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CUTTING EDGE |
Geriatric Research Education and Clinical Center, Salt Lake City Veterans Affairs Medical Center and University of Utah School of Medicine, Salt Lake City, Utah, 84112
Autoimmune processes are initiated when tolerance to self-proteins fails to be established or maintained and immune cells are stimulated by self-Ags. Although intracellular autoantigens are common, the origin of extracellular autoantigens is poorly defined and possibly more dangerous. In this study, we considered a mechanism for the origin of an extracellular autoantigen from the neuronal glutamate receptor subunit 3 (GluR3) in Rasmussen’s encephalitis, a severe form of pediatric epilepsy. We demonstrate that specific cleavage of GluR3 by granzyme B (GB), a serine protease released by activated immune cells, can generate the GluR3B autoantigenic peptide, but only if an internal N-linked glycosylation sequon within the GluR3-GB recognition sequence (ISND*S) is not glycosylated. However, this N-glycon sequon while glycosylated normally is inefficiently used and glycosylation can fail. These results suggest that GB/N-glycon sites may escape normal tolerance mechanisms and contribute to autoantibody-mediated immune diseases.
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