Dr. I would be interested in your feeback? Would this make a possible challenge for you, to took outside the box.? Who knows, maybe chronic illensses and diseases are connected in someway.Eco
This is really fascinating, Ecolimber. I looked at the abstracts and will download the full papers later. What I am thinking is that this is telling us that things are connected in some ways, but not all ways. One aspect of the 'way of modelling' that Dr Jo Cambridge and I have found useful is the idea that autoimmune diseases are loops based on random events but that for every autoantigen (self protein) the loop will behave in a slightly different way. Coeliac disease is already an instance where an environmental trigger does seem to creep in (gliadin) but the randomness should still come in with the antibody to transglutaminase arising in only a few people. Multiple sclerosis is again a bit 'outside of our outside box' because its epidemiology suggests an environmental factor. Hugh Willison has shown that post-infective polyneuropathy or Guillain Barre syndrome may after all fit the 'molecular mimicry' idea that we think is overrated in other situations. The association between narcolepsy and DR1 has been around for decades but I had not realised just how useful narcolepsy could be as a pointer to new variants on how loops might form.
The Mignot review is very helpful. It seems that there are other susceptibility genes related to T cell function so this confirms that immune signalling is almost certainly involved. The DR1 association pointed to that but for years nobody could quite believe the implications. Also the occurrence of narcolepsy in children after flu jabs looks very hard data. The time course of development over a year but not more is also very interesting. That could be the time course of a short lived plasma cell response. There is also the fact that most people with DR1 do not get narcolepsy so there is still a random factor involved. Finally, he admits that no autoantibodies or T cell responses to hypocretin have been found. That to me confirms the suspicion that molecular mimicry is too simple a theory. Something more subtle is going on, just as coeliac is a bit more subtle.
But the idea that is forming in my head now is that all these illnesses that seem to be a bit outside our outside box are neurological. Maybe the old theory of 'hidden antigens' in the brain is nearly right, although the original version has proved to be dubious. (A lot of antigens that might seem to be hidden are made available on the surface of blood vessel cells.) One of the ideas we had about MS was that if the brain is designed to work free of lymphocytes, very particular problems may arise if lymphocytes do manage to work their way in there.
So I am starting to think that ME might be a cluster of these neurological illnesses that are sort of in the autoimmune box, but like other neurological problems may be half out of the outside box. Some ME seems to have a trigger episode so it might work like narcolepsy. But what makes me rather optimistic is not only that the Norwegian study seems to show improvement with removal of B cells but the improvement may drop off when B cells come back and reappear with further treatment. This might not sound so good but to me the key point is that it suggests that at least a good proportion of ME is dependent on continual renewal of plasma cells and antibodies, not just a single post-trigger episode of short lived plasma cells. Paradoxically, that to me makes it more likely that ME can be treated succesfully. The problem with some post-infective neurological problems is that the damage may be done in the first few weeks and after that it makes no difference whether you alter antibodies or not. What is also encouraging about ME is that there as rarely any evidence of structural damage. In narcolepsy it is known that cells disappear. Narcolepsy may still be treatable by replacing the signalling molecules but if the cells have gone it seems likely that replacement would need to continue. In contrast, Fluge and Mella seem to have shown that in some cases of ME/CFS removing B cells can lead to continued remission without regular treatment.
Maybe another way of putting it is that the narcolepsy story is showing just how subtle and unexpected these mechanisms can be and that if narcolepsy can work this way there is every reason to think ME might work in a similar but slightly different way, or maybe more likely several ways with a similar outcome. We need to get rid of the old one size fits all genetic/environmental mimicry model and tease out the subtleties.
