The autoimmune condition myasthenia gravis results from the production of self-reactive antibodies to the nicotinic acetylcholine receptor (AChR). Because this receptor is required for the transmission of signals at the neuromuscular junction, the aberrant nerve-muscle communication that results from an antibody-mediated inhibition of AChR clustering leads to muscular weakness at a range of anatomic locations.
A small proportion of myasthenic patients do not carry detectable levels of AChR antibodies, and most of these present instead with antibodies directed against muscle-specific kinase (MuSK). Using an experimental model for myasthenia, Shigemoto et al. show that such self-reactive antibodies may mediate pathogenesis, too. After the induction of antibodies to MuSK by vaccination with a chimeric protein, rabbits developed progressive muscular weakness. Reduced AChR clustering was detected at neuromuscular junctions in tissue sections taken from these animals; and in cell culture, antibodies to MuSK diminished experimentally induced AChR clustering. It will be important to establish whether antibodies to MuSK or other neuromuscular targets have an equivalent influence on myasthenia gravis in humans; if this is the case, then improved mechanistic understanding of the disease and new therapeutic options may follow. -- SJS
J. Clin. Invest. 116, 10.1172/JCI21545 (2006).
