MOG-induced experimental autoimmune encephalomyelitis in the rat species triggers anti-neurofascin antibody response that is genetically regulated.
BACKGROUND
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. 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.


METHODS
We 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.


RESULTS
Spreading 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.


CONCLUSIONS
Inter-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.
Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, CMM L8:04, Stockholm, Sweden. Sevasti.Flytzani@ki.se.
Sevasti
S
Flytzani
Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, CMM L8:04, Stockholm, Sweden. Andre.Ortlieb@ki.se.
Andre Ortlieb
AO
Guerreiro-Cacais
Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, CMM L8:04, Stockholm, Sweden. Marie.N.Diaye@ki.se.
Marie
M
N'diaye
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK. Maren.Lindner@glasgow.ac.uk.
Maren
M
Lindner
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK. Christopher.Linington@glasgow.ac.uk.
Christopher
C
Linington
Institute of Clinical Neuroimmunology, Ludwig-Maximilians-Universität, Munich, Germany. Edgar.Meinl@med.uni-muenchen.de.
Edgar
E
Meinl
Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, CMM L8:04, Stockholm, Sweden. Pernilla.Strid@ki.se.
Pernilla
P
Stridh
Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, CMM L8:04, Stockholm, Sweden. Maja.Jagodic@ki.se.
Maja
M
Jagodic
Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, CMM L8:04, Stockholm, Sweden. Tomas.Olsson@ki.se.
Tomas
T
Olsson
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000276:immunology*; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000939:Epitopes; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D008297:Male; D004676:Myelin Basic Protein / Q000494:pharmacology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology*; D009414:Nerve Growth Factors / Q000235:genetics* / Q000276:immunology*; D010455:Peptides / Q000494:pharmacology; D051381:Rats
D015815:Cell Adhesion Molecules; D000939:Epitopes; D007074:Immunoglobulin G; D004676:Myelin Basic Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009414:Nerve Growth Factors; C504594:Nfasc protein, rat; D010455:Peptides