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
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.
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