**3. Conclusion**

448 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

Fig. 5. The effect of MuSK-antibodies at the neuromuscular junction (NMJ) in mice immunized with MuSK. Confocal microscopy images with 100x magnification of

presynaptic nerve terminal area is significantly smaller and the AChR clusters are

fragmented and scattered along the muscle fiber. Scale bar is 10 μm.

of the postsynaptic morphology and less folding. Scale bar is 10 µm.

and EAMG.

immunostained whole mount muscle fibers from the sternomastoid muscle. A) A normal NMJ, where α-bungarotoxin labels the AChR clusters (green) and antibodies against synaptophysin and neurofilament labels the nerve terminal (red). Note the close alignment between the motor nerve terminal and clustered postsynaptic AChRs. B) In MuSK+ MG, the

Fig. 6. Immunolabeling of whole mount muscle fibers from the omohyoid muscle, where postsynaptic acetylcholine receptors (AChRs) are labelled with α-bungarotoxin (white). In the control mice (A) a normal pattern with postsynaptic AChR clusters are seen in the junctional folds, adjacent to the motor nerve. In MuSK+ EAMG mice (B), the AChRs are very faint, with a subsequent reduction in postsynaptic AChR cluster area. In AChR+ EAMG mice (C), the staining intensity of the α-bungarotoxin was less reduced than in the MuSK+ EAMG mice, however there is a disruption in AChR cluster morphology with simplification

an increased plasticity (Punga, Maj et al, 2011). n the contrary, low muscle-intrinsic MuSK levels render some muscles, such as the masseter, more vulnerable to the postsynaptic perturbation of MuSK antibodies with subsequent denervation and atrophy (Punga, Lin et al, 2011). This is hypothesized to play a role for the muscle selectivity also in MuSK+ MG In summary, studies in the recent years of the murine EAMG model provide further insights regarding the action of MuSK antibodies at the NMJ and give evidence for their pathogenetic role, especially in facial and bulbar muscles. The results of the MuSK antibody attack is fragmentation and dispersion of nicotinic AChRs, postsynaptic perturbation and a subsequent impaired neuromuscular transmission. Since MuSK+ MG is very focal in its clinical manifestations it is very important to examine the clinically weak muscles also neurophysiologically to confirm the diagnosis, and for morphological purpose when examining the NMJ pathophysiology. The findings of dispersion of AChRs may also indicate irreparable changes at the NMJ, explaining muscle atrophies in these patients. It is therefore of importance to identify MG patients as early as possible, and especially MuSK+ MG, since delayed treatment may result in muscle atrophies and even functional denervation due to long time of blocked neuromuscular transmission. Immunosuppressive treatment should always be the main medication in MG and AChEIs is not receommended as symptomatic treatment in MuSK+ patients due to the cholinergic hypsersensitivity and unbeneficial effects.
