Antibodies and disease activity

A
Epub ahead of printDurante et al. Intrathecal synthesis of IgM measured after a first demyelinating event suggestive of multiple sclerosis is associated with subsequent MRI brain lesion accrual. Mult Scler. 2011 Sep 30.


Background: Previous studies have demonstrated that production of a type of antibody called IgM within the brain and spinal cord is observed in MS’ers and correlates with a worse disease course.


“Antibodies are specialised proteins produced by our immune system to fight infections; IgM is a very large protein and is usually the first antibody produced in response  to an infection or vaccine.”

There is also basic research that  suggest that IgM participates in the formation of MS lesions.

Objective: The aim of the present study was to assess the potential association between the level of spinal fluid IgM measured after a clinically isolated syndrome (CIS or first presentation of MS) and the subsequent formation of brain lesions. 

Methods: 57 MS’ers with a CIS and a high risk developing MS were enrolled in a longitudinal study. Examination of cerebrospinal fluid was performed after the CIS. MS’ers were assessed with MRI at baseline and after an average follow-up period of 49 months (range 36-60). 

Results: The level of IgM in the spinal fluid was correlated with the number of active or enhancing lesions at baseline and with accrual of brain lesions during the follow-up period. Interestingly, the level of IgG (a smaller antibody that is produced later during an immune response) did not correlate with MRI activity.

Conclusion: The present study demonstrates that the level of IgM synthesis within the brain and spinal cord measured after a CIS is associated with subsequent lesion accrual during the first years of MS. This result emphasizes the involvement of IgM in plaque formation.

“This study emphasises the need to provide some teaching posts on the immune system to make sure you are all up to speed on terms related immunology or the immune system.”

“This study supports previous studies that have shown that antibody production within the brain and spinal cord plays a role in the pathology of MS and drives disease activity. Other studies have linked this phenomenon to progressive disease and cortical or gray matter pathology. This is why it is important to develop drugs that target the cells in the brain that produce these antibodies. Unfortunately, to date none of the drugs we use in MS or ones in development have been shown to reduce the antibody production within the brain and spinal cord. This is why I have a nagging suspicion that the emerging drugs, including the more effective ones, may not necessarily prevent the development of progressive disease, but may slow it down. Let’s hope I am wrong.”


“This post tells us how little we really know about the mechanisms of disease progression. We have hypotheses or theories, but don’t know if they are correct. By doing clinical trials we will find the answers to these questions.”

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

16 comments

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  • Why is it that whenever a new drug gets near to being available e.g. Alemtuzumab, there are doubts as to whether it will address progressive disease? MS is always about dashed hopes in terms of treatments. If the issue is about anti-body production, why aren't drugs being developed / tested which stop the production of these anti-bodies? We really need some definitives with this disease – a detailed understanding of what triggers it and what drives it (especially the driver behind progression). I'm interested in Alemtuzumab for my active RRMS, but if I decide (have a choice) to go this route in the future, I'd really want to balance the risks with the benefits. If it doesn't have any impact on converting to progressive disease, then I'd probably think twice. This has to be one of the most frustrating diseases in terms of having no real answers to the most fundamental questions. EAE is a key reason for this (please don't go all defensive Dr Mouse).

  • Can I just ask, when LPs are performed during diagnosis, do they measure both IgG levels and IgM levels?

    Which of these does positive oligoclonal banding refer to? (if any)? Or am I getting confused?

  • Re: “This is why I have a nagging suspicion that the emerging drugs, including the more effective ones, may not prevent the development of progressive disease. Let's hope I am wrong."

    I hope you’re wrong too. I’m confused now because only a few days ago you said that you think both Fingolimod and Ocrelizumab have a better than average chance of effectively treating PPMS. Are these not emerging drugs?

    This post pretty much contradicts everything you’ve said about the role of aggressively treating MS with emerging drugs in a bid to stop progression. From what I understand by what you’ve just said, DMT and disease progression are separate things. One has no bearing on the other.

    This is a very bleak post and signals you and your team are literally fishing in the dark when it comes to dealing with progressive MS.

  • Arrrrrrrrrrgh!

    How bloody frustrating to read this post.

    Progressive MS is beyond hope! I feel like we've been lied to in terms of these drugs preventing MS progression.

  • The data show that the level of disease activity early-on has a bearing on future disability. Aggressive early treatment is therefore likely to have benefit.

    Will this stop progression?-unknown in humans but some of the answers are known in EAE (Even if it an artifical system and P.S. Mr/Ms Anon you are shooting the messenger-again!)

    Will DMT slow the rate of accumulation of disability?-probably, but the data is not there and it will only be the results of your response to therapy with the New DMT that will determine the answer (Again in EAE there is an answer)

    If you have been reading our recent posts (e.g. treating progressive MS)you will notice we have been saying that DMTS and treatment of progression are different things. However they may be inter-related at some stage!

    We are certainly not fishing in the dark when it comes to progression, but we have learnt that it is not a simple problem and solution….that is, until we learn how to treat it them it becomes simple.

    If there is immune activity in the brain and your drugs that aimed at stopping immune activty are not working, then there is a problem, you don't need EAE to tell you that.

  • The more that people respond to this post, the more I am confused.

    Your role is to simplify research, not make it more muddy.

