It was shown many years ago that expansion and activation of T cells is the critical part in this process, which allows T cells to circulate round the blood and then enter the tissues. This enter of cells into the brain, is the important process that determines whether disease will develop of not. In normal animals this expansion and maturation of such damaging T cells has not happened. However in the genetically engineered mice they are full of such cells, waiting for a stimulus such as a bacterial protein, to trigger them into activation. This stimulus could be part of our normal gut flora. Therefore, in the scenario it is obvious that the immune system, rather than the nervous system, is the problem and may be more akin to triggering further disease episodes, where the immune system has been activated, rather than starting disease from scratch.
In this new report, they suggest that the T cells help generate myelin-acting B cells, the white blood cells that produce antibodies and that together they conspire to work in a co-ordinated fashion to trigger disease, as has been shown before in this, and other models. This new study elegantly shows this sequence of events.
However, there are other studies that demonstrate that disease in mice can develop in the complete absence of B cells, in contrast to the new report, so this pathway is not necessarily the only route to generate lesions that could occur in MS. As such there are other alternative hypothesises such as via immunity triggered by molecular mimicry, response to heat shock responses or that is secondary to a primary damaging event or that MS is not autoimmune (but response to therapy tells us at least some elements of MS are due to the immune response).
It is being suggested that MS is just an "Outside-In" Disease (Autoimmunity entering and attacking the brain) rather than the Inside-Out (Brain problem leading to development of (auto)immunity) as suggested by some people actually looking at MS, rather than animal models that we know are outside-In diseases. However, we know that elements of MS don't not respond to immunosuppression, so in my view we still need to keep an open mind about "driving forces"
Modification of immune responsiveness by our internal and external environments appears to be sensible and this study adds to the jigsaw. Spare a thought for the scientist hunting through the stools (now that's a shit job) to find the trigger, but let's find it/them before we have a new dietary regime.
Currently it appears that B cells contribute to the damage in MS by producing damaging antibodies, but perhaps more importantly they can also act a antigen presenting cells to stimulate the damaging immune response. Thus inhibition of this function would be beneficial in relapsing MS, as has been shown with ocrelizumab and rituximab, which are anti CD20 B cell depleting antibodies
However, there is also data that B cells can be bad and B cells can be good and importantly the gut flora can influence the development of regulatory B cells responses that control autoimmunity. Therefore, the situation is going to be complex, and the inhibition of their function can make autoimmunity worse as well as better.
This can happen in MS and it is clear that inhibiting every B cell target is not always beneficial in MS, so over to Prof G to describe Atacicept activity and worsening of MS from ECTRIMS News 2011.