At ECTRIMS last week, there were a few Docs talking about digging in Pooh, looking for the Gold (Gut Flora) that teaches Us about the Trigger of MS, others were adding parasites to influence disease.
Now in a Top Science Mag, scientitists bring us the new idea (or is it?) about the role of Gut Flora (Nothing to do with Margarine, but the bacteria that live in the Gut) and the development in MS. Story hitting the News stands near you!
Active multiple sclerosis lesions show inflammatory changes suggestive of a combined attack by T and B lymphocytes against brain white matter. These pathogenic immune cells derive from progenitors that are normal, innocuous components of the healthy immune repertoire but become autoaggressive upon pathological activation. The stimuli triggering this autoimmune conversion have been commonly attributed to environmental factors, in particular microbial infection. However, using the relapsing-remitting mouse model of spontaneously developing experimental autoimmune encephalomyelitis, here we show that the commensal gut flora-in the absence of pathogenic agents-is essential in triggering immune processes, leading to a relapsing-remitting autoimmune disease driven by myelin-reactive white blood cells. We show further that recruitment and activation of autoantibody-producing B cells from the endogenous immune repertoire depends on availability of the target autoantigen and commensal microbiota. Our observations identify a sequence of events triggering organ-specific autoimmune disease and these processes may offer novel therapeutic targets”.
They say “Thus, the disease is caused by changes in the immune system and not by disturbances in the functioning of the nervous system. “Multiple sclerosis research has long been preoccupied with this question of cause and effect. Our findings would suggest that the immune system is the driving force here,” says Hartmut Wekerle, Director at the Max Planck Institute in Martinsried.
“The scientists are certain that the intestinal flora can also trigger an overreaction of the immune system against the myelin layer in persons with a genetic predisposition for multiple sclerosis. Therefore, nutrition may play a central role in the disease, as diet largely determines the bacteria that colonise the intestines. “Changing eating habits could explain, for example, why the incidence of multiple sclerosis has increased in Asian countries in recent years,” explains Hartmut Wekerle.
Precisely which bacteria are involved in the emergence of multiple sclerosis remains unclear. Possible candidates are clostridiums, which can have direct contact with the intestinal wall. They are also a natural component of healthy intestinal flora but could possibly activate the T cells in persons with a genetic predisposition. The scientists would now like to analyse the entire microbial genome of patients with multiple sclerosis and thereby identify the differences in the intestinal flora of healthy people and multiple sclerosis patients.
(The Guys in Boston are already doing this.. so the race is on!)
We all know that we are what we eat, but before we become antibiotic junkies, the Scots dump the Haggis, we all start to eat ManFood (MS is increasing in Women) and South African (Has low incidence of MS, Genetics of the Brits) let’s look at the story.
When you make mice, whose white blood cells are all made to react to the brain, then you have a time bomb waiting to explode and cause disease. This happens once enough white blood cells, namely T cells, are triggered to circulate around the blood stream looking for their target (prey). Once they enter the brain, they trigger the attack the brain cells. It has been known for years that the level of cleaniness of animals, which represents the number of infections/bacteria/viruses they harbour, will influence this. In some cases of autoimmunity, this is inhibitory but in the case of the type of mouse model used in the new study, the more bacteria the more rapidly the disease occurs. The gut has often been a site for problems in mice have genetically engineered immune systems.
In this new study the wheel was re-invented or perhaps refined, using new tools to track events, and the finger is now pointed firmly at gut flora as a trigger for autoimmunity. It was shown that germ-free mice do not develop spontaneous disease compared to mice with a normal gut flora. Such disease returned when the gut flora was re-colonised, where they activated the T cells (white blood cells).
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.