How subtle differences in MHC class II affect the severity of experimental myasthenia gravis.
Myasthenia gravis is an autoimmune disorder characterized by muscle weakness, due to an antibody-mediated deficit of acetylcholine receptors (AChRs) at neuromuscular junctions. We analyzed the factors that determine the severity of experimental myasthenia gravis (EAMG) induced by immunization with Torpedo AChR, in two congenic strains of mice--B6 mice, which are highly susceptible to EAMG; and bm12 mice, which are relatively resistant, and differ only in a change of three amino acids in MHC Class II. We prepared large numbers of AChR-specific T cell hybridomas from each strain and characterized their epitope specificities and T cell receptor (TCR) gene usage: Half the B6 hybridomas responded to a single AChR peptide (alpha 146-162), and their TCR genes encoded restricted V alpha and V beta chains and CDR3 motifs. bm12 hybridomas had different epitope specificities and different, less restricted TCR genes. APCs were able to present AChR or AChR-derived peptides virtually exclusively to hybridomas of their own strain. Levels of antibodies to Torpedo and autoantibodies to mouse AChR were higher in B6 mice, and were biased toward the IgG2b isotype. We conclude that the "better fit" of MHC II, peptide, and TCR in the B6 mice enhanced cognate interactions of APCs with T cells, and T cells with B cells, resulting in a more abundant and pathogenic AChR antibody response, and thus more severe EAMG.
Yang
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B
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287-7519, USA.
McIntosh
K R
KR
Drachman
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DB
D000818:Animals; D000918:Antibody Specificity; D017951:Antigen Presentation; D001323:Autoantibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D015329:Gene Rearrangement, T-Lymphocyte; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006825:Hybridomas / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009157:Myasthenia Gravis / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D011950:Receptors, Cholinergic / Q000276:immunology*; D013045:Species Specificity; D014101:Torpedo / Q000276:immunology
D001323:Autoantibodies; D018076:DNA, Complementary; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011950:Receptors, Cholinergic