Abstract
BackgroundΙn multiple sclerosis (MS), axonal damage leads to permanent neurological disabilities and the spreading of the autoimmune response to axonal antigens is implicated in disease progression. Experimental autoimmune encephalomyelitis (EAE) provides an animal model that mimics MS. Using different EAE models, we investigated the pathophysiological basis of epitope spreading to neurofascin, a protein localized at the node of Ranvier and its regulation by non-MHC genes.MethodsWe used two different EAE models in DA rat; one which is induced with myelin oligodendrocyte glycoprotein (MOG) which leads to disease characterized by profound demyelination, and the second which is induced with myelin basic protein (MBP) peptide 63–88 which results in severe central nervous system (CNS) inflammation but little or no demyelination. We determined anti-neurofascin antibody levels during the course of disease. Furthermore, the anti-neurofascin IgG response was correlated with clinical parameters in 333 (DAxPVG.1AV1) x DA rats on which we performed linkage analysis to determine if epitope spreading to neurofascin was affected by non-MHC genes.ResultsSpreading of the antibody response to neurofascin occurred in demyelinating MOG-induced EAE but not in EAE induced with MBP peptide 63–88. Anti-neurofascin IgG levels correlated with disease severity in (DAxPVG.1AV1) x DA rats, and a genomic region on chromosome 3 was found to influence this response.ConclusionsInter-molecular epitope spreading to neurofascin correlates with disease severity in MOG-EAE is dependent on extensive demyelination and is influenced by non-MHC genes. The findings presented here may shed light on factors involved in the severity of MS and its genetics.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0417-2) contains supplementary material, which is available to authorized users.
Highlights
Ιn multiple sclerosis (MS), axonal damage leads to permanent neurological disabilities and the spreading of the autoimmune response to axonal antigens is implicated in disease progression
Epitope spreading to neurofascin occurs in myelin oligodendrocyte glycoprotein (MOG)-EAE To assess whether an antibody response to neurofascin could arise secondary to a response to another central nervous system (CNS) antigen, we used the two most prevalent EAE models in DA rats, namely immunization with MOG in incomplete Freund’s adjuvant (IFA) and with MBP63–88 in complete Freund’s adjuvant (CFA)
Anti-rat recombinant neurofascin (rrNF) IgG antibodies could be detected in these sera, but only at a late stage of MOG-induced EAE; 16 out of 31 (52 %) MOG-immunized rats were seropositive for rrNF-specific IgG antibodies at day 26 p.i
Summary
Ιn multiple sclerosis (MS), axonal damage leads to permanent neurological disabilities and the spreading of the autoimmune response to axonal antigens is implicated in disease progression. Anti-neurofascin antibody titers were more pronounced in secondary progressive MS than in relapsing-remitting MS, and adoptive transfer of neurofascin-specific antibodies caused rapid worsening of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. This clinical effect was associated with deposition of neurofascin-specific antibody and complement at nodes of Ranvier resulting in inhibition of neurotransmission and axonal damage [14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
