Environmental triggers of MS

Reynolds CJ, Sim MJ, Quigley KJ, Altmann DM, Boyton RJ.
Autoantigen cross-reactive environmental antigen can trigger multiple sclerosis-like disease. J Neuroinflammation. 2015;12:91

BACKGROUND: Multiple sclerosis is generally considered an autoimmune disease resulting from interaction between predisposing genes and environmental factors, together allowing immunological self-tolerance to be compromised. The precise nature of the environmental inputs has been elusive, infectious agents having received considerable attention. A recent study generated an algorithm predicting naturally occurring T cell receptor (TCR) ligands from the proteome database. Taking the example of a multiple sclerosis patient-derived anti-myelin TCR, the study identified a number of stimulatory, cross-reactive peptide sequences from environmental and human antigens. Having previously generated a spontaneous multiple sclerosis (MS) model through expression of this TCR, we asked whether any of these could indeed function in vivo to trigger CNS disease by cross-reactive activation.
FINDINGS:A number of myelin epitope cross-reactive epitopes could stimulate T cell immunity in this MS anti-myelin TCR transgenic model. Two of the most stimulatory of these ‘environmental’ epitopes, from Dictyostyelium slime mold and from Emiliania huxleyi, were tested for the ability to induce MS-like disease in the transgenics. We found that immunization with cross-reactive peptide from Dictyostyelium slime mold (but not from E. huxleyi) induces severe disease.
CONCLUSIONS:These specific environmental epitopes are unlikely to be common triggers of MS, but this study suggests that our search for the cross-reactivity triggers of autoimmune activation leading to MS should encompass epitopes not just from the ‘infectome’ but also from the full environmental ‘exposome.

In this study they take a mouse that has a HLA-DR and a T cell receptor specific for myelin basic protein and they inject peptides from a slime mould and it induces EAE, so an example how autoimmunity can result from cross-reactivity to an environmental trigger. 

To be clear, they interpret this as proof of principle rather than specific evidence that exposure to slime mold sequences are pathogenic in clinical MS: the TCR stimulated by this peptide is not a public receptor across MS patients in general, and therefore, one would not generalize a case based on its specific cross-reactivities. Sequencing of the TCR repertoire from MS patients has demonstrated substantial diversity in myelin epitope-specific disease-implicated receptors. Clearly, a further caveat in considering the implications of environmental cross-reactivities is that of predicted epitopes; not all could actually stimulate T cells in this model, and not all peptides that could stimulate could induce disease. This an example where a wider environment can trigger MS-like disease

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  • So if something like a common mould / fungus present in environments which are cooler with less UV has the potential to trigger MS, this could partly account for the geographic distribution of MS globally? And vitamin D levels might then seem slightly overrated?

    • If we go to the original paper describing a TCR transgenic against myelin from over twenty years ago, in some cases you do not have to inject any antigen, simply activating the T cells was enough to make them migrate and once in the CNS you get EAE.

      Goverman J, Woods A, Larson L, Weiner LP, Hood L, Zaller DM.Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell. 1993 Feb 26;72(4):551-60.

    • Your recent post described myelin-reactive T cells, which are activated in MS patients, yet still present (although not activated) in healthy controls. Is this finding related to the transgenic mice work you just linked above?

    • Could be…. the mouse work says that if you get activated T cells against myelin then you can get autoimmunity….we have know this for years this is another fancy way of dotting an i or is that crossing a t

  • The cool thing here, as I understand it, is the technique used to identify the potential mimic peptides – by using yeast to generate libraries of many, many peptide-MHC complexes and seeing which ones the T cell receptors would recognise [1]. Then going on to show that at least one of these mimics can induce disease in a TCR transgenic mouse. The old way was to search sequence databases for peptide-binding motifs and TCR contacts – as per [2], which didn't find any mimics for the Ob.1A12 TCR discussed in the present paper but did (kind-of inadvertently in one case) pull out a couple of mimics for two of the other TCRs tested.

    The caveat about Ob.1A12 being a bit atypical also rings true – in addition to the points already mentioned it has a really unusual binding mode where the footprint is over the n-terminus of the peptide instead of being more central [3].

    [1] http://www.ncbi.nlm.nih.gov/pubmed/24855945/
    [2] http://www.cell.com/cell/pdf/0092-8674(95)90348-8.pdf
    [3] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415330/

    • Ob.1A12 is the name of the T cell where the T cell receptor was cloned these were put into mice. I guess the cells was from a donor Ob in tissue culture plate number 1 .These are 96 well plates of 8 rows of twelve so I guess the cell clone came from row A, column 12. This clone recognises myelin basic protein in the context of a human expressing HLA-DR15 (a risk factor for MS). Look at the lnk in the post above to look at peptides and HLA. Any protein has a start end = N terminus and and end = C terminus as it has a carboxylic acid

    • Beautiful structure in reference 3 – but the authors had to covalently attach the myelin peptide to the N-terminus of the TCR (apparently the binding is relatively weak, and no crystals of the complex could be obtained without "artificially enforced" proximity, accomplished by chemically linking the peptide to the TCR. While the technique is clever, it may have biased the binding footprint.

    • Not sarcasm: the T-Rex peptides discovery is my favorite of all time… right after whomever cures this shitty disease.



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