Wednesday, 8 February 2017

Childhood MS shows us that Memory B cells are Important in MS

Schwarz A, Balint B, Korporal-Kuhnke M, Jarius S, von Engelhardt K, F├╝rwentsches A, Bussmann C, Ebinger F, Wildemann B, Haas J. B-cell populations discriminate between pediatric- and adult-onset multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016;4(1):e309

OBJECTIVE:

To comparatively assess the B-cell composition in blood and CSF of patients with paediatric-onset multiple sclerosis (pedMS) and adult-onset multiple sclerosis (adMS).

METHODS:

In this cross-sectional study, we obtained blood and CSF samples from 25 patients with pedMS (8-18 years) and 40 patients with adMS (23-65 years) and blood specimens from 66 controls (1-55 years). By using multicolour flow cytometry, we identified naive, transitional, isotype class-switched memory, non-switched memory, and double-negative memory B-cell subsets as well as plasmablasts (PB) and terminally differentiated plasma cells (PC). Flow cytometric data were compared to concentrations of B-cell-specific cytokines in serum and CSF as determined by ELISA.

RESULTS:

Frequencies of circulating naive B-cells decreased with higher age in controls but not in patients with multiple sclerosis (MS). B-cell patterns in CSF differed between pedMS and adMS with an acute relapse: in pedMS-derived CSF samples, high frequencies of non-switched memory B cells and PB were present, whereas class-switched memory B cells and PC dominated in the CSF of patients with adMS. In pedMS, PB were also elevated in the periphery. Accumulation of PB in the CSF correlated with high intrathecal CXCL-13 levels and augmented intrathecal synthesis of immunoglobulin G and immunoglobulin M.

CONCLUSIONS:

We demonstrate distinct changes in intrathecal B-cell homeostasis in patients with pedMS during active disease, which differ from those in adults by an expansion of plasmablasts in blood and CSF and similarly occur in prototypic autoantibody-driven autoimmune disorders. This emphasizes the particular importance of activated B-lymphocyte subsets for disease progression in the earliest clinical stages of MS.

This provides further evidence for a role of B cell memory in MS. 

The authors are not looking for anything other than B cells and so they don't really focus on the memory B cell, but if you think that this population harbours what drives MS then the data jumps at you.

First thing as you get older and encounter more things the immune system is interested in the number of naive (Mature) B cells drops to be replaced with memory B cells.You have to remember these are percentages so if the naive (mature) cells go up memory cells must go down and vice versa, the best way to do this is to calculate absolute numbers then you can see if there are more or less cells.

However, here they look at the B cell populations in young and adult pwMS and compared to health in the young it is clear that people with MS have more B memory cells in their blood.

In relapse the percentage of memory cells go down. 

Is this because they are off into the CNS?.

The memory cells (CD19+, CD27+) make up 66%/75.9% (Paedatric/adult) of B cells in CSF compared to 30.1%/33.2% in the remission blood. 


So memory B cells are being recruited to or they are retained with in the CNS in MS. 

The data in the CSF may create some complexity as it looks like young and adult memory pool is not quite the same, but we have to remember, it is unlikely that every cell found in CNS is pathogenic, many get drawn in because of the adhesion molecules/chemokines and there may be ectopoic resident cells in CNS contributing to the pool.

So the question is which memory B cell subset is causing the damage? However, is it the memory cell is more important than the type of memory cell, which could support the EBV idea as they will get infected in the unswitched (IgD+) state and this will persist in the switched B (IgD-) cells. 

11 comments:

  1. Interesting. That's a very helpful B cell diagram, thanks.
    I'd love to get a profile of my peripheral blood and CSF lymphocytes just out of sheer interest. Might find out how much it costs ££££. I don't have many peripheral lymphocytes, keep telling them they're looking in the wrong place ;-)

    ReplyDelete
    Replies
    1. all you need is a haemo who actually understands your request and a LP.

      my partner has MS. i suggested that she has a LP to satisfy my curiosity and, even after arguing my case, was told where to go in no uncertain terms.

      the bloods was an easier argument and i won that one... and it turns out it wasn't all that informative in the grand scheme of things.

      sigh lol.

      Delete
  2. We have asked companies for the data they have on trials and disease activity, let's see if it is important first, if it is then it should be part of your health monitoring.

    ReplyDelete
  3. I like the overall theme I've been seeing over the past couple of years. Namely, the growing focus on treat-2-target/NEDA is encouraging. I wish more trials would be constructed around this idea instead of just "make you worse slower" compared to placebo.

    I also like that the industry/community is opening its eyes to the shortcomings and pitfalls of the EAE model since it is so T-cell focused. Now we just need a good reliable B-cell model. Is there one or does it still need to be constructed?

    On the EBV front are there any trials or efforts that combine the work of MSologists with that of those searching for an EBV vaccine? I think it would be helpful to everyone if these two groups worked together on some things.

    ReplyDelete
    Replies
    1. "I also like that the industry/community is opening its eyes to the shortcomings and pitfalls of the EAE model since it is so T-cell focused"

      Not sure they have.

      "Now we just need a good reliable B-cell model"

      Stand-by for B cell EAE.

      Delete
    2. Ooooh, tantalizing. I can't wait to see the B-cell model. Hopefully it is more reflective of reality than EAE is. It's so frustrating to see trials that show 75+ percent effectiveness in EAE to then turn around only see 10-20% effectiveness in real patients.

      Delete
    3. Frustrating I agree....but my cynical eye can spot that most of the stuff will never go anywhere, if you hunt through the blog i have posted a number of times on reading EAE work...You can become a cynic like me.

      It does have to be like this but we have to put some quality control measures in the experiments to gret rid of the chaff

      Indeed I started writing a paper on CD20 B cells in EAE, largely un reproducible studies that will trun out to be tosh.

      Hope I finsih it, the one on glaterimer acetate in EAE has been sat there for a few years, guess you know the punchline:-(
      Maybe it is Marmoset model

      As to B cell model maybe you have it
      The Primate EAE Model Points at EBV-Infected B Cells as a Preferential Therapy Target in Multiple Sclerosis. 't Hart BA et al. Front Immunol. 2013 Jun 13;4:145.

      Delete
    4. very very interesting information about the primate EAE model! I was particularly intrigued by the CMV information. This was the first I'd ever seen of that.

      Are there any studies actually being conducted with this EAE model as their basis??

      Delete
    5. There are no primate work on eae in UK to be honest not that much eae work in mouse in UK

      I have my concerns about non human primate use and do not think half the stuff that comes from these studies has any real merit.it is no more predictive than the mouse and so as a safety test it fails. Likewise studies after the event is fitting a story to a known result. The atacicept made marmosets better not worse The studies are too small to be meaningful and there is flight of fancy.

      Delete
    6. Panorama one have the resource to reproduce the work so no-one to find the mushroom food should it occur.

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.