Uveitogenic epitopes of retinal S-antigen are generated in vivo via an alternative antigen-presentation pathway.
We have found that different antigen-processing pathways are involved in the induction of experimental autoimmune uveoretinitis (EAU) by the retinal autoantigens S-antigen and interphotoreceptor retinoid-binding protein (IRBP). Although in vitro T-cell proliferative responses to IRBP were completely inhibited in the presence of irreversible cysteine protease inhibitors, no significant reduction of S-antigen proliferative responses was found. Furthermore, acidic proteolysis of S-antigen by the cysteine protease cathepsin B prior to immunization radically reduced pathogenicity (disease severity). In addition, in vitro processing of S-antigen, but not IRBP, was also found to be resistant to the action of cycloheximide and lysosomotropic agents, inhibition of proliferation only occurring after extended exposure of antigen-presenting cells to methyl amine or high concentrations of chloroquine. These data indicate that an alternative pathway of antigen processing exists for S-antigen, which is independent of processing within the normal endolysosomal pathway and that uveitogenic peptides of naturally processed S-antigen bind to major histocompatibility complex class II antigens either at the cell surface or within very early endosomes where cathepsin B is inactive.
Liversidge
J
J
Department of Ophthalmology, University of Aberdeen Medical School, Foresterhill, UK.
Dawson
R
R
Dick
A D
AD
Forrester
J V
JV
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D019393:Arrestin / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D002401:Cathepsin B / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D000939:Epitopes / Q000096:biosynthesis*; D005136:Eye Proteins / Q000276:immunology; D008247:Lysosomes / Q000276:immunology; D051381:Rats; D011919:Rats, Inbred Strains; D012177:Retinol-Binding Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D015866:Uveitis, Posterior / Q000276:immunology*; D000099214:Retinol-Binding Proteins, Interstitial
D019393:Arrestin; D001324:Autoantigens; D002401:Cathepsin B; D015853:Cysteine Proteinase Inhibitors; D000939:Epitopes; D005136:Eye Proteins; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial