there is no reason why one DQ allele should confer risk on developing T cell responses to a range of proteins from a particular cell type unless of course DQ alleles are involved in something else-maybe trafficking to hypothalamus.
There may well be "something else" that the DQ allele does, but I don't see remotely any reason to believe that HLA is somehow involved in trafficking to specific areas of the body. That is not a finding that needs to be observed under very specific conditions--I can think of a dozen various experiments that would have already shown even the hint of that possibility. Again, it's positing a completely unobserved mechanism of T cells that (in the absence of positive evidence in any other context) must somehow only happen in a particular region of the brain, based on speculation that T cells in the brain
might do something in other cases where we have no details.
What about T cell immunity to tumours that manifests purely as the absence of tumours?
I don't think that's an example to the contrary when T cells are targetting cancerous tissues, and you can see the T cell infiltration as well as cell debris from those dead cancer cells. It's still a case of targetted tissue damage, just to the "tissues" we want to be targetted.
And what about feeling ill with 'flu'? Whatever the process is that makes us feel ill with flu doesn't damage anything at the site where it does that - likely the hypothalamus. That might not beTcell derived cytokine but itmight well be.
We know that direct administration of interferon causes flu-like symptoms on its own. Sure, one could speculate that there are multiple ways to end up with the same presentation or that this specific case operates through some T-cell dependent mechanism. But that would be picking one option out of dozens without evidence to consider it more likely than any other candidate. The same amount of evidence exists for receptors detecting circulating levels across the BBB, or any other interferon-producing cell type. Which happens to be all cell types.
We actually have more evidence
against T cells being causative for those symptoms since I know several colleagues doing viral infection studies on congenitally T-cell deficient mice and there is no lack of observable symptoms or sickness behavior in those cases. Is it possible that the generation of flu-like symptoms occurs via two completely different mechanisms between mice and human? Sure, there's always a chance. But it seems far from likely.
So the two examples given are not evidence of T cell activity in the absence of targeted tissue damage. Perhaps the other unlisted examples would be helpful here.
You are beginning to sound very much like the people in 1997 who told me I was a fool to suggest that B cells might be a good therapeutic target in rheumatoid, lupus, MS, myositis... Several tens of billions of dollars of useful healthcare further on ... I have been right in the past by saying maybe there are other ways things might happen. So I am entitled to think that I do not need to stick to received dogma 'throughlines'!!
Sure, everyone's entitled to speculation. But even if the case of B cells in those autoimmune diseases, there were hints of evidence in that direction before it was proven. You yourself said that the answer came in a previous paper from your group that you had not viewed in the correct light at the time.
I just simply don't see a comparable case here--and there is a difference between a theory simply challenging "dogma" and a theory that relies on multiple consecutive unevidenced leaps based on only the possibly of unobserved phenomena without any supporting positive indications from any similar context.
Like I've said before, I'd be happy to be proven wrong. I can only judge on what's available to me, and I don't think anyone on this forum is particularly inclined to take anyone's word on the basis of a track record, even from someone with as robust a track record as you.
(I also have some other information that is not generally available and that is partly why I am following this line of thought.)
I would be happy to make judgements when that evidence becomes available. If this happens to be a reference to HLA allele associations, I will note that HLA associations don't mean that T cells are causative in an illness. It could just as likely be an indication of increased susceptibility to certain infections which are more likely to trigger post-viral sequelae via a currently unknown HLA-independent mechanism.
Which may well be the case in narcolepsy too given the association with influenza A, or perhaps it is also the case in anklyosing spondylitis, or other contexts where specific antigens have yet to be identified--as you imply, we simply don't know for sure. The evidence for T cell involvement in narcolepsy is not any stronger than the specific evidence for T-cell recognition and damage of orexin neurons, so T cells may well be completely irrelevant.
As for ME/CFS, if you have anything more definitive than an HLA association, I'd be excited to see it.
