“I have been saying for some time now that what differentiates the big boys from the small boys in terms of DMT efficacy is an impact on B cell biology. I have done a matrix of all the disease-modifying therapies and what is common to all the highly-effective therapies is an impact on B cells. The study below shows that fingolimod also has a profound effect on B cell biology; it reduces B cell numbers in the periphery in particular activated B cells. It did not have an impact on plasmablasts. What is so important about B cells that is different to plasmablasts? Plasmablasts are a later down the development pathway of B cells. B cells are responsible for antigen presentation and a host of other roles. B cells are also the cell in which EBV shacks-up. Could the common-denominator be via EBV? Now this is an experiment I have being trying to get done for the best part of a decade.”
Epub: Nakamura et al. Differential effects of fingolimod on B-cell populations in multiple sclerosis. Mult Scler. 2014 Feb.
BACKGROUND: Fingolimod is an oral drug approved for multiple sclerosis (MS) with an ability to trap central memory T cells in secondary lymphoid tissues; however, its variable effectiveness in individual MSers indicates the need to evaluate its effects on other lymphoid cells.
OBJECTIVE: To clarify the effects of fingolimod on B-cell populations in MSers.
METHODS: We analysed blood samples from 9 fingolimod-treated and 19 control MSers by flow cytometry, to determine the frequencies and activation states of naive B cells, memory B cells, and plasmablasts (antibody producing).
RESULTS: The frequencies of each B-cell population in peripheral blood mononuclear cells (PBMC) were greatly reduced 2 weeks after starting fingolimod treatment. Detailed analysis revealed a significant reduction in activated memory B cells, particularly those expressing Ki-67, a marker of cell proliferation. Also, we noted an increased proportion of activated plasmablasts (CD138+) among whole plasmablasts, in the MSers treated with fingolimod.
CONCLUSIONS: The marked reduction of Ki-67+ memory B cells may be directly linked with the effectiveness of fingolimod in treating MS. In contrast, the relative resistance of CD138+ plasmablasts to fingolimod may be of relevance for understanding the differential effectiveness of fingolimod in individual MSers.
I can see a scenario (results of the current B cell depleting trials, further work by Prof Pender on targeting EBV, perhaps hints from the Charcot project) where there will be a lightbulb moment where it becomes obvious that EBV infected B cells and the response to them of the immune cells of genetically predisposed individuals underpins MS. As Prof Pender hinted – this disease could be pretty simple. If so, it's a tragedy that it took 50+ years to get to this point. The focus on EAE has been a disaster in terms of getting to grips with this disease. Perhaps the thousands of MS researchers who wasted so much time on models of the disease which bore resemblance to the real disease can redeem themselves by identifying repair treatments for those with deficits. If it comes to pass that the solution to this disease was depleting B cells or using antivirals, you really have to ask why it took so long to get to this point.
As the EAE model is vital to develop repair and neuroprotective therapies, you shouldn't be too hasty in dismissing it out of hand. 😉
It is possible that B-cells play a role in progression, especially in the CNS. However, people at the forefront of HSCT transplants which are very, very highly effective at halting disease activity are finding a change in the T cell repetoire after HSCT. Those that failed treatment had less T cell diversity post HSCT than those who were successful.http://www.jci.org/articles/view/71691
Yes but that paper looked at T cell diversity and not B cell function. That too will have taken a hit. Maybe in another study they will be looking at antibody (B cell receptor) diversity, but thats for tomorrows post
I agree. But just wiping out B cells (and possibly EBV) will not guarantee that you won't be re-infected by EBV. So, if MS is caused by EBV as has been proposed by this site, what prevents you from acquiring MS again once you re-acquire the EBV after treatment (which is highly likely)?I prefer the HSCT researcher's proposal that a new T cell repeioire is responsible for efficacy in these types of treatment.
Yes getting rid of the old rertoire seems to do the the trick. It is interesting thatthe CD4 t cell repetoir looks different but some of the CD8s return. This may because infections drive the return of certain immune responses that are necessary or anti-viral responsesand