(CLICK FOR FULL STORY).
Although multiple sclerosis (MS) is considered to be a CD4,Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the perceived failure of CD4-depleting antibodies to control relapsing MS. Therefore it was of interest to find that current MS-treatments, believed to act via T cell inhibition including: beta-interferons, glatiramer acetate, cytostatic agents, dimethyl fumarate, fingolimod, cladribine, daclizumab, rituximab/ ocrelizumab physically, or functionally in the case of natalizumab, also depleted CD19+,CD27+ memory B cells. This depletion was substantial and long-term following CD52 and CD20-depletion, and both also induced long-term inhibition of MS with few treatment cycles, indicating induction-therapy activity. Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS. This creates a unifying concept centered on memory B cells that is consistent with therapeutic, histopathological and etiological aspects of MS.
- Memory B cells express CD19+, CD27+ and CD21, CD20, CD25, CD49d, CD52, S1P1, and have higher endogenous proliferative background than T cells.
- Memory B cells express CD21, which is the EBV receptor
- Memory B cells are elevated in MS and accumulate in the CNS in MS
- Memory B cells are depleted or functionally silenced by all treatments of MS.
- Memory B cell depletion potential correlates with drug efficacy
- Memory B cell augmentation is associated with MS worsening
- Memory B cell-tailored therapy may allow personalised and safer induction treatment
So do alemtuzumab, rituximab/ocrelizumab, daclizumab and natalizumab have anything in common?
Some publishers wanted too much money for us to include every example for every treatment in the publication. But we give some references if you want to look and the paper is “open source”.
So this was revelation part one. The next one has additional implications.
The data can be interpreted to suggest that ocrelizumab and alemtuzumab could work in the same way (bad news for both companies, sorry).
They are probably “both” induction therapies of PIRT (pulsed immune reconsitution therapies)
One wonders why such important data has not been properly published? It was dumped in an ECTRIMS abstract in 2012 and an AAN abstract in 2013 (where we found them. Do neurologists have enough time in a couple of hours to see and digest a 1000 posters?) and so there is no excuse from the companies or authors that they have not had enough time to publish the work. There are enough journals desperate for papers.
In some treatments there are some indivudals that make more memory B cells and treatments that do this have in some cases been associated with MS worsening
In many cases both unswitched (Have not change the antibody subtype they can produce) and switched (IgM and IgD are down regulated and IgG is upregulated from the unswtichted to switched) memory B cells are affected. Which subset is the critical one, the one that has already been reported to be increased in MS.
Is the data that suggests a T cell action solid or is it simply circumstantial. Have a read of the paper for your self it is open access (CLICK to DOWNLOAD).