title: The pathogenicity of self-antigen decreases at high levels of autoantigenicity: a computational approach.
abstract: Recent experimental evidence suggests that antigenic stability facilitates antigen shuttling from target tissue to dendritic cells (DCs), enabling cross-priming of naive T cells. On the other hand, antigenic stability affects the efficiency of peptide-MHC (p-MHC) complex formation, altering a target cell's susceptibility to killing by the resulting CTLs. Using a mathematical model, we show how antigenic stability and p-MHC production efficiency interplay in autoantigenicity and pathogenic potential of target cell proteins in autoimmune disease. We consider protein allocated to both rapidly degraded versus stable functional pools [fractions f, 1 - f], contributing, with relative efficiency eta, to p-MHC presentation on a target cell, as well as to cross-presentation on a DC; we analyze the combined effect of these parameters. Our results suggest that autoantigenicity and pathogenicity (ability to elicit T cell activation versus target cell lysis) are not equivalent and that pathogenicity peaks at low to moderate levels of autoantigenicity.
authors.affiliation: Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 12A, Room 4007, 12 South Drive MSC 5621, Bethesda, MD 20892-5621, USA. khadraa@niddk.nih.gov
authors.forename: Anmar
authors.initials: A
authors.lastname: Khadra
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
authors.forename: Leah
authors.initials: L
authors.lastname: Edelstein-Keshet
mesh_terms: D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology*; D015551:Autoimmunity / Q000276:immunology*; D003198:Computer Simulation; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001324:Autoantigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell