The Effect of Plasma From Muscle-Specific Tyrosine Kinase Myasthenia Patients on Regenerating Endplates

Abstract

Muscle-specific tyrosine kinase (MuSK) is essential for clustering of acetylcholine receptors (AChRs) at embryogenesis and likely also important for maintaining synaptic structure in adult muscle. In 5 to 7% of myasthenia gravis (MG) cases, the patients' blood contains antibodies to MuSK. To investigate the effect of MuSK-MG antibody on synapse regeneration, notexin was used to induce damage to the flexor digitorum brevis muscle. We administered aliquots of MuSK-MG patients' plasma to the flexor digitorum brevis twice daily for a period up to 21 days, and muscles were investigated ex vivo in contraction experiments. AChR levels were measured with 125 I-␣-bungarotoxin, and endplates were studied with quantitative immunohistochemistry. In normal muscles and in 14-day regenerated muscles, MuSK plasma caused impairment of nerve stimulus-induced contraction in the presence of 0.35 and 0.5 mmol/L Ca 2؉ with or without 100 to 400 nmol/L tubocurarine. Endplate size was decreased in regenerated muscles relative to controls; however, we did not observe such differences in muscle not treated with notexin. MuSK plasma had no effect on the amount and turnover rate of AChRs. Our results suggest that anti-MuSK anti-

Anti-MuSK autoantibodies block binding of collagen Q to MuSK

“…Similarly, injection of MuSK-IgG into mice reduces the number of AChRs at the NMJ to 22% of controls, compromises the apposition of the presynaptic and postsynaptic components of the NMJ, 24 and reduces muscle contractility. 27 A recent report demonstrates that MuSK-IgG enhances internalization of MuSK from plasma membrane, which leads to progressive dispersal of postsynaptic AChRs by disruption of the MuSK scaffold and not by disruption of the agrin/LRP4/MuSK signaling pathway. 26 To summarize, MuSK-IgG does not reduce AChR expression in cultured cells, but active and passive immunization of model animals results in AChR deficiency, which is not likely due to blocking of the agrin/LRP4/MuSK pathway.…”

“…We found that even at 100 g IgG of control 2 or patient 2 did not block binding of LRP4 to MuSK ( figure 3B). DISCUSSION Molecular basis of MuSK-MG has been examined in cultured cells 30,31 as well as in active 28,29 and passive 24,26,27 immunization models. Application of MuSK-MG antibodies to TE671 muscle cells induces inhibition of cell proliferation and secondarily leads to downregulation of AChR and rapsyn.…”

Acute Severe Animal Model of Anti–Muscle-Specific Kinase Myasthenia

“…In some NMJs, there is misalignment between the presynaptic and postsynaptic portions of these synapses. The latter findings, some of which were also observed in the study of passive transfer of human AMM serum into mice 35 and in one of the three studies of AMM 40 , suggest that there is abnormal “signaling” between nerve terminal and muscle endplate in both directions resulting in failure of maintenance of the mature synapse in these animals 41 .…”

The auto-antigen repertoire in myasthenia gravis

“…In addition, mice [76] and rabbits [77,78] immunized with domains of MuSK protein show less nAChR clustering at the NMJ and develop myasthenic symptoms, although it should be borne in mind that these immunization procedures elicit antibodies with the ability to activate complement, as anti-nAChR antibodies do, in contrast to human anti-MuSK antibodies that mostly lack this function (see below). Passive transfer of human anti-MuSK antibodies influences the activity of MuSK in regenerating endplates in mice, but without reducing MuSK levels, and thereby diminishes the size of the endplate affecting the functioning of AChRs [79]. Nevertheless, the exact pathways leading to disturbed neuromuscular transmission in MuSK-MG patients are still unclear and need further investigation.…”