Longitudinally persistent cerebrospinal fluid B-cells can resist treatment in multiple sclerosis.Greenfield AL, Dandekar R, Ramesh A, Eggers EL, Wu H, Laurent S, Harkin W, Pierson NS, Weber MS, Henry RG, Bischof A, Cree BA, Hauser SL, Wilson MR, von Büdingen HC. JCI Insight. 2019 Feb 12. pii: 126599. doi: 10.1172/jci.insight.126599. [Epub ahead of print]
B-cells are key contributors to chronic autoimmune pathology in multiple sclerosis (MS). Clonally related B-cells exist in the cerebrospinal fluid (CSF), meninges, and central nervous system (CNS) parenchyma of MS patients. We sought to investigate the presence of clonally related B-cells over time by performing immunoglobulin heavy chain variable region repertoire sequencing on B-cells from longitudinally collected blood and CSF samples of MS patients (n=10). All patients were untreated at the time of the initial sampling; the majority (n=7) were treated with immune modulating therapies 1.2 (+/-0.3 SD) years later during the second sampling. We found clonal persistence of B-cells in the CSF of five patients; these B-cells were frequently immunoglobulin (Ig) class-switched and CD27+. We identified specific blood B-cell subsets that appear to provide input into CNS repertoires over time. We demonstrate complex patterns of clonal B-cell persistence in CSF and blood, even in patients on immune modulating therapy. Our findings support the concept that peripheral B-cell activation and CNS-compartmentalized immune mechanisms can in part be therapy-resistant.
Scientists are frightened of speculation and this is a good example where doing the the experiment says I told you so.
This study looks at the genes expressed by the target antigen receptor in B cells and concludes that some of them came from the blood. They may create antibody producing cells
I guess this is a No s**t sherlock (NSS) moment. Where do we think they come from if immune modulating drugs that do not get in the brain and stop cells arriving in the CNS work in MS?
Some hung around for some time..again NSS. Immunity is to give you life-long protection from infection so once you form protective (or damaging cells in the case of MS), you must expect them to linger.
Now to the conclusions these B cell repertoires (ie. the things that the B cells respond to) can resist treatment…I say NSS but the treatments are ineffective, so why would you expect the cells to go?
Study reports on the immunoglobulin of serially sampled B cells from the CNS (Cerebrospinal fluid) and the peripheral blood and conclude that there are persistent B cell clones.
Although of interest this observation is hardly surprising because:
(1) It is well known that the treatments taken by the individuals are not cures. The drugs are continuously used and are not immune-reconstitution therapies. It is clear that disease can continue to be progressive despite treatments that inhibit relapses.
However, this is even more to be expected because
(2) it seems that treatments are not sufficiently effective as 7/8 patients on treatment have new MRI lesions and of the people with persistent clusters, it seems that none have the status of being no edivence of disease activity
(3) The treatments are mainly low/moderate efficacy (fingolimod, dimethyl fumarate and interferon) consistent with disease activity seen.
(4) The highly-effective treatment (natalizumab) has not effectively worked as there has been relapse and importantly natalizumab and fingolimod are migration inhibition drugs and not depletion agents. Rebound disease activity rapidly occurs following cessation of treatment, therefore it would be surprising if persistent clones were not seen and importantly
(5). It is well known that oligoclonal bands persist with all current MS treatments, accepted that there is some debate around natalizumab, perhaps in part because the agents do not penetrate and act within the CNS, e.g. as less than 0.1% of rituximab or other antibodies and proteins will enter the CNS and rituximab and ocrelizumab do not target plasma cells as they do not express CD20.
However they apply a newer technology to the question and supports what I think (speculate), so I’m happy.
They say “Our findings raise the possibility that drugs which effectively reduce clinical and MRI relapses may not sufficiently target CNS compartmentalized immune mechanisms that have been associated with gradual and relapse-independent MS worsening in relapsing MS and progressive forms of the disease”.
Again NSS. Is the penny dropping? (I’ve added links so you can understand my English slang). By the speed of progress it must have originally been a groat that started to drop. We have been saying this for years and years and year and I am now a very blue faced mouse (This is what speculation-averse science gives you ..snail-paced progress), but means that maybe people will start taking this view seriously (but don’t hold your breathe) and think that you need more than just the current Disease modifying drugs to tackle progression. I am still waiting to see combination studies
No wonder you tear your hair out. I’m trying…… but if people won’t listen..more frustration:-(