Clinical and immunological correlates in myasthenia gravis associated with musk antibodies [Abstract]

Myasthenia Gravis (MG) is an autoimmune disorder affecting the neuromuscular junction. Muscle specific kinase (MuSK) antibodies are found in a variable proportion of patients with generalised disease who are acetylcholine receptor (AChR) antibody negative. Typically these patients have more prominent ocular, facial, bulbar, neck and respiratory weakness and often require long term immunosuppressive therapy. We document the clinical course of two such patients who have been under long term follow up at our centre.We correlated this with their MuSK antibody titres using the standard radio-immunoprecipitation assay. We examined the IgG subclasses and ability to activate complement (C3/Membrane Attack Complex) in vitro at several time points during their disease using a cell based assay. Finally we analysed the functional effects of the IgG antibodies on cultured C2C12 muscle cells. The MuSK antibodies in both patients were mainly of the IgG4 subclass although IgG2 and IgG1 antibodies were also seen later in the disease course.We found that the MuSK antibodies have the ability to activate complement in vitro, although the role of complement in vivo remains unclear. We also demonstrate that MuSK antibodies from these patients have variable ability to cause dispersal of acetylcholine receptor clusters in fully differentiated C2C12 muscle cells. These studies show that MuSK antibodies cause instability of preformed AChR clusters which has potential to disrupt neuromuscular transmission in vivo. Furthermore, IgG subclass switching and increased ability to activate complement in vitro may be responsible for fluctuations during the disease course