Sunday, 4 January 2015

What is MS? clues in paediatric MS

Quintana FJ et al. Epitope spreading as an early pathogenic event in paediatric multiple sclerosis. Neurology December, 2014 vol. 83 2219-2226

Objectives: For most adults with initial clinical presentation of multiple sclerosis (MS), biological disease was likely initiated many years prior. Paediatric-onset MS provides an opportunity to study early disease processes.
Methods: Using antigen microarrays, including CNS-related proteins, lipids, and other autoantigens, we studied early immunologic events involved in clinical onset of paediatric MS. Serum samples were collected at the time of incident acquired CNS demyelinating syndromes (ADS) in children who, in subsequent prospective follow-up, were ascertained to have either pediatric MS (ADS-MS) or a monophasic illness (ADS-mono). Samples were obtained both at the time of ADS presentation and 3 months into follow-up. We used an initial training set of samples to implicate antibody signatures associated with each group, and then a test set. An additional set of follow-up samples (stability set) was used as a form of internal validation.
Results: Children with ADS-MS tended to have distinguishable serum antibody patterns both at the time of ADS presentation and 3 months into follow-up. At the time of ADS, serum samples from patients with ADS-MS or ADS-mono reacted against similar numbers of CNS antigens, although CNS antigens implicated in adult MS were more often targeted in children with ADS-MS. The follow-up ADS-MS samples reacted against a broader panel of CNS antigens, while corresponding ADS-mono samples exhibited a contraction of the initial antibody response.
Conclusions: Our findings in this prospective cohort of paediatric-onset CNS demyelinating diseases point to an active process of epitope spreading during early stages of MS, not seen in monophasic CNS inflammatory conditions.

Heat map (red meaning high IgG antibody reactivity) of antigens to which antibodies are detected in monophasic inflammatory attack (MONO) and MS at baseline and at follow up

Comparing monophasic inflammatory episode seen in children to those who go onto develop MS (or relapsing-remitting disease) can hold the clue to discovering what in fact leads to MS; irrespective of whether it is childhood or adult MS. A looking glass into early MS is the key here, unhampered by the dilution of factors which have occurred by the time a person becomes an adult.

The authors looked specifically at the immunologic/immune system which takes place between the monophasic presentation and the established MS. They looked at two time points, first presentation of the event and at three month follow up. What they found, was an expansion of the initial antibody response to CNS antigens; a concept called epitope spreading in the scientific communities. In their heat map (see diagram) they also address possible culprits, and the usual suspects are there (PLP, MOG, MBP) and some interesting ones (Helicobacter pylori, CNPase, ssDNA,).

What you may  ask is the utility of this research? 

This is very simple, develop treatments targeted at boosting immunoregulatory mechanisms (targets the entire autoantibody response) or control the effector T cells at an antigen-specific level (e.g. targeting MOG, PLP, MBP, H. pylori, CNPase, ssDNA) using vaccines. And there you have it, the cure for MS - or is it...


  1. Do you think this represents the end-point for epitope spreading or does it continue to spread further over the course of the disease?

    Could this be related to why some treatments work better earlier in the course of the disease, but are less effective later (when the autoreactive epitope has spread too far?)

    1. Spreading enlarges further with time i suspect.

      Wny do immune treatments work less well with time... Nothing to do with epitope spread i suspect but it would mean more self reactive cells deal with. I personally think that in progressive ms there is a fundementally different mechanisms to deal with. Intravenous MBP failed in progressive MS because it was never going to work for multiple reasons and the studies were in my opinion doomed before they started and i said so before the trials started.

  2. It seems the rest of the world acknowledges that epitope spreading is real. Team G has bashed this concept on repeated occasions and have promoted concepts such as EBV being the direct cause of MS. This is just more evidence of how backward Team G is in the mainstream MS scientific community.

  3. Whilst I am sure we have probably spoken on this issue in the past.....and maybe in the future

    To make it very clear you are mistaken....we acknowledge that epitope spread is a phenomenon that occurs in CNS autoimmunity and have shown it ourselves.

    However the problem with the concept is that some people believe that this occurs in a co-ordinated and obligate sequence for relapsing disease to occur. This means that in response to immune attack on one antigen, there is sensitization to another antigen and this causes the next attack and then the next antigen and the next attack and so on and so on.

    I am happy to be backward but I do not believe that this it is required to be obligate nor does it have to occur in a co-ordinated sequence.
    There are many examples of this in the literature.

    As to concepts of EBV being involved in the development of MS there are a few mavericks out there:-)

    However your troll comment was in response to the question, Do you think epitope spread is why immunotherapy does not work very well in progressive MS?...... I guess you are from the yes school. That is your opinion and i respect that.

    However, I am happy to be backward to think it is not all about peripheral T cells in progressive MS and I believe it is not all about peripheral T cells in progressive EAE.

    Many of our colleagues (maybe the mainstream) do not agree and this is why we see an endless stream of trials of peripheral immunosuppressive agents in primary/secondary progressive MS. Maybe they will be proved right and their trials will work.

    I will be happy and modify my world view...but at present history of the reality of these trials may suggest a different world view is needed:-)

  4. Please could an explanation be given on what is meant by "peripheral immunosuppressive" versus whatever it's opposite is..........

    1. in terms of inflammation and other things there is "peripheral" and "central". Central means inside the CNS which is the brain and spinal cord (and eye) whereas "peripheral" is outside of the CNS such as the peripheral nervous system or the peripheral blood (which is the blood system. The blood in the brain blood vessels is still outside of the brain).

      Current DMT work by blocking the immune response in the periphery. Gilenya works in the lymph gland and tysabri blocks white blood cells in the blood to stop them getting into the brain. Immunosuppressive drugs (which suppress (block) the immune system act on cells within the periphery to stop them entering the brain to stop relapses.

      The question is what is the extra value of having centrally active immunosuppression, to suppress the immune responses within the brain. Will this be enough and progressive MS will be blocked or do we need something else?


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