Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction
Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction
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DOI：
10.1002/ana.21371
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发表时间：
2008-06-01
影响因子：
11.2
通讯作者：
Phillips, William D.
中科院分区：
文献类型：
--
作者：
Cole, Rebecca N.;Reddel, Stephen W.;Phillips, William D.
目的：一组血清抗乙酰胆碱受体（anti-AChR）抗体阴性的重症肌无力患者血清抗肌肉特异性激酶抗体阳性（anti- musk阳性）。在这里，我们测试了从抗麝香阳性患者转移到小鼠体内的IgG是否会导致神经肌肉连接损伤和肌肉无力。方法：6周龄雌性FVB/NJ和C57BL/6J小鼠腹腔注射抗麝香阳性重症肌无力患者IgG或对照IgG（血清AChR和麝香阴性）（45mg / d，连续14 d）。采用荧光毒素染色的achr共聚焦荧光成像评估胫骨前肌和膈肌神经肌肉连接处的变化。通过肌电图评估功能丧失。结果：在注射抗麝香阳性患者IgG的实验小鼠中，突触后AChR染色减少到对照小鼠的22%。实验小鼠显示神经末梢（用抗突触素和神经丝的抗体标记）和突触后AChR簇（用荧光- α -兔毒标记）的附着减少。注射了来自三名抗麝香病毒阳性患者中的两名的IgG的小鼠体重减轻，并出现肌肉无力，这与重复神经刺激的肌电图痕迹减少有关。解释：抗麝香抗体阳性患者的IgG注射到小鼠体内可引起重症肌无力。这可能是由于突触后AChR密度的逐渐降低，同时神经末梢的变化及其与突触后结构的关系。
Objective: A subset of myasthenia gravis patients that are seronegative for anti-acetylcholine receptor (anti-AChR) antibodies are instead seropositive for antibodies against the muscle-specific kinase (anti-MuSK-positive). Here, we test whether transfer of IgG from anti-MuSK-positive patients to mice confers impairment of the neuromuscular junction and muscle weakness.Methods: IgG from anti-MuSK-positive myasthenia gravis patients or control IgG (seronegative for AChR and MuSK) was injected intraperitoneally (45mg daily for 14 days) into 6-week-old female FVB/NJ and C57BL/6J mice. Changes at neuromuscular junctions in the tibialis anterior and diaphragm muscles were assessed by confocal fluorescent imaging of AChRs stained with fluorescent-a-bungarotoxin. Loss of function was assessed by electromyography.Results: In experimental mice injected with anti-MuSK-positive patient IgG, postsynaptic AChR staining was reduced to as little as 22% of that seen in control mice. Experimental mice showed reduced apposition of the nerve terminal (labeled with antibodies against synaptophysin and neurofilament) and the postsynaptic AChR cluster (labeled with fluorescent-alpha-bungarotoxin). Mice injected with IgG from two of three anti-MuSK-positive patients lost weight and developed muscle weakness associated with a decremental electromyographic trace on repetitive nerve stimulation.Interpretation: IgG from anti-MuSK-positive patients can cause myasthenia gravis when injected into mice. This may be explained by a progressive reduction in the density of postsynaptic AChR combined with changes in the nerve terminal and its relation to the postsynaptic structure.