Specific immunotherapy of experimental myasthenia gravis by a novel mechanism.
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 alpha1 subunits.


CONCLUSIONS
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.
Luo
Jie
J
Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, PA 19104-6074, USA.
Kuryatov
Alexander
A
Lindstrom
Jon M
JM
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods*; D018482:Muscle, Skeletal / Q000276:immunology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology* / Q000628:therapy*; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D021122:Protein Subunits / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000276:immunology*; D013997:Time Factors
D001323:Autoantibodies; D007074:Immunoglobulin G; D010446:Peptide Fragments; D021122:Protein Subunits; D011950:Receptors, Cholinergic; D010047:Ovalbumin