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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...
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... encom- passed peptide sequences from Encephalitozoon romaleae, Chlorobium chlorochromatii, Rhodococcus sp. AW25MO9, Clostridium papyrosolvens, Anoxybacillus flavithermus, Macrophomina phaseolina, Emiliania huxleyi, Rhizobium leguminosarum, Runella slithyformis, Dictyostelium fasci- culatum, Ogataea parapolymorpha, and Myxococcus stipi- tatus (Table 1). Screening Line 7 splenocytes, IFNγ responses from unprimed mice, we observed a spectrum of response to the epitopes that had been previously iden- tified as cross-reactive for this receptor (Figure 1). ...
Citations
... Cross-reactive T cells that can be activated by both autoantigens and non-autoantigens have been detected in several autoimmune diseases in addition to lupus e.g. rheumatoid arthritis, antiphospholipid syndrome, celiac disease, autoimmune encephalomyelitis, multiple sclerosis and diabetes (24)(25)(26)(27)(28)(29)(30)(31)(32)(33). In a mouse model of SLE, mouse H-2 tetramers were used to probe for U1-70 131-150 (another lupusrelated autoantigen epitope) reactive T cells. ...
HLA-DR3 (DR3) is one of the dominant HLA-DR alleles associated with systemic lupus erythematosus (SLE) susceptibility. Our previous studies showed multiple intramolecular DR3 restricted T cell epitopes in the Smith D (SmD) protein, from which we generated a non-homologous, bacterial epitope mimics library. From this library we identified ABC247-261 Mimic as one new DR3 restricted bacterial T cell epitope from the ABC transporter ATP-binding protein in Clostridium tetani. It activated and induced autoreactive SmD66-80-specific T cells and induced autoantibodies to lupus-related autoantigens in vivo. Compared to healthy donors, SLE patients have a greater percentage of cross-reactive T cells to ABC247-261 Mimic and SmD66-80. In addition, we analyzed the ability of single DR3 restricted Tetanus toxoid (TT) T cell epitopes to induce autoimmune T cells. We found that the immunodominant TT epitope TT826-845 stimulated SmD66-80 reactive T cells but failed to induce persistent anti-SmD autoantibodies compared to the ABC247-261 Mimic. Thus, exposure to the ABC247-261 Mimic epitope may contribute to autoimmunity in susceptible DR3 individuals.
... Viral or bacterial infections [92,93], commensal microbiota [94] have been associated to MS. Crossconserved or redundant T cell epitopes may be involved in MS pathogenesis [95]. For example, a number of stimulatory, cross-reactive peptide sequences from environmental and human antigens were found in MS patient-derived anti-myelin TCR [96]. Furthermore, a peptide from H. ...
T cells are extensively trained on 'self' in the thymus and then move to the periphery, where they seek out and destroy infections and regulate immune response to self-antigens. T cell receptors (TCR) on T cells' surface recognize T cell epitopes, short linear strings of amino acids presented by antigen-presenting cells. Some of these epitopes activate T effectors, while others activate regulatory T cells. It was recently discovered that T cell epitopes that are highly conserved on their TCR face with human genome sequences are often associated with T cells that regulate immune response. These TCR-cross-conserved or 'redundant epitopes' are more common in proteins found in pathogens that have co-evolved with humans than in other non-commensal pathogens. Epitope redundancy might be the link between pathogens and autoimmune disease. This article reviews recently published data and addresses epitope redundancy, the "elephant in the room" for vaccine developers and T cell immunologists.
... Similarly, it has been shown that microbial antigens derived from Mycobacterium avium and Escherichia coli are capable of inducing disease in a humanized transgenic mouse model of MS (72). Likewise, peptides derived from Dictyostelium fasciculatum and Emiliania huxleyi are also capable of inducing EAE in a separate humanized transgenic mouse model of MS (73). Recently, it has become clear that structural mimicry of peptide bound to MHC is a major determinant of this process (72). ...
... Exactly how peripheral infection increases the risk for relapse is not yet known. Mechanistically, infection could promote the antigen stimulation capacity for peripheral antigen-presenting cells (105) including dendritic cells (107), decrease Treg cell function, activate T-cells with dual TCR, activate T-cells via molecular mimicry (71)(72)(73)108), or promote T-cell trafficking and activation to the CNS. Perhaps, there are biological differences between organs that can account for an increased or decreased ability to promote neuroinflammatory responses (109). ...
Over the past several decades, significant advances have been made in identifying factors that contribute to the pathogenesis of multiple sclerosis (MS) and have culminated in the approval of some effective therapeutic strategies for disease intervention. However, the mechanisms by which environmental factors, such as infection, contribute to the pathogenesis and/or symptom exacerbation remain to be fully elucidated. Relapse frequency in MS patients contributes to neurological impairment and, in the initial phases of disease, serves as a predictor of poor disease prognosis. The purpose of this review is to examine the evidence that supports a role for peripheral infection in modulating the natural history of this disease. Evidence supporting a role for infection in promoting exacerbation in animal models of MS is also reviewed. Finally, a few mechanisms by which infection may exacerbate symptoms of MS and other neurological diseases are discussed. Those who comprise the majority of MS patients acquire approximately two upper-respiratory infections per year; furthermore, this type of infection doubles the risk for MS relapse, underscoring the contribution of this relationship as being potentially important and particularly detrimental.
