Antibodies to Clustered Acetylcholine Receptor in Myasthenia Gravis
Abstract & Commentary
By Norman Latov, MD, PhD. Professor of Neurology and Neuroscience, Director of the Peripheral Neuropathy Center, Weill Cornell Medical College. Dr. Latov has served a consultant to Grifols, Novartis, CSL Behring, Pfizer, Baxter Biotherapeutics, Elan Pharmaceuticals, and Eisai Inc. He owns stock in Therapath LLC, and is the beneficiary of a licensing agreement between Cornell University and Teva Pharmaceuticals.
Synopsis: Up to 50% of patients with seronegative ocular myasthenia gravis have antibodies to clustered acetylcholine receptor antibodies that can fix complement and passively transfer disease to experimental mice.
Source: Jacob S, et al. Presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis. Arch Neurol 2012;69:994-1001.
In generalized myasthenia gravis, 80-85% of the patients have antibodies to the acetylcholine receptor (AChR) detected by the standard radio immunoprecipitation assay, and an additional 5-8% have antimuscle specific kinase (MuSK) antibodies. The remainder, approximately 10%, are considered to be seronegative. In ocular myasthenia, approximately 10% are seronegative or have no detectable autoantibody activity. Proposed mechanisms included differential expression of fetal AChRs in the extraocular muscles or the presence of low-affinity antibodies that cannot be detected by the standard assay.
Using a newly developed immunofluorescence assay for detecting antibodies to clustered AChR on the surface of human embryonic kidney cells, the authors detected anticlustered AChR in 50% of previously seronegative patients with ocular myasthenia. The cells were transfected with recombinant AChR subunits in association with the clustering protein rapsyn, resulting in the expression of high-density AChR clusters, as occurs at the neuromuscular junction. This allowed for detection of antibodies with lower intrinsic affinities, whose apparent affinity would be enhanced by formation of stable bonds by both F(ab)s with neighboring AChR on the cell membrane.
Antibodies to AChR can bind, block, or modulate the receptor on skeletal muscle.1 The anticlustered AChR antibodies were of the IgG1 subtype and were capable of activating complement. IgG binding and complement deposition correlated with the mean consecutive difference (jitter) on single-fiber electromyography, and passive transfer of purified IgG from two patients with clustered AChR antibodies into wild type or complement regulator-deficient mice reduced miniature end-plate potential amplitudes, with complement deposition at the end plates, providing further support for their pathogenicity.
In addition to providing a potentially more sensitive assay for anti-AChR for diagnosing ocular myasthenia gravis, these studies indicate that the anticlustered anti-AChR receptor antibodies are similar to non-clustered AChR antibodies that are typically present in patients with generalized myasthenia gravis, and they act by similar mechanisms. The anticlustered anti-AChR antibodies react with the adult form of the AChR rather than the fetal form, making it unlikely that differential expression of the fetal form of AChR plays a role. The studies also support a role for complement activation in the disease process, providing a rationale for testing novel agents that inhibit the complement cascade2 as potential therapies.
References
1. Howard FM Jr, et al. Clinical correlations of antibodies that bind, block, or modulate human acetylcholine receptors in myasthenia gravis. Ann NY Acad Sci 1987;505:526-538.
2. Soltys J, et al. Novel complement inhibitor limits severity of experimental myasthenia gravis. Ann Neurol 2009;65:67-75.
Up to 50% of patients with seronegative ocular myasthenia gravis have antibodies to clustered acetylcholine receptor antibodies that can fix complement and passively transfer disease to experimental mice.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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