Myasthenia gravis and the tops and bottoms of AChRs: antigenic structure of the MIR and specific immunosuppression of EAMG using AChR cytoplasmic domains.
The main immunogenic region (MIR), against which half or more of the autoantibodies to acetylcholine receptors (AChRs) in myasthenia gravis (MG) or experimental autoimmune MG (EAMG) are directed, is located at the extracellular end of alpha1 subunits. Rat monoclonal antibodies (mAbs) to the MIR efficiently compete with MG patient autoantibodies for binding to human muscle AChRs. Antibodies bound to the MIR do not interfere with cholinergic ligand binding or AChR function, but target complement and trigger antigenic modulation. Rat mAbs to the MIR also bind to human ganglionic AChR alpha3 subunits, but MG patient antibodies do not. By making chimeras of alpha1 subunits with alpha7 subunits or ACh binding protein, the structure of the MIR and its functional effects are being investigated. Many mAbs to the MIR bind only to the native conformation of alpha1 subunits because they bind to sequences that are adjacent only in the native structure. The MIR epitopes recognized by these mAbs are not recognized by most patient antibodies whose epitopes must be nearby. The presence of the MIR epitopes in alpha1/alpha7 chimeras greatly promotes AChR expression and sensitivity to activation. EAMG can be suppressed by treatment with denatured, bacterially expressed mixtures of extracellular and cytoplasmic domains of human alpha1, beta1, gamma, delta, and epsilon subunits. A mixture of only the cytoplasmic domains not only avoids the potential liability of provoking formation antibodies to pathologically significant epitopes on the extracellular surface, but also potently suppresses the development of EAMG.
Department of Neuroscience, Medical School of the University of Pennsylvania, 217 Stemmler Hall, Philadelphia, PA 19104, USA. JSLKK@mail.med.upenn.edu
Jon
J
Lindstrom
Jie
J
Luo
Alexander
A
Kuryatov
D000818:Animals; D000941:Antigens / Q000737:chemistry / Q000276:immunology; D003593:Cytoplasm / Q000276:immunology* / Q000378:metabolism*; D004594:Electrophysiology; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007167:Immunotherapy; D009157:Myasthenia Gravis / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D009865:Oocytes; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000737:chemistry / Q000276:immunology; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D014982:Xenopus laevis
D000941:Antigens; D021122:Protein Subunits; D011950:Receptors, Cholinergic