More B cell stuff. Don’t deal with the B cells…Don’t deal with disease?

M

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:-(

T

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MouseDoctor

21 comments

  • So in light of this what do you think this means in your opinion for hsct, alemtuzumab both of which do reconstitute the immune system to different degrees and cladribine which does get in the CNS?

    • We don’t know if cladribine penetration into the CNS is sufficient to have an impact on the cells within the CNS. This is being studied at present.

        • Horse for courses, each agent has advantages but they also have disadvantages and so serious disadvantages in some people

  • “(5). It is well known that oligoclonal bands persist with **all current MS treatments**, accepted that there is some debate around natalizumab,”

    Hey, what about Cladribine? And if your theory about how Cladribine is correct, this means that Clad will gradually get rid of OCBs in a large proportion of patients via tolerance reconstitution.

    • In science, nothing becomes a fact until it is confirmed at least once. This is why we try and deal with true facts. Similarly, the claim from Canada that aout of third of HSCT treated patients lose their OCBs needs to be published and confirmed.

      • True- But as this is important (unconfirmed) effect of just some DMTs (and as such can heavily influence the choice of a particular DMT, e.g. HSCT or Cladribine), you and other centers that had already(!) collected large serial samples of CSFs could confirm/reject this quite quickly. As being an observational study this is less work than a new trial (which is obviously needed too, but it will take years).

        • in a study from Poland OCB went in half the people on cladribine, but this was after a number of years. If you read the review on cladribine, you will see that I am not sure that the antibody producing cells will be targeted. As you say we have the CSF to address some of these issues, but because of ethics it is not something you can do straight away. You need the permissions

  • Great post MD, thanks.

    Is there a treatment out there for treatment of CNS lymphoma, myeloma or a leukaemia that penetrates CNS? Wouldn’t that be your answer if you are correct? Cyclophosphamide crosses the BBB into CNS and is this why HSCT is so effective?

    I do not think any current DMTs, including cladribine, are the answer for eliminating the oligoclonal banding or B-cell activity otherwise they would have better outcomes on both relapses and progression of disease shown currently..

    These non specific oligoclonal bands are present in a plethora of other CNS disease. How close do these non-specific oligoclonal band elimination correlate with disease progression in MS?

    • Is there a treatment out there for treatment of CNS lymphoma, myeloma or a leukaemia that penetrates CNS?

      Good question…ProfG and NDG are just about start such a study

    • Cyclophosphamide crosses the BBB into CNS and is this why HSCT is so effective?

      HSCT is so effective because of the degree of immune depletion. CY may get into the CNS, but it only kills proliferating cells and cells do not have to proliferate to be a problem.

      Did you know that CY is not the active ingredient.

    • What do you mean? You’re saying that getting rid of OCBs has no effect on progression? How do you know that?
      What we need to be careful is how quickly we jump to conclusions: getting rid of OCBs is a long process (takes years), and like so for progression. So if you gradually get rid of OCBs, you could see the effect on progression only after a certain amount of time, not immediately.
      But what we do know is that there is no MS without OCBs. Maybe we can interpret this as: no OCBs, no inflammation? And if you do that early enough, maybe that means also no progression, aka the cure.
      That theory is especially valid for example if Cladribine really gets rid Of OCBs (needs to be validated in the second observational trial) and then really introduces tolerance back into CNS (DrK and MouseD’s theory how Clad works). Again, you need to do that early enough to stop the shredder.

  • Can you comment on this?

    RESULTS: MS patients had significantly higher anti-EBV nuclear antigen-1 (EBNA-1) titer when compared to HCs (107.9 U/mL vs 27.8 U/mL, p < 0.001). Within the MS group, higher serum anti-EBNA-1 titer was significantly correlated with lower T1-LV MTR ( r = -0.287, p = 0.035). Within the RRMS group, higher serum anti-EBNA-1 titer was associated with T1-LV MTR ( r = -0.524, p = 0.001) and NAGM MTR ( r = -0.308, p = 0.043). These associations were not present in HCs or SPMS patients.

    "These associations were not present in HCs or SPMS patients."

    Higher EBV response is associated with more severe gray matter and lesion pathology in relapsing multiple sclerosis patients: A case-controlled magnetization transfer ratio study.
    https://www.ncbi.nlm.nih.gov/pubmed/30755085?dopt=Abstract&fbclid=IwAR0KqyqUndjewA42kyq7-U1XD09toRV2rxM_910M_Fz1umh5-ZOtsF9_Wng

    Is the approach of targeting EBV in PMS the right approach?
    Or is it that those potentially pathogenic Plasma cells are not associated straight to EBV?

  • Question: What are, in your view, the most promising contenders for combination therapy to deal with atrophy / progression? Is the problem that some contenders aren’t financially viable for companies to test?

    Since it seems you all have been thinking about how to make the blogging more efficient, maybe it would help both the readers and you if you wrote some “state of the research” posts that sum up where things are in the pipeline. It would to read debates among you all or with other guest contributors.

    Those of us with non-“active” PPMS don’t have time to waste, and although I realize doctors don’t like it, I think many of us will do whatever we can based on our best and hopefully well-informed assessment of risks/rewards.

    For ex.,
    – lipoic acid studies are impressive
    – mitochondrial “support” seems helpful
    – biotin? – what else seems promising?
    – fasting studies seem all upside (no cancer risk at least)
    – optimize diet in general
    – avoid sedentary behavior

    ** This last one is harder because with PPMS the fatigue from walking a few blocks wipes me out for over 12 hours. To get through daily tasks I am constantly engaging in energy conservation planning. Adding more movement on top of that seems . . . difficult. I’m willing to try Compex and other devices to help avoid deconditioning. I have to admit I find it frustrating to read on this blog admonishments about this when it is so difficult to do basic tasks to get through the day.

    • I second that.

      Some ‘State of the Nation’ pieces, perhaps split into three dealing with current therapies, new arrivals and the research pipeline with roughly predicted arrival points for trial conclusion, licence approval and the ever joyful NICE.

      There are many lay people who appreciate a simpler synopsis of the current state of play and direction of travel.

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