More evidence that myelin basic protein is unlikely to be a major target in MS.

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Brain Citrullination Patterns and T Cell Reactivity of Cerebrospinal Fluid-Derived CD4+ T Cells in Multiple Sclerosis.Faigle W, Cruciani C, Wolski W, Roschitzki B, Puthenparampil M, Tomas-Ojer P, Sellés-Moreno C, Zeis T, Jelcic I, Schaeren-Wiemers N, Sospedra M, Martin R.Front Immunol. 2019 Apr 10;10:540

“Immune responses to citrullinated (or deimination is the conversion of the amino acid arginine in a protein into the amino acid citrulline) peptides have been described in autoimmune diseases like rheumatoid arthritis (RA) and multiple sclerosis(MS). We investigated the post-translational modification (PTM), arginine to citrulline, in brain tissue of MS patients and controls (C) by proteomics and subsequently the cellular immune response of cerebrospinal fluid (CSF)-infiltrating T cells to citrullinated and unmodified peptides of myelin basic protein (MBP). Using specifically adapted tissue extraction- and combined data interpretation protocols we could establish a map of citrullinated proteins by identifying more than 80 proteins with two or more citrullinated peptides in human brain tissue . We report many of them for the first time (But this does not include the protein (RASGRP2) they suggested was important in the recent “Cell” paper. Have a read for yourself it is open access). For the already described citrullinated proteins MBP, GFAP, and vimentin, we could identify additional citrullinated sites. The number of modified proteins in MS white matter was higher than control tissue. Citrullinated peptides are considered neoepitopes that may trigger autoreactivity. We used newly identified epitopes and previously reported immunodominant myelin peptides in their citrullinated and non-citrullinated form to address the recognition of CSF-infiltrating CD4+ T cells from 22 MS patients by measuring proliferation and IFN-γ secretion. We did not detect marked responses to citrullinated peptides, but slightly more strongly to the non-modified version. Based on these data, we conclude that citrullination does not appear to be an important activating factor of a T cell response, but could be the consequence of an immune- or inflammatory response. Our approach allowed us to perform a deep proteome analysis and opens new technical possibilities to analyze complex PTM patterns on minute quantities of rare tissue samples.

A couple of weeks ago Prof martin presented a new idea that he had found the antigenic cause (RASGRP2) of MS and was doing a trial with intravenous peptide to tolerise against it. I had read the paper and asked “why MS?”, given that the protein they had found was not really expressed in the CNS, very much (See below), and was present in the immune system.

Data from www.biogps.org

The picture of RSPGRP2 expression in the brain showed expression (brown) in the grey matter, when many lesions are in the white matter which had no staining and the blood vessel top left was like a light house showing the blood was positive…or that endogenous peroxidase was not bloock and red cells were been detected.


“Why MS?”…The answer to my surprise was “I don’t know “.

Next I said the “trial was not going to work” based on animal studies that show that intravenous antigen alone was not good enough in sensitized animals, so why would it work in humans?….Deadly hush..I guess this was a bit of a shock……So maybe I will be called “ignorant” twice in a week for this view. Yep, I will be struck off the christmas card list for being out-spoken. It is a dying art. At least I have the eggs to express an alternative view.

As a digression…The talk I (and incidentally MD2 also.. who was there too) remember the most in my research life was by a bloke called Jan Klein. (A big lad with a little name:-). He had a keynote lecture at the British Society of Immunology Meeting and threw down the guantlet. He was an editor of a major International transplantation antigen journal and he said he would not publish anypaper on a suppressive molecule that most people were working on because it did not exsist! The era of molecular biology had just arrived and you could not find the suppressor molecule [I-J…I guess it now means information Junk] where the dogma brigade had said it would be located. Anyone who wanted to challenge that view was welcome to come to his lab in Germany and do the (repeat) experiment. The dogma brigade got up to give a reposte to the talk and they were minced into the ground. We loved it….this is Science.

However, now we have this paper.. The suggstion here is that MS is a problem of citrullinated proteins which was an idea that surfaced some time ago. Here the work focuses on myelin basic protein. I would ask “Have you forgotten about your new idea for the causative protein?” Because if you have forgotten about it, maybe we should not even bother to learn about it, because if I thought it was important, it would be the only thing I would be talking about.

However, the focus here is on the old standard myelin basic protein…In my opinion a really unlikely candidate autoantigen in MS, because it it is found in the peripheral nervous system too and attempts to neutralise the anti-MBP response has universally failed in MS. It is studied because in my humble (yep I am humble:-) opinion, it is easy to make and soluble in water, so that T cell imunologists can use it.

However, when they use it , it shows that people without MS respond to it as well as people with MS d.o. This is not the dominant T cell autoantigen in MS and antibodies are not really responsive to this protein. In my mind Myelin basic protein is not a good candidate autoantigen in MS and has been discredited so many times, but we stick to the idea, ecause we keep reading about it in Immunology papers..

Their conclusion was “The immunological testing in the present study focussed on citrullinated MBP epitopes based on previous reports, and, even though we examined CSF-infiltrating CD4+ T cells, we did not find a marked response, which argues against a major pathogenetic involvement of autoimmune T cells directed against citrullinated MBP epitopes in MS”.

Well of coaurse citrullinate proteins to MBP are no good, because MBP is no good. It doesn’t kill off the citrulllination idea… Just yet.

See what you think. All open access. Read and enjoy

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MouseDoctor

8 comments

  • The expression data certainly does not support that CNS would be the target, but maybe the B cells are.
    We published previously, and posted a guest post here, on the idea of idiotope-driven T-B collaboration. This process is what we call an “Unlinked” T-B collaboration, meaning that the T and B cell recognizes different antigens, but still interact and undergo expansion.

    In idiotope T-B interactions, the B cell may be specific for anything, but let’s just say myelin for the ease. The T cell however, is specific for the B cell receptor (which is located in the same compartment as the B cell antigen).

    Such unlinked T-B collaboration could occur with other proteins too? RASGRP2 perhaps?
    In my opinion less likely than idiotopes, as RASGRP2 is present mainly in cytosol, as opposed to the endosomal compartments of typical antigens made for HLA-II presentation. But nothing is impossible in immunology..

    • Used to work on idiotype networks when they were in vogue back in the early eighties. It destroyed many a promising research career back then. I’m surprised it’s still mentioned in polite society 😉

      • Key difference is the focus on idiotope, and not idiotype. Take a look at Khodadoust et al 2017 and 2019, and you’ll see 🙂

          • And yet B cell lymphomas mainly display mainly IGHV fragments (=idiotopes) on their HLA-II molecules. Why?

          • And if it helps, consider it in light of standard clonal selection, and not symmetrical immune networks (referencing the I-J paradox smacking by MD above).

          • Not sure what you refer to by circumvention. If anything, this would be a way for evolution to secure T cell help by an alternate epitope. Alternately, a way of suppressing immune responses if the responsive cells are of suppressive nature.

            Anyway, the MS patients we’ve tested so far have T cells specific for variable region fragments from CSF. I think MD barely missed the preliminary results last month. Could be physiological, could be pathological, but they’re there.

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