Malondialdehyde modification of myelin oligodendrocyte glycoprotein leads to increased immunogenicity and encephalitogenicity.
Self proteins may become autoantigenic through structural modification. We studied malondialdehydation of recombinant rat (rr) myelin oligodendrocyte glycoprotein (MOG), an autoantigen in multiple sclerosis. Malondialdehyde (MDA) modification changed protein weight and charge, the location of these adducts being mapped by Fourier transform ion cyclotron resonance. Molecular modelling revealed significant differences in the MDA-rrMOG three-dimensional structure. DBA/1 mice immunised with MDA-rrMOG developed greater proliferative responses and more severe experimental autoimmune encephalomyelitis than mice immunised with unmodified rrMOG. MDA-rrMOG was taken up more effectively by antigen-presenting cells (APC), at least partially through scavenger receptors. Exposure to MDA-rrMOG led to increased expression of IL-23, IL-12 and IL-12R, indicating a role not only for increased antigen uptake but also for activation of APC. We thus provide biochemical, structural, immunological and clinical data that suggest that the post-translationally modified form of this myelin autoantigen is a more relevant form of the molecule.
Wållberg
Maja
M
Department of Clinical Neurosciences, Applied Immunology, Centre for Molecular Medicine, Karolinska University Hospital at Solna, Stockholm, Sweden.
Bergquist
Jonas
J
Achour
Adnane
A
Breij
Esther
E
Harris
Robert A
RA
D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D005583:Fourier Analysis; D007525:Isoelectric Focusing; D008315:Malondialdehyde / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D063308:Myelin-Oligodendrocyte Glycoprotein; D016133:Polymerase Chain Reaction; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D017434:Protein Structure, Tertiary; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization
D001323:Autoantibodies; D001324:Autoantigens; C571327:Mog protein, mouse; C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D008315:Malondialdehyde