Abstract
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ). Autoantibodies target key molecules at the NMJ, such as the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (Lrp4), that lead by a range of different pathogenic mechanisms to altered tissue architecture and reduced densities or functionality of AChRs, reduced neuromuscular transmission, and therefore a severe fatigable skeletal muscle weakness. In this review, we give an overview of the history and clinical aspects of MG, with a focus on the structure and function of myasthenic autoantigens at the NMJ and how they are affected by the autoantibodies’ pathogenic mechanisms. Furthermore, we give a short overview of the cells that are implicated in the production of the autoantibodies and briefly discuss diagnostic challenges and treatment strategies.
Highlights
Autoantibodies target key molecules at the neuromuscular junction (NMJ), such as the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (Lrp4), that lead by a range of different pathogenic mechanisms to altered tissue architecture and reduced densities or functionality of AChRs, reduced neuromuscular transmission, and a severe fatigable skeletal muscle weakness
The downstream signaling cascade induces the formation of the NMJ, including postsynaptic differentiation characterized by the accumulation of AChRs at synaptic sites and presynaptic differentiation illustrated by the development of active zones [157] (Figure 3A)
There are only a few studies on Agrin autoantibodies, but in one study, patient serum was found to inhibit Agrin-induced MuSK phosphorylation in C2C12 myotubes, suggesting a blocking of Lrp4-Agrin interaction [78], and in line with these findings the active immunization of mice with neural Agrin-induced myasthenic weakness and fragmented synapses [88]. These results suggest that the autoantibodies may be directed against the B/Z loop located in LG3, which would explain the observed lack of MuSK activation due to an impairment of Agrin-LRP4 interaction
Summary
Pathogenic mechanisms of serum or purified IgG from MG patients with AChR or MuSK autoantibodies have been identified, the passive transfer of patient serum or purified IgG has reproduced myasthenic weakness in experimental animals, and clinical cues for the autoimmune nature of the disease is the improvement of the symptoms after immunosuppression and after the removal of antibodies by plasmapheresis or B-cell depletion (discussed below in detail). Lrp MG patients are predominantly female (female to male ratio of 2.5:1) and have usually a generalized mild muscular weakness, unless additional antibodies to MuSK or AChR are present [48]. A pilot study with four Lrp MG thymi showed no thymic abnormalities, but the positive clinical response in two of the patients still suggests a potential benefit of thymectomy [50]
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