ProfG wants the real MS to stand-up and asks about smouldering lesions. We think that hot microglia at the centre of these. A few years ago MD2 came up with the idea that antibodies within the oligoclonal bands could activate microglial by binding to receptors on the microglia and that may mean that it doesn’t matter what the antibodies are reactive against, so stop looking for anti-myelin antibodies.

Oligoclonal bands in multiple sclerosis; Functional significance and therapeutic implications. Does the specificity matter? Pryce G, Baker D.Mult Scler Relat Disord. 2018 Oct;25:131-137.

This new paper (below) still hangs onto the view that the oligoclonal bands are anti-myelin….they are not! There are hundreds of papers that fail to show anything consistent but the point here is that a complex of myelin and antibodies activate microglia, but surely a complex of any old protein/lipid and antibodies will do the same thing. Will MD2 get a mention? What do you think?

IgG Immune Complexes Break Immune Tolerance of Human Microglia.van der Poel M, Hoepel W, Hamann J, Huitinga I, Dunnen JD.J Immunol. 2020 Sep 23:ji2000130. doi: 10.4049/jimmunol.2000130. Online ahead of print.

Microglia are phagocytic cells involved in homeostasis of the brain and are key players in the pathogenesis of multiple sclerosis (MS). A hallmark of MS diagnosis is the presence of IgG Abs, which appear as oligoclonal bands in the cerebrospinal fluid. In this study, we demonstrate that myelin obtained post mortem from 8 out of 11 MS brain donors is bound by IgG (Antibodies) Abs. Importantly, we show that IgG immune complexes strongly potentiate activation of primary human microglia by breaking their tolerance for microbial stimuli, such as LPS and Poly I:C, resulting in increased production of key proinflammatory cytokines, such as TNF and IL-1β. We identified FcγRI and FcγRIIa as the two main responsible IgG receptors for the breaking of immune tolerance of microglia. Combined, these data indicate that IgG immune complexes potentiate inflammation by human microglia, which may play an important role in MS-associated inflammation and the formation of demyelinating lesions.

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  • I have been thinking about this for a while… it’s fine to me that antibodies activate microglia, it make sense.
    What I do not understand is why microglia strikes myelin, nerves, oligodendrocytes. I would expect microglia to strike something that is in contact with antibodies, so at some extent antibodies must be physically on the “target”.
    Then why antibodies should be attached to myelin, nerves, oligodendrocytes if they are not specific for any of them? How?

  • Thank you for your post. I’m the senior author on the paper you mentioned, I picked up your blog via Altmetric. It actually seems that our thoughts are very much alike. It doesn’t matter what the antibodies are directed against. Yet, the (IgG) antibodies ARE bound to myelin of MS patients, leading to immune complex formation, which in turn activates human microglia (but: only in the presence of a second signal, such as a viral stimulus).

    I will definitely read the paper you mentioned (sorry we missed it). I’m new to the MS field (we have never published about it before), so there’s lot of catching up to do for us. But it’s great to hear that you and others have similar thoughts.

    • You might find the following observations in primary MS lesions, which appear to be highly characterised by microglial activation and the presence of complement/IgG complexes. Bacterial transportable proteins are detected within the complexes and within microglial pinocytotic vesicles.
      I would be very interested in your take on this.

      Staphylococcal immune complexes and myelinolytic toxin in early acute multiple sclerosis lesions. -An immunohistological study supported by multifactorial cluster analysis and antigen-imprint isoelectric focusing. Gay F. MS and related disorders.(2013) 2,213-232.

    • How did you detect the complex between myelin and IgG? I am not an expert but I would like to know how this is done in the laboratory can you explain, please?

        • Yes Fab binding to me was clear, but my question was if they are not specific for myelin then how would you know if they bind myelin in other ways?
          Also what our seen during the ex cement to say they have been bound? Use of Fluorescent probes?
          I did not explain clearly what I meant.
          Thank you!

          • Most antibodies in the CSF do not bind myelin. They have cloned them.and.produced them and tested.them.and they do not bind to myelin

          • @mousedoctor: I assume you’re right about the CSF antibodies not recognizing myelin. So how do you think IgG ends up associated with postmortem MS myelin (and not control myelin)? Just trying to learn here.

      • We determined IgG binding to myelin using ELISA (we coated postmortem myelin on a plate, and detected binding of antibodies with anti-human IgG antibodies). Myelin from most people that had MS was bound by IgG, while that was not the case for the controls.

  • Another theory is that the HERV-W envelope protein, which activates the immune-linked toll-like receptor 4 on microglia and macrophage cells, could drive the disease’s pathology.

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