Response to human acetylcholine receptor alpha 138-199: determinant spreading initiates autoimmunity to self-antigen...

NZW rabbits immunised with a mixture of synthetic peptides representing alpha 138-199 of the human acetylcholine receptor (AChR) alpha-subunit exhibited clinical, biochemical and electrophysiological signs of experimental autoimmune myasthenia gravis (EAMG), with raised levels of anti-rabbit AChR antibodies. Surprisingly, these were partly directed at the main immunogenic region (MIR, thought to be alpha 67-76) and alpha-Bungarotoxin binding sites on rabbit AChR, and reacted less well with human AChR. Moreover, they could be separated from the anti-peptide antibodies by fractionation on immobilised peptide. We conclude that immunisation with these peptides led, by 'determinant spreading', to a response directed at self-AChR. Similar phenomena may have been overlooked in previous studies of responses to synthetic or recombinant AChR sequences. These findings suggest that autoimmunity could be induced by low-affinity, cross-reacting epitopes even when the observed serum response is highly specific for the autoantigen.