Hyper-reactivity of CD8+ T cells and high expression of IL-3 correlates with occurrence and severity of Long-COVID, 2025, Renner et al.

Jonathan Edwards said:
That is a reasonable concern and certainly our logic for standard autoimmune disease. However, it is conceivable that people accumulate plasma cells that produce high affinity antibody to some past antigen that just happens to react enough with 'everyday junk' from gut or bits of virus to cause trouble. If you clear out the old plasma cells there may be no drive to make antibody with those particular properties if the old antigen is no longer around. With autoimmunity the auto antigen is always still around unless you have destroyed the relevant organ totally.

I think this may be being optimistic but if antibody is involved in ME/CFS it seems to be doing something unusual like this.
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I guess I was mostly curious about RA. Was there ever an attempt to clear out central memory B cells to see if the effect lasts longer?
 
forestglip said:
Was there ever an attempt to clear out central memory B cells to see if the effect lasts longer?
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We did our best with ritual and cycle but didn't have the justification for going more aggressive - and it was not clear how we could do that, other than ramping up the cycle to really toxic levels or adding in nasty things like vincristine or adriamycin.
 
Jonathan Edwards said:
We did our best with ritual and cycle but didn't have the justification for going more aggressive - and it was not clear how we could do that, other than ramping up the cycle to really toxic levels or adding in nasty things like vincristine or adriamycin.
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Oh ok, understood. Out of curiosity, I was trying to look up information about the procedure that's apparently cured three people of HIV by wiping out their immune system. I stumbled on this from BBC about measles also destroying memory T cells and resetting immune memory: The race to understand 'immune amnesia'
Enter "immune amnesia", a mysterious phenomenon that's been with us for millennia, though it was only discovered in 2012. Essentially, when you're infected with measles, your immune system abruptly forgets every pathogen it's ever encountered before – every cold, every bout of flu, every exposure to bacteria or viruses in the environment, every vaccination. The loss is near-total and permanent. Once the measles infection is over, current evidence suggests that your body has to re-learn what's good and what's bad almost from scratch.
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Article says this about autoimmune:
(Unfortunately there's no evidence this immune reset can be beneficial for those who have malfunctioning immune systems, such as people with autoimmune disorders – and even if it was, Swart points out that measles-based treatments would only work in those who had never encountered measles or the vaccine before.)
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But doing a quick search, I can't find much about it actually being tested if autoimmune disorders improve at all after measles. Maybe it'd be worth trying to do a retrospective study to see if RA prevalence decreased in those who were infected in a measles epidemic?
 
forestglip said:
But doing a quick search, I can't find much about it actually being tested if autoimmune disorders improve at all after measles. Maybe it'd be worth trying to do a retrospective study to see if RA prevalence decreased in those who were infected in a measles epidemic?
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Thing is, most of us had measles as young children. The commonest age for the eldest sibling to bring it home from school was probably around eight or nine. Most of those who're getting it now because they're unvaccinated are probably in the same age band.

T1 diabetes and JIA can develop in young children, but would other autoimmune conditions be common enough to pick up signals like this? Presumably in the years following measles infection the risks of autoimmune conditions revert to normal.
 
Kitty said:
Thing is, most of us had measles as young children. The commonest age for the eldest sibling to bring it home from school was probably around eight or nine. Most of those who're getting it now because they're unvaccinated are probably in the same age band.

T1 diabetes and JIA can develop in young children, but would other autoimmune conditions be common enough to pick up signals like this? Presumably in the years following measles infection the risks of autoimmune conditions revert to normal.
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Yeah, just floating the idea because I thought the measles thing was really interesting and wouldn't it be cool if measles could help solve autoimmune diseases. I have no idea if the sample size would be too small or if the data needed is there to look at.

But maybe doing something like looking at health records of everyone who had fairly severe measles and survived, then narrowing down to those who, before the infection, also had an autoimmune disease that they were on medication for, then checking in those people if their use of prescription drugs for autoimmune diseases decreased for at least a few months or years after.

Edit: But good point about it mostly being children getting measles.
 
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forestglip said:
Oh ok, sorry, I thought I remembered central memory B cells needing T cell help in some way to mount a secondary response, but looking back through the book I read, that's not in it.
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Yes B cells require T cell help but as far as we know they get help from T cells recognising foreign antigens, as they should. The problem lies in the fact that B and T cells can talk to each there without realising that they are recognising different antigens.
 
So a bit like when an alarm call goes off in a forest and all the animals start shouting but nobody really knows what they’re shouting about? (and it may be that once it’s done the rounds some of those making the noise may have been the ones the others were scared of in the first place)
 
Jonathan Edwards said:
Yes B cells require T cell help but as far as we know they get help from T cells recognising foreign antigens, as they should. The problem lies in the fact that B and T cells can talk to each there without realising that they are recognising different antigens.
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Oh right, but then even if the T cells aren't self reactive, if you clear out every last one, wouldn't it tamp down the potentially self-reactive B cell response then? I mostly was thinking of the measles thing to provide evidence that central B cells are involved, but admittedly this would be quite a roundabout way to do that.
 
forestglip said:
Oh right, but then even if the T cells aren't self reactive, if you clear out every last one, wouldn't it tamp down the potentially self-reactive B cell response then?
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Yes, it could. I think I was responding to what looked like an assumption that autoimmunity required some special T cell memory in the article quoted. It does seem reasonable that just having fewer T cells of any sort would damp down the B cells. On the other hand the interesting thin gas that when people with RA had cam path and lost almost all their T cells, it didn't actually help the RA at all. Which suggests that although T cell help is almost certainly necessary to get an autoimmune disease going, once it has got started the B cells may be able to keep the problem ticking over without T cell help.
 
