Breakdown of Tolerance to a Self-Peptide of Acetylcholine Receptor alpha-Subunit Induces Experimental Myasthenia Gravis in Rats

摘要

Experimental autoimmune myasthenia gravis (EAMG),a model for human myasthenia (MG),is routinely induced in susceptible rat strains by a single immunization with Torpedo acetylcholine receptor (TAChR).TAChR immunization induces anti-AChR Abs that cross-react with self AChR,activate the complement cascade,and promote degradation of the postsynaptic membrane of the neuromuscular junction.In parallel,TAChR-specific T cells are induced,and their specific immunodominant epitope has been mapped to the sequence 97-116 of the AChR a subunit.A proliferative T cell response against the corresponding rat sequence (R97-116) was also found in TAChR-immunized rats.To test whether the rat (self) sequence can be pathogenic,we immunized Lewis rats with R97-116 or T97-116 peptides and evaluated clinical,neurophysiological,and immunological parameters.Clinical signs of the disease were noted only in R97-116-immunized animals and were confirmed by electrophysiological signs of impaired neuromuscular transmission.All animals produced Abs against the immunizing peptide,but anti-rat AChR Abs were observed only in animals immunized with the rat peptide.These findings suggested that EAMG in rats can be induced by a single peptide of the self AChR,that this sequence is recognized by T cells and Abs,and that breakdown of tolerance to a self epitope might be an initiating event in the pathogenesis of rat EAMG and MG.