    Emmerging treatments cannot stop progression, and yet ask anyone and stopping progression is what we need.

    Will Fingolimod improve progression or not? You all seemed to think it would but now it propably won't.

  • Gilenya has not been approved efficacious in the treatment of PPMS, though (‘FREEDOMS III’) trials continue.

    I’m no scientist, but progressive MS has less to do with the immune system and more to do with the actual nerve fibres in the CNS themselves. It seems obvious that treatments targeting the immune system will not work in treating the CNS because they are two entirely separate biological systems.

    What will be needed is a two-pronged approach, one for the immune system and one for the CNS. Therefore, progression is more of a CNS issue than an immune problem that can be shepherded via DMT.

    I agree, this post was somewhat confusing.

  • "“If we can
    show that drugs
    targeting RXRgamma
    and Axin 2
    can promote myelin
    repair in people
    with MS then we
    should be around
    10 or 15 years from a
    therapy” CAMBRIDGE CENTRE FOR MYELIN REPAIR Oct 2011

    Seriously, why even bother if it's going to take so long. I've lost my youth to MS and it sucks that I'll be too old, possibly even dead, to benefit from treatments to stop MS progression.

    Maybe you scientists don't feel the urgency, but we MS'ers most certainly do.

  • I'm confused too. Drugs like alemtuzumab may reboot the immune system and prevent lymphocytes from damaging the myelin. B cell lymphocytes produce antibodies. Is it that the antibodies also attack the myelin? When I was diagnosed investigations (in the blood I presume) showed CMV IgM negative, Rubella IgG positive ammongst other things- does this mean that different diseases produce IgG or IgM, that we've had to have had the disease or been exposed to it to have them, or are there lots circulating in the blood and CNS fluid anyway?

  • Re: "why aren't drugs being developed / tested which stop the production of these anti-bodies?"

    There are numerous posts on this blog about plasma cells and B cells being linked to gray matter and cortical pathology. These are the cells that produce antibodies within the brain and spinal cord. At present none of the MS treatments have been shown to clear the spinal fluid of these antibodies including the most aggressive therapies; i.e. bone marrow transplantation or alemtuzumab.

    Biogen-Idec was developing a therapy called Baminercept targeting the structures that support these cells. Unfortunately, the company pulled the plug on the drug before the trial was started. I will re-post that information for you.

  • Re: "Can I just ask, when LPs are performed during diagnosis, do they measure both IgG levels and IgM levels?"

    Yes, we tend only to measure the IgG levels which are sufficient for diagnosis. The test we do detects IgG bands called oligoclonal bands and in the correct context these are very specific for MS. However they do occur in other diseases, for example infections of the brain and other rare immune disorders.

    The IgM levels are currently only measured as part of research, but are relatively easy to measure as well.

  • Re: "Fingolimod and Ocrelizumab"

    At the moment we don't know what these drugs to immunoglobulin levels in the brain and spinal cord. I am not aware of any spinal fluid studies to date. However, spinal fluid studies have been done with Rituximab, that is closely related to ocrelizumab, and unfortunately it does not get rid of the oligoclonal IgG bands.

    At the moment the B-cell hypothesis, i.e. plasma cells, B cells, IgG and IgM being responsible for progressive disease is simply that a hypothesis and has it not been definitively established as the mechanism behind disease progression. In my opinion, it only one possible mechanism. We must lose sight of what we know for sure and what we don't know.

    We have to wait for the results of the Fingolimod and Ocrelizumab studies before making premature judgements.

  • Re: "This is a very bleak post and signals you and your team are literally fishing in the dark when it comes to dealing with progressive MS."

    We are not fishing in the dark. Every clinical trial is an experiment or should be an experiment. We have an hypothesis that inflammation plays a role in priming the nervous system for degeneration, i.e. progressive disease, if we can switch off the inflammation will be prevent, stop or slow down that process. The fingolimod and ocrelizumab trials in PPMS are testing this.

  • "RE: The IgM levels are currently only measured as part of research, but are relatively easy to measure as well."

    But as I understand from your post, higher IgM levels seem to indicate a possibility of more active MRIs following a first episode, whereas the levels of IgG don't seem to make a difference. If IgM levels are relative easy to measure and someone is going to go through the hassle of an LP in the first place, surely it would make sense to measure both levels? If a high IgM level is found, would it not make a case for early more aggressive treatment, as it would seem that IgM could be a predictor as to how progressive the disease course may be?

    I know there is currently no one indicator that can "predict" disease course, however, there seems to be all these little things that could point towards some sort of projection. Why are we not putting them altogether/using them at the time of diagnosis to allow for more informed therapy decisions?

    Sorry, I may be viewing things rather simplistically or have got completely the wrong end of the stick!

  • Re: "I know there is currently no one indicator that can "predict" disease course, however, there seems to be all these little things that could point towards some sort of projection. Why are we not putting them altogether/using them at the time of diagnosis to allow for more informed therapy decisions?"

    I agree with you completely. However the published studies to date are very small and need to be confirmed. In addition the laboratory assays used in the different studies need to be validated. This is often the problem in moving these discoveries into the clinic.

    We are trying. We started and organisation called Biomarkers in MS to improve the quality of biomarker studies and to help translate them asap.

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