Lc. Gahring et al., Cutting edge: Granzyme B proteolysis of a neuronal glutamate receptor generates an autoantigen and is modulated by glycosylation, J IMMUNOL, 166(3), 2001, pp. 1433-1438
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 f
rom the neuronal glutamate receptor subunit 3 (GluR3) in Rasmussen's enceph
alitis, a severe form of pediatric epilepsy. We demonstrate that specific c
leavage of GluR3 by granzyme B (GB), a serine protease released by activate
d immune cells, can generate the GluR3B autoantigenic peptide, but only if
an internal N-linked glycosylation sequon within the GluR3-GB recognition s
equence (ISND*S) is not glycosylated. However, this N-glycon sequon while g
lycosylated normally is inefficiently used and glycosylation can fail. Thes
e results suggest that GB/N-glycon sites may escape normal tolerance mechan
isms and contribute to autoantibody-mediated immune diseases.