Dear Woolie,
There was a lot of discussion about plausible mechanisms, under the more general heading of ME possibly being autoimmune, in other threads maybe a year or so ago. But it is interesting to revisit this specifically in the EBV context since EBV is so unusual in its relation to B cells.
@Jonathan Edwards
The series of studies I recently read (not just Hadinoto, the others above too), suggest there may also be differences in EBV dynamics. So T cell crossreactivity, sure, but perhaps also a less effective response against EBV overall.
I was not aware that anybody had implicated T cell cross reactivity in the genesis of mono symptoms. It sounds highly implausible to me. The real difficulty here is that, unlike you Woolie, most immunologists really are sheep. They keep following each others' ideas round and round and generally can only cope with ideas that are 50 years old. My understanding is that autoreactive T cells have never been substantiated in any autoimmune or other process except for a few oddities like the AIRE thymic genetic defect and perhaps type 1 diabetes. And even where there is autoreactivity reliable evidence for cross reactivity with a foreign antigen is as far as I know not there. T cell autoreactivity due to cross reactivity never made any epidemiological sense. It was just an idea dreamt up by the early T cell enthusiasts who didn't actually know anything about patients in clinics much. If it has reared its head in EBV talk I am not surprised but hopefully it sounds as if the sheep have decided to follow something else!
@Jonathan EdwardsNone of this is about MECFS directly, its about mono and EBV. But many people here who got sick after severe mono
want to know why. Just saying "your immune system overreacted and is still doing so" doesn't, for many, add up to a full explanation of why they continue to be so sick when prior to mono they were perfectly healthy. The other story, "you were probably immunologically abnormal to start with, you just didn't know it till you got the mono" seems also problematic (again prior good health in many), and more importantly, difficult to falsify.
What's needed is a full explanation of the mechanism which transformed these folks from healthy to chronically sick people during the course of fighting a single, very common infection. If you have one yourself, then I think people would really welcome it, because what's out there just doesn't add up.
This is what was discussed on the threads dealing with autoimmunity. As you say 'overreacting and still doing so' is not a theory and although genetic factors are important they are only part of the answer. The main barrier to understanding is I think the repetition of the idea that causation is just genetic and environmental. If you ask an epidemiologist she will add
internal stochastic to that. When Stastny provided the first evidence for genetic risk in autoimmunity he emphasised that the epidemiology indicated a major stochastic component. The same applies to ME - who gets it seems to be to a large extent random (stochastic).
That might seem strange until you realise that a random internal event followed by a perpetuating process is entirely reasonable as a basis for immune diseases. It is of course the main mechanism in cancer - a random mutation leads to a failure of control of cell growth. The immune response is interesting in that it is the one system in the body that uses a random internal mutation followed by a change in regulatory signals to do its daily work. All antibodies are initially generated at random and are produced in significant amounts if they engage a new positive feedback loop.
So the suggestion I have made previously is that there are probably several forms of ME but maybe most of them involve some random event in the immune system or maybe in the central nervous system (which also makes use of random allocations) that might be made more likely to occur during the 'cytokine storm' of a severe mono infection, which sets up a positive feedback loop either in antibody production or again maybe within neural circuits. There is probably also a T cell version, which is the chronic fatigue that comes with Reiter's syndrome, in which there seems to be a persistent shift in T cell behaviour, although there is no suggestion of autoreactivity or cross reactivity.
So when we decided to do the experiment of giving people with RA rituximab, much to the horror of most of our colleagues who believed in autoreactive T cells, we based that decision on a theory of RA with a stochastic origin based on autoantibody genesis, followed by feedback loop. The results actually turned out to be closer to what that would predict than we even expected. It looks as if the Norwegian results might point to an analogous mechanism, although probably only for some cases and it does not necessarily imply autoantibody.
To my mind the other main contender for ME would be some form of loop set up within the brain itself, not perpetuated through immune signals - rather as the Dubbo authors tend to suggest. I find this less convincing and less interesting but it may be part of the story. Moreover, even if the loop is brain based continued input from antibody mediated signals might have an effect in the long term so the two ideas may overlap.
So that's my various theories. WIthin this context EBV has the unique potential to lower the threshold for B cell mediated problems because it permanently alters survival signals for B cells. And since everyone gets it it may have an important 'permissive' role. From here on there are complexities relating to immunoglobulin Vh genes and all sorts but we need more hard data on the EBV/ME epidemiology link before I think a major investment should be put into looking for a causal connection.