Finally one can ask whether these
Finally, one can ask whether these results throw any light on the nature of the target in SNMG patients. Interestingly, the results of the in vitro incubations suggested that SNMG sera might increase AChR expression to a small extent, raising the possibility that SNMG patients, who have thymic changes not unlike those in AChR-MG patients (Leite et al., 2005), may contain low levels of antibodies that bind to the AChR and lead to down-stream effects on AChR and MuSK expression. Indeed, binding of some SNMG IgG antibodies to AChRs by immunofluorescence on AChR-transfected cell lines has recently been demonstrated (Leite et al., in preparation). Half of the SNMG sera used in the TE671 cell experiments, and the SNMG serum used in the C2C12 experiments, were positive by this method.
Introduction Myasthenia gravis (MG) is an autoimmune disease, affecting the neuromuscular junction of the skeletal muscles. Patients present various symptoms usually due to destruction of muscle nicotinic LY2874455 receptors (AChRs) in the neuromuscular junction. Anti-AChR autoantibodies are detected in about the 85–90% of MG patients and lead to AChR loss, impaired neuromuscular signal transmission, and muscle weakness and fatigability (Meriggioli and Sanders, 2009). In the remaining 10–15% of MG patients, no such autoantibodies are detectable with established immunoassays (Padua et al., 2006), but antibodies against another protein at the neuromuscular junction, the muscle-specific kinase (MuSK), are detected in several of these patients (Hoch et al., 2001, McConville et al., 2004). MuSK mediates AChR clustering at the postsynaptic membrane, which is critical for neuromuscular transmission. MG patients with anti-MuSK antibodies seem to constitute a distinct MG subgroup (MuSK-MG) with somewhat different clinical characteristics from those of MG patients with anti-AChR antibodies (AChR-MG) and with normal thymus. In MuSK-MG sera, the majority of anti-MuSK antibodies are of the non-complement-binding IgG4 subclass (McConville et al., 2004, Tsiamalos et al., 2009), in contrast to AChR-MG, in which most anti-AChR antibodies are complement-binding IgG1, an observation suggesting different pathogenetic mechanisms in MuSK-MG and AChR-MG. The coexistence of different autoimmune diseases in the same patient is very often observed, indicating common immunogenetic mechanisms (Fridkis-Hareli, 2008). Nevertheless, coexistence of anti-MuSK and anti-AChR antibodies in the same MG patient is very rare (Suhail et al., 2010). d-penicillamine is a pyridoxine antagonist used as therapeutic agent in several diseases, such as rheumatoid arthritis, primary biliary cirrhosis, cystinuria, and scleroderma. Its effect on immunoregulation is indicated not only by its activity against autoimmune diseases, but also by the paradoxical induction of a number of immune-mediated disorders, such as MG, polymyositis, systemic lupus erythematosus, and pemphigus (Jaffe, 1964, Jaffe, 1976, Main and Roffe, 1976, Epstein et al., 1979). Approximately 1–7% of patients on d-penicillamine develop MG (Barrons, 1997, Vincent et al., 2001). It is also used for the treatment of Wilson's disease, as a cupper chelating drug, but without autoimmune side effects. The development of MG during d-penicillamine treatment demonstrates its immunologic toxicity (Bucknall et al., 1975, Gordon and Burnside, 1977, Masters et al., 1977, Atcheson and Ward, 1978, Dawkins and Zilko, 1979, Barrons, 1997, Vincent et al., 2001). Anti-AChR antibodies, thymic hyperplasia, and abnormal T cells have been reported in patients who developed d-penicillamine-induced MG (Bucknall et al., 1975). Patients with d-penicillamine-induced MG typically have a mild form of the disease, often limited to the extraocular muscles (Masters et al., 1977). Onset of disease varies, usually occurring 2 to 12months after commencement of d-penicillamine treatment and most patients show resolution of the disease 2 to 6months following its discontinuation (Conti-Fine et al., 2003).