I think this is a cogent point. When I saw the claim that improvement after rituximab correlated with a fall in anti-GPCR antibodies I was unimpressed by that as evidence for anti-GCPR being important. We can see they aren't from the initial levels in patients and controls.
But, as for the NK cell number data, it does lend some support to the idea that antibodies are contributing to mediation of symptoms. In other words that F&M are on the right track in broad terms. That is not trivial, even if it is another piece of soft data.
But one possibility here is that antibodies in general, or perhaps certain subtypes, are one of the things that can feed signals in to hyper-responsive neuro-immune pathways and that ME/CFS is the hyper-responsiveness, not the antibodies. Maybe normal spectra of antibodies contribute to making people with the neuroimmune signalling problem, just as light and touch do. In a way that is what we proposed in the Qeios paper.
One possibility is that over time we accumulate an increasing number of 'dirty' antibody species in our long lived plasma cell compartment and that a dose of Daratumumab is like a spring clean. It does nothing to the ME/CFS state per se but makes life easier for the person with ME/CFS. The received wisdom has been that antibodies only do harm if they are directed against specific self antigens. But a wide spectrum of apparent autoantibodies does not fit with generating one type of illness. Each autoantibody we know of that goes with a disease has a separate clinical syndrome. What I think people forget is that antibodies bind to other things - like Fc receptors - and can interact with molecular shapes that are not strictly either self or foreign. Anti-citrullinated protein antibodies are a good example. The antibody recognises a degradation of lots of proteins.
Modern lab science focuses a lot on what you can measure and generate vast banks of data but almost of all of those data tell us nothing useful. Having seen knowledge of autoantibodies develop from the findings of my departmental mentors, like Doniach and Roitt, to the highly detailed findings on variious anti-synthetase antibodies in myositis and spent hours pouring over pharmacodynamic profiles of VH gene usage in rheumatoid patients I am sceptical that broad profiles of ubiquitous low level autoantibodies will tell us much.
This is a really exceptional breakdown of the situation - thank you Jonathan Edwards and sorry if we got off on the wrong foot.
Let's talk this specifically as this is a very productive direction: "
One possibility is that over time we accumulate an increasing number of 'dirty' antibody species in our long lived plasma cell compartment and that a dose of Daratumumab is like a spring clean"
I think there is a decent chance the 'spring clean' helped in the Fluge/Mella trial. So far - the data points to 'the amount of spring cleaning that happened' as correlating to improvement more than other things like total IgG change or NK at baseline. Just off a meeting with them and have a full set of figures prepare for a paper that should go out later this summer.
If we start from the assumption that their trial worked and is not an artifact (TBD with their expanded randomized trial) - I think the 'spring cleaning' is a decent hypothesis for why it worked.
Why did spring cleaning help? Is there a single culprit or small family of 'ME/CFS symptom creating autoantibody' that is more likely to have been 'removed' in the patients with wider spring cleaning? Or existed only in responders at baseline and was there to be removed in them as a subgroup? This is my favorite hypothesis. We have an enrichment direction for such a pathway in the data - but it is a discussion point not proof. An antibody sticking to something does not prove mechanism; deep functional studies are needed on potential culprits and this rarely happens other than with some of the best funded groups.
It is also possible that the specific antigens don't matter as much, that autoabs get in the way in general, and that spring cleaning 'just helps' as it reduces total autoantibody events - plausible, and I think the direction you were going - but these 'background' autoantibody signatures are so pervasive I tend to think 'literal mechanisms' occur more often, and matter more, than most currently assume. Also - not all of these events are 'low titer / weak' - their titer is often undetermined - but that doesn't say that it is weak. I do know in some cases where I've chased outliers in titered minichips some preserve in the same HuProt microarray assay above background at 1:10,000,000+ dilution - but I don't actually know the frequency of a standard repertoire that preserves to this level and may go run some so that I know....!
A third theory is that maybe the spring clean frees up 'useful space' in the repertoire - or directly removes aberrant actions it was doing - maybe something like a latent virus infection was getting out of hand via being tolerized in the IgG4 sub compartment - maybe the 'spring clean' allows restoration of immunity to some pathogen that causing havoc and creating symptoms (apologies if we clearly know viruses are not linked - I know far less of the literature here than you).
A bit more on why I think we might find a 'culprit' autoantigen that goes away is that such things are far more frequent than you might expect and would not be surprised if ME/CFS had specific findable pathogenic autoantibodies (perhaps triggering "
hyper-responsive neuro-immune pathways" directly)!
There is emerging literature that 'background' autoantibodies have profound effect. 4% of people over 70 have Type I IFN-blocking autoantibodies:
Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower...
pubmed.ncbi.nlm.nih.gov
I know from conversations that this is reproducing 'at scale' across tens of thousands of samples ( I see this event in my own data too regularly) - some portion of the 'healthy' population has vitamin B12-import blocking autoantibodies:
pmc.ncbi.nlm.nih.gov