Autoimmunity to the glutamate receptor in mice - A model for Rasmussen's encephalitis?

We investigated the in vivo pathogenic potential of murine autoimmunity to peptides of the glutamate/AMPA receptor subunit 3 (GluR3). Antibodies to Gl uR3 are found in human epilepsy, Rasmussen's encephalitis (RE). In our acco mpanying paper in this issue we found that murine antibodies to the GluR3B peptide (amino acids 372-395) bind neurons in culture, evoke GluR channel a ctivity, and kill neurons in a complement-independent excitotoxic manner, m imicking the pathophysiologic effects of excess of glutamate. In the presen t study, we immunized four mouse strains (BALB/c, C3H/HeJ, SJL/J and C578L/ 6) with the GluR3B peptide, and investigated the development of (1) anti-Gl uR3B antibodies; (2) anti-GluR3 T cells; (3) clinical symptoms and abnormal behaviour; (4) brain pathology. We found that BALB/c, C3H/HeJ and SJL/J mi ce strains developed high titres of anti-GluR3B antibodies. The low levels anti-GluR3B antibodies raised in C57BL/6 mice suggest that the genetic back ground of mice influences their ability to mount a humoral autoimmune respo nse towards the GluR3B peptide. The GluR3B-immunized mice also developed an ti-GluR3B T cells, and their splenocytes showed significantly biased freque ncies of particular (V beta 11, V beta 7 and V beta 8) TCR V beta families. Surprisingly, GluR3B-immunized mice also raised high anti-ssDNA humoral im munoreactivity. GluR3B-immunized mice exhibited multiple brain pathology, p artially resembling that observed in RE, and subclinical behavioral abnorma lities, but no epilepsy, even upon facilitating the entry of the autoreacti ve antibodies into the brain, by weakening the blood-brain barrier. Taken t ogether, these results suggest that autoimmunity to the GluR3B epitope may account for the neuronal death and brain pathology seen in neurodegenerativ e diseases Like RE, but may not be sufficient to underly epilepsy, at least not in mice. (C) 1999 Academic Press.