Skewing of the B cell receptor repertoire in myalgic encephalomyelitis/chronic fatigue syndrome, 2021, Sato et al

That's a terrific find @jaded. What an interesting conversation.

I have made some notes and will try to write them up. The auto antibodies Avi refers to are, I think anti-idiotypic antibodies. (The captions on my screen kept referring to them as anti-idiotic antibodies, which was a little disconcerting...)

So, that's getting quite meta.

 

Referring to the video: Part 1

The President of the Japan ME Association hosted the conversation - Ms Miyako Shinohara (apologies if I have that wrong). She said a little about ME/CFS and Long Covid in Japan - I summarised it on the 'News from Japan' thread.

The conversation was between Avi Nath of the US NIH and Takashi Namamura. Dr Namamura is a physician and scientist working in the field of neuroimmunology. He's worked on MS for over 30 years, is the Director of the Department of Immunology and of the Multiple Sclerosis Centre in the National Centre of Neuroscience.

Dr Nath - Is Long Covid ME/CFS?
The pandemic started in January 2020 and they ('we')knew right at that time that they would probably see patients developing ME/CFS, given Covid-19 is a respiratory virus and there were presentations of neurological problems. By the middle of the year, they knew that they were seeing patients with symptoms that overlapped with ME/CFS. He said 'Yes, I think there is substantial overlap between the two diseases. There may not be complete overlap but a lot of the symptoms are quite similar and the manifestations are quite similar. What we do not know is if their immunology is the same or not. Certainly LC is initiated by a virus and, ME/CFS, there may be multiple triggers for it. So there are some differences but the overlap is quite significant'.

Dr Nath - prevalence of LC?
NHS England large study - 3 months after the acute illness, 30-50% of people still have persistent symptoms.
Netherlands study - found that those people who don't recover by 5 or 6 months tend to have symptoms that persists for over a year - they account for about 20 to 30% of acute cases.
It's affecting all age groups although they are seeing it particularly in the 30 to 40 age range. It has huge socio-economic consequences.

Dr Nath - NIH research?
Although they are still analysing the data from the intramural study, it is very clear that there is immune dysfunction in these patients. There is also mitochondrial impairment. Maybe the two problems go hand in hand. They are still trying to put it all together.

They have plans to do clinical trials for LC and ME/CFS - but starting with LC. He felt that the findings from LC research would 'certainly be applicable to ME/CFS'. They are putting together the protocol for a placebo controlled study of hydrocorticosteroids or IVIG. The aim is to treat the patients and see what happens - the results should allow them to identify more specific immune therapies. Nath said that there are a lot of interesting clinical trials planned by many groups in the US.

Nath and Yamamura - Mutual admiration of each other's work

Dr Nath - what's going on in Covid-19?
He's a virologist, so the first thing he did was try to find the virus in the brain, to explain the neurological effects. They tried hard to find it using all sorts of techniques, but failed to do so. Maybe they missed it, but it is clear that there is no overwhelming infection in the brain.

But, if there is no virus, why are people losing their sense of smell? Certainly there is virus in the nasal mucosa, although the olfactory bulb is not infected. So they think the effects on the brain are immune-mediated. They found that the blood vessels in the brain are leaky and that immune complexes are deposited there. They found a lot of macrophage infiltration in the prevascular region. There were very few t-cells - if there had been a viral encephalitis, they would have expected to find t-cells.

They think the macrophages are there because the blood vessels are leaky; they are trying to remove the proteins that are leaking from the blood into the brain. So, most of the pathology is driven by the innate immune responses within the brain.

'On the surface of the blood vessel, it could all be antibody-mediated, I don't know'.

Dr Nath - autonomic dysfunction?
Yes, a lot in LC. Even if patients don't report it, if you do testing, you find it. Dr Nath mentioned a neurologist who has LC and had commented how bad it was, that she was having trouble even just sitting up. (So I think he does understand how debilitating the illness is.)

Dr Yamamura - about his work
They saw Carmen Scheibenburg's paper about the adrenergic and muscarinic antibodies (apologies for spelling in all of the long words there) and tried to replicate it. And they did - they found 40% of their patients were positive for these autoantibodies. The test was ELISA, so not very sensitive, so they are developing a cell based assay system to increase the chance of detection.

The B-cell receptor analysis published in the Brain, Behaviour and Immunity journal is supportive of the idea of an antigen-driven mechanism for ME/CFS.

Dr Yamamura - treatment for ME/CFS?
They have started to use corticosteroids or IVIG or drugs used for rheumatoid arthritis, and some patients seem to be very happy with them. He comments that 'of course, this is not driven by clinical science'. He is supportive of the NIH approach to the planned trial.

Dr Nath - on the possible cause of ME/CFS and LC
Dr Nath effusively praised Yamamura's work: 'You have done really nice work, I'm very impressed by the work you have published. I had an opportunity to look at your paper and your findings are remarkable. I think you are on the right track. B cell abnormalities make a lot of sense. I think targeting those cells could be good if it's done in a controlled study in the right population. I think that is very encouraging.'

(See what I mean? That is very enthusiastic praise. It's nice to hear that they both agree - but then, we have had a big controlled study for a B-cell targeting drug, so why did rituximab not work?)

Nath said 'The antibodies to ACE2 are also quite fascinating' - some of the LC patients have antibodies to ACE2. He would like to see if the antibodies are of pathogenic significance. He said 'Somebody told me that they could be anti-ideotypic antibodies because it binds to the ACE2 receptor and antibodies to spike protein can then generate antibodies to the antibodies. And you actually end up with anti-ideotypic antibodies.' He said that might explain why they can't find any virus and yet there is all the immune complexes and the pathology there.

 

Video - Part 2

Dr Yamamura - what's coming up
They are phenotyping (Long Covid?) and are about to publish a paper on gut microbiota - specifically gut microfilms. They are planning a clinical trial targeting B cells, but he said that he can't say more on that. Nath felt that such a trial made a lot of sense and that it had to be worth a try.

On whether the B-cell receptor repertoire reported by Yamamura could be a biomarker
Nath said that it was a very important finding, suggesting that the disease is driven by some kind of antigen, activating a very specific population of B cells. He asked Yamamura if it is possible to identify the target antigens. Yamamura that it was very difficult to identify the target antigen. They are trying to reduce the cost of the test, to make it more clinically useful. And that it will soon be used as a biomarker in clinical trials.

The video came to a close with much mutual admiration again.