything about the reliabilty about these anecdotes or whether this rate of improvement surpasses the natural rate of improvement present in mild/moderate ME/CFS patients (presumably mainly patients on the "milder spectrum" of ME/CFS would get pregnant) and presumably people on the internet are more likely to report "improvement stories" than the opposite. If data existed on this, would improvements during pregnancy be more indicative of the involvement in B-cells in women or are there abundantly alternative explanations involving NK or T-cell processes (for example has improvement during pregnancy been reported in T cell diseases) that could also explain such a phenomenon, if it even exists?
Your observations seem to imply that it is very important for studies to record whether patients had a sudden onset following infection (so possibly more likely to be T cell related) or whether they had a gradual onset (so possibly more likely to be B cell related), which unfortunately is not commonly enough reported. A similarly easy thing, which I haven’t seen asked/recorded, is asking whether there is a history of autoimmune diseases running in the family, should that be something that is recorded and could recording a history of "enthusiastic T-cell diseases" also be fruitful (if they are all linked to MHC Class I genes and DecodeME shows that ME/CFS isn't then it probably wouldn't be useful, but maybe some diseases not associated to MHC Class I genes could be picked up)?
ME/CFS is pretty strongly related to immune stimuli from intracellular organisms - viruses and some bigger things like Q fever. Autoimmune B cell diseases are not.
The exception to this would probably be the link between MS and EBV, however that seems to be a very slow or gradual process taking place over years whilst the association between EBV and ME/CFS seems to be operating on a much smaller time scale.
Would it even be plausible to you that B-cell infection with EBV could somehow lead to a very fast onset of ME/CFS as autoimmune disease?
I can’t claim to understand anything about the CD16 and T-cell mechanisms you are proposing here, but would this not be something that Efgartigimod could potentially target?
I once again had a quick glimpse at the RituxME paper to see if there were perhaps marginally different response rates between sexes. I am 100% certain the Norwegian group will have looked at this and probably saw no differences, but I couldn’t find this data, does anybody have it at hand?