The pathogenicity of self-antigen decreases at high levels of autoantigenicity: a computational approach.

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.