Autoantibodies targeting the enteric nerve and non-myelin epitopes in relapsing-remitting multiple sclerosis: diagnostic relevance and viral mimicry

BackgroundRelapsing-remitting multiple sclerosis (RRMS) involves autoimmune responses against central nervous system (CNS) self-epitopes, potentially triggered by Epstein-Barr virus (EBV) and Human Herpesvirus 6 (HHV-6) reactivation. ObjectivesTo evaluate IgG/IgA/IgM responses targeting the enteric nerve and non-myelin antigens in RRMS and investigate associations with EBV and HHV-6 markers and explore molecular mimicry between viral and host antigens. MethodsThe study included 55 RRMS patients and 63 matched healthy controls. ELISA is used to examine IgG/IgA/IgM levels against nine non-myelin self-epitopes and viral proteins (EBNA-1, dUTPases of EBV and HHV-6). Luminex immunoassay is used to quantify cytokines, chemokines, and growth factors. Disability was evaluated using the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS). In-silico molecular mimicry was analyzed using UniProt, AlphaFold, PyMol, Alignmentaj, and the Immune Epitope Database (IEDB), comparing 41 viral and 36 ENS non-myelin antigens. ResultsIgG/IgA/IgM levels targeting the enteric nerve and non-myelin antigens were significantly higher in RRMS than in controls. A large part of the variance in the EDSS and MSSS scores (>60%) was explained by IgG-chondroitin sulfate, IgM-Asialo-ganglioside, and IgG-enteric nerve. There were highly significant correlations between autoimmunity to those self-antigens and either immune profiles indicating immune activation or Ig-responses to EBNA-1, and EBV/HHV-6 DUTPases. Molecular mimicry analysis confirmed the association between EBV/HHV-6 and the self-antigens by identifying shared pentapeptides, which might cause T-cell immunogenicity. ConclusionRRMS is characterized by autoimmune responses targeting the enteric nerve and non-myelin proteins. EBV and HHV-6 reactivation contribute via molecular mimicry mechanisms. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/25330145v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@2b452borg.highwire.dtl.DTLVardef@ca1465org.highwire.dtl.DTLVardef@10105c1org.highwire.dtl.DTLVardef@20ea6c_HPS_FORMAT_FIGEXP M_FIG C_FIG