Jonathan Edwards said:
On the other hand the interesting thin gas that when people with RA had cam path and lost almost all their T cells, it didn't actually help the RA at all. Which suggests that although T cell help is almost certainly necessary to get an autoimmune disease going, once it has got started the B cells may be able to keep the problem ticking over without T cell help.
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Ah very interesting, thanks.
 
Jonathan Edwards said:
Yes, it could. I think I was responding to what looked like an assumption that autoimmunity required some special T cell memory in the article quoted. It does seem reasonable that just having fewer T cells of any sort would damp down the B cells. On the other hand the interesting thin gas that when people with RA had cam path and lost almost all their T cells, it didn't actually help the RA at all. Which suggests that although T cell help is almost certainly necessary to get an autoimmune disease going, once it has got started the B cells may be able to keep the problem ticking over without T cell help.
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For what it's worth, even though the BBC article only mentions T cells, I looked further and it seems that the measles virus uses the CD150 receptor to infect and deplete memory B cells as well.

Studies into the mechanism of measles-associated immune suppression during a measles outbreak in the Netherlands (2018, Nature Communications)
MV infects cells after binding to cellular receptors CD150 or nectin-4, expressed on subsets of immune cells or the adherens junctions of epithelial cells, respectively9,10,11. In experimentally infected non-human primates (NHPs), MV initially targets myeloid cells in the respiratory tract, which act as Trojan horses by transmitting MV to CD150+ lymphocytes in lymphoid tissues, leading to viraemia and systemic virus dissemination12,13,14,15. Ensuing lymphocyte depletion and follicular exhaustion in lymphoid tissues have been described during prodromal measles in both humans and NHPs16,17. In vitro and in vivo studies showed that memory T cells are more susceptible to MV infection than naive T cells, due to higher expression of CD15017,18. This difference in susceptibility is less pronounced in the B cell lineage, with both naive and memory B cell subsets being highly susceptible and permissive to MV infection in vitro17,19. Based on these findings, we hypothesised that MV causes immunological amnesia by infecting and depleting pre-existing memory lymphocytes17,20. Consistent with this hypothesis, a subsequent epidemiological study found that rates of non-measles infectious disease mortality are tightly coupled to measles incidence—with a greater mortality rate at higher recent measles incidence. It was concluded that the reduction in host resistance following measles infection may extend over a period of more than 2 years2.
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We found that peripheral B cells, especially those belonging to the class-switched memory subsets, were significantly reduced in frequency after measles. This loss was more prominent in the IgG+ memory B cells than in their IgA+ equivalents, most likely due to the higher susceptibility of IgG+ memory B cells to MV infection19. Accompanying the loss of memory B cells after measles was a significant influx of transitional B cells. Transitional B cells represent recent bone marrow emigrants in the circulation that will develop into mature naive B cells and have a reduced proliferation capacity31. We speculate that the expansion of this subset reflects a compensation for depletion of pre-existing memory B cells.
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Jonathan Edwards said:
We did our best with ritual and cycle but didn't have the justification for going more aggressive - and it was not clear how we could do that, other than ramping up the cycle to really toxic levels or adding in nasty things like vincristine or adriamycin.
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It seems a large chunk of patients treated with Thiamazole that suffer from Graves disease go into permanent remission, so in that case the memory relatively often seems to go away from a very safe therapy. Allegedly there is some evidence that suggests that staying on this therapy for longer also increases the chances of remission to some degree. Does that have to do with this specific autoimmune disease somehow intrinsically having less memory than others (a sufficiently long reboot often being enough to remove memory without having to address medications depleting CD19 or CD20) and can something similar work for other autoimmune diseases? Does anybody know how this works at all? Why does it delete memory for some people but not or others?
 
EndME said:
It seems a large chunk of patients treated with Thiamazole that suffer from Graves disease go into permanent remission, so in that case the memory relatively often seems to go away from a very safe therapy.
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I don't think thiamazole has any effect on the autoimmune process that triggers the hyperthyroidism, it just poisons the thyroid enough to stop it producing huge amounts of hormone. The antibodies carry on regardless. Graves' patients often have protruding eyes (exophthalmos) and less often swelling on the shin or of the fingers. These tend not to reduce with any treatment directed at the thyroid gland and eye disease can be the most serious aspect of Graves'. Nobody knows exactly what is going on but it is generally assumed that the eye disease is due to antibodies, independent of the thyroid problem.
 
For about twenty five years friends of mine have talked of manufacturing 'bispecific' monoclonal antibody drugs that in theory are very clever but have not broken into the market much.

A typical idea would be to have one arm of the antibody bind a T cell surface label protein like CD8 and the there arm would bind an activation marker - some protein only expressed if the cell was angry or excited. The idea would be that you only kill off cells that have got out of hand when really they should be laid back doing nothing.
 
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