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Specific immunotherapy of experimental myasthenia gravis by a novel mechanism
Author(s) -
Luo Jie,
Kuryatov Alexander,
Lindstrom Jon M.
Publication year - 2010
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21901
Subject(s) - myasthenia gravis , epitope , acetylcholine receptor , autoantibody , neuromuscular junction , immunology , extracellular , immunotherapy , antigen , autoimmunity , medicine , antibody , receptor , biology , neuroscience , microbiology and biotechnology , immune system
Objective Myasthenia gravis (MG) and its animal model, experimental autoimmune myasthenia gravis (EAMG), are antibody (Ab)‐mediated autoimmune diseases, in which autoantibodies bind to and cause loss of muscle nicotinic acetylcholine receptors (AChRs) at the neuromuscular junction. To develop a specific immunotherapy of MG, we treated rats with ongoing EAMG by intraperitoneal injection of bacterially‐expressed human muscle AChR constructs. Methods Rats with ongoing EAMG received intraperitoneal treatment with the constructs weekly for 5 weeks beginning after the acute phase. Autoantibody concentration, subclassification, and specificity were analyzed to address the underlying therapeutic mechanism. Results EAMG was specifically suppressed by diverting autoantibody production away from pathologically relevant specificities directed at epitopes on the extracellular surface of muscle AChRs toward pathologically irrelevant epitopes on the cytoplasmic domain. A mixture of subunit cytoplasmic domains was more effective than a mixture containing both extracellular and cytoplasmic domains or than only the extracellular domain of α1 subunits. Interpretation Therapy using only cytoplasmic domains, which lack pathologically relevant epitopes, avoids the potential liability of boosting the pathological response. Use of a mixture of bacterially‐expressed human muscle AChR cytoplasmic domains for antigen‐specific immunosuppression of myasthenia gravis has the potential to be specific, robust, and safe. ANN NEUROL 2010;67:441–451