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Breakdown of Tolerance to a Self-Peptide of Acetylcholine Receptor -Subunit Induces Experimental Myasthenia Gravis in Rats ¹

Fulvio Baggi^2,*, Andrea Annoni^*, Federica Ubiali^*, Monica Milani^3,*, Renato Longhi, Widmer Scaioli, Ferdinando Cornelio^*, Renato Mantegazza^* and Carlo Antozzi^*

^* Neurology IV, Neuromuscular Diseases and Autoimmunity, and Neurophysiology and Clinical Epileptology, Istituto Nazionale Neurologico Carlo Besta, Milan, Italy; and National Research Center, Institute of Chemistry of Molecular Recognition, Milan, Italy

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 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.

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				F. Ubiali, S. Nava, V. Nessi, R. Longhi, G. Pezzoni, R. Capobianco, R. Mantegazza, C. Antozzi, and F. Baggi Pixantrone (BBR2778) Reduces the Severity of Experimental Autoimmune Myasthenia Gravis in Lewis Rats J. Immunol., February 15, 2008; 180(4): 2696 - 2703. [Abstract] [Full Text] [PDF]