肌肉特异性激酶重症肌无力(MuSKMG)是由神经肌肉接头(NMJ)中针对MuSK的自身抗体引起的。MuSKMG患者有波动,易疲劳的骨骼肌无力,尤其是延髓肌肉。患者之间的严重程度差异很大,尽管自身抗体水平相当。患者间和肌肉间敏感性变异性的一种解释可能是代偿性肌肉反应的变化。以前,我们为MuSKMG开发了被动转移鼠标模型。在初步的离体实验中,我们观察到一些小鼠的肌肉收缩,特别是那些患有轻度肌无力的人,已经对μ-Conotoxin-GIIIB的抑制作用部分不敏感,骨骼肌NaV1.4电压门控钠通道阻断剂。我们假设NaV通道表达谱的变化,可能共表达(μ-毒素-GIIIB不敏感)NaV1.5型通道,可能降低肌肉纤维的放电阈值,促进神经肌肉突触传递。为了检验这个假设,我们在免疫受损的小鼠中进行了被动转移,使用\'高\',纯化的MuSKMG患者IgG4的“中间”和“低”给药方案。我们比较了肌无力的程度,μ-Conotoxin-GIIIB抗性和肌纤维动作电位特征和激发阈值。高剂量和中等剂量的小鼠显示清晰,进行性肌无力,在低剂量动物中没有见过。然而,NMJ膈肌电生理学显示,在所有方案中,肌无力的严重程度几乎相等。尽管如此,低剂量的小鼠隔膜显示出更高的μ-Conotoxin-GIIIB抗性。这不能通过Scn5a(NaV1.5基因)的上调来解释,降低肌纤维放电阈值或组织学上可检测到的上调的NaV1.5通道。尚待确定的因素是导致观察到的μ-Conotoxin-GIIIB不敏感性的原因,以及NaV库的变化是补偿性有益还是旁观者效应。
Muscle-specific kinase myasthenia gravis (
MuSK MG) is caused by autoantibodies against
MuSK in the neuromuscular junction (NMJ).
MuSK MG patients have fluctuating, fatigable skeletal muscle weakness, in particular of bulbar muscles. Severity differs greatly between patients, in spite of comparable autoantibody levels. One explanation for inter-patient and inter-muscle variability in sensitivity might be variations in compensatory muscle responses. Previously, we developed a passive transfer mouse model for
MuSK MG. In preliminary ex vivo experiments, we observed that muscle contraction of some mice, in particular those with milder myasthenia, had become partially insensitive to inhibition by μ-Conotoxin-GIIIB, a blocker of skeletal muscle NaV1.4 voltage-gated sodium channels. We hypothesised that changes in NaV channel expression profile, possibly co-expression of (μ-Conotoxin-GIIIB insensitive) NaV1.5 type channels, might lower the muscle fibre\'s firing threshold and facilitate neuromuscular synaptic transmission. To test this hypothesis, we here performed passive transfer in immuno-compromised mice, using \'high\', \'intermediate\' and \'low\' dosing regimens of purified
MuSK MG patient IgG4. We compared myasthenia levels, μ-Conotoxin-GIIIB resistance and muscle fibre action potential characteristics and firing thresholds. High- and intermediate-dosed mice showed clear, progressive myasthenia, not seen in low-dosed animals. However, diaphragm NMJ electrophysiology demonstrated almost equal myasthenic severities amongst all regimens. Nonetheless, low-dosed mouse diaphragms showed a much higher degree of μ-Conotoxin-GIIIB resistance. This was not explained by upregulation of Scn5a (the NaV1.5 gene), lowered muscle fibre firing thresholds or histologically detectable upregulated NaV1.5 channels. It remains to be established which factors are responsible for the observed μ-Conotoxin-GIIIB insensitivity and whether the NaV repertoire change is compensatory beneficial or a bystander effect.