Antibodies to LRP4 and Agrin Are Pathogenic in Myasthenia Gravis: At the Junction Where It Happens

Autoimmune myasthenia gravis (MG) is a T-cell–dependent, B-cell/antibody–mediated disease. The clinical symptoms and signs, as well as the clinical neurophysiologic and pharmacologic dysfunction, are due to abnormalities at the neuromuscular junction (NMJ). In the large majority of patients with generalized MG and 50% of patients with ocular MG, antibodies to the postsynaptic nicotinic acetylcholine receptor (AChR) are present in the serum.1 The presence of these antibodies has proved to be a useful test to aid in the diagnosis of autoimmune MG.2 A large number of in vitro, in vivo, and in situ studies, including immunization of experimental animals with AChR and passive transfer of AChR antibodies to animals to reproduce the disease, have demonstrated that AChR immunoglobulin G (IgG) antibodies are pathogenic. They mediate disease through several mechanisms, including activating the classic complement cascade, increasing the rate of normal endocytosis of AChR (modulating antibodies) at the muscle membrane, and blocking the binding site for acetylcholine on the α peptide of AChR via steric hindrance. All these result in less available AChR to bind acetylcholine released from the presynaptic nerve terminal (reviewed by Ruff and Lisak3). The identity of the other pathogenic antibodies was unknown for almost 3 decades until the demonstration of antibodies to muscle-specific kinase (MuSK) in 50% of patients with AChR-seronegative generalized MG.4 Antibodies to MuSK, a protein at the NMJ critical for the development and maintenance of NMJ and the proper positioning and anchoring of AChR, are pathogenic.3 More recently, antibodies to other important constituents of the NMJ, including low-density lipoprotein receptor–related protein 4 (LRP4) and agrin, have been described. Agrin activates LRP4 to interact with MuSK, which, as noted, is critical for proper expression of AChR, allowing normal neuromuscular transmission. The usefulness of these antibodies in the diagnosis of MG in patients without AChR or MuSK antibodies, so-called double-seronegative (DSN) MG, is still under investigation, but only a small percentage of patients with DSN MG have LRP4 and/or agrin antibodies.5

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