Breakdown of tolerance to a self-peptide of acetylcholine receptor alpha-subunit induces experimental myasthenia gravis in rats.
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 alpha 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.
Baggi
Fulvio
F
Neurology IV, Neuromuscular Diseases and Autoimmunity, Istituto Nazionale Neurologico Carlo Besta, Milan, Italy. baggi@istituto-besta.it
Annoni
Andrea
A
Ubiali
Federica
F
Milani
Monica
M
Longhi
Renato
R
Scaioli
Widmer
W
Cornelio
Ferdinando
F
Mantegazza
Renato
R
Antozzi
Carlo
C
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D005260:Female; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D021122:Protein Subunits / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011978:Receptors, Nicotinic / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*
D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D021122:Protein Subunits; D011978:Receptors, Nicotinic