Novel complement inhibitor limits severity of experimentally myasthenia gravis
- 1 January 2009
- journal article
- research article
- Published by Wiley in Annals of Neurology
- Vol. 65 (1), 67-75
- https://doi.org/10.1002/ana.21536
Abstract
Objective Complement mediated injury of the neuromuscular junction is considered a primary disease mechanism in human myasthenia gravis and animal models of experimentally acquired myasthenia gravis (EAMG). We utilized active and passive models of EAMG to investigate the efficacy of a novel C5 complement inhibitor rEV576, recombinantly produced protein derived from tick saliva, in moderating disease severity. Methods Standardized disease severity assessment, serum complement hemolytic activity, serum cytotoxicity, acetylcholine receptor (AChR) antibody concentration, IgG subclassification, and C9 deposition at the neuromuscular junction were used to assess the effect of complement inhibition on EAMG induced by administration of AChR antibody or immunization with purified AChR. Results Administration of rEV576 in passive transfer EAMG limited disease severity as evidenced by 100% survival rate and a low disease severity score. In active EAMG, rats with severe and mild EAMG were protected from worsening of disease and had limited weight loss. Serum complement activity (CH50) in severe and mild EAMG was reduced to undetectable levels during treatment, and C9 deposition at the neuromuscular junction was reduced. Treatment with rEV576 resulted in reduction of toxicity of serum from severe and mild EAMG rats. Levels of total AChR IgG, and IgG2a antibodies were similar, but unexpectedly, the concentration of complement fixing IgG1 antibodies was lower in a group of rEV576‐treated animals, suggesting an effect of rEV576 on cellular immunity. Interpretation Inhibition of complement significantly reduced weakness in two models of EAMG. C5 inhibition could prove to be of significant therapeutic value in human myasthenia gravis. Ann Neurol 2009;65:67–75Keywords
This publication has 38 references indexed in Scilit:
- Structure of and influence of a tick complement inhibitor on human complement component 5Nature Immunology, 2008
- Classical Complement Pathway in Experimental Autoimmune Myasthenia Gravis PathogenesisAnnals of the New York Academy of Sciences, 2008
- The Structure of OMCI, a Novel Lipocalin Inhibitor of the Complement SystemJournal of Molecular Biology, 2007
- Deficiency of decay accelerating factor and CD59 leads to crisis in experimental myastheniaExperimental Neurology, 2006
- Myasthenia gravis: past, present, and futureJCI Insight, 2006
- The membrane attack pathway of complement drives pathology in passively induced experimental autoimmune myasthenia gravis in miceClinical and Experimental Immunology, 2006
- Concerning the mechanism of pexelizumab's benefit in acute myocardial infarctionAmerican Heart Journal, 2006
- Rhabdomyosarcoma cell line can be used for the isolation of soluble acetylcholine receptor and for assaying blocking and modulating autoantibodiesJournal of Clinical Laboratory Analysis, 1993
- Complement-Mediated Muscle Damage Produced by Myasthenic SeraAnnals of the New York Academy of Sciences, 1987
- Myasthenic Antibodies Cross-Link Acetylcholine Receptors to Accelerate DegradationNew England Journal of Medicine, 1978