Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Medical School, New York, New York.
Ann N Y Acad Sci. 2018 Feb;1413(1):111-118. doi: 10.1111/nyas.13543. Epub 2018 Jan 21.
Myasthenia gravis (MG) with antibodies to muscle-specific kinase (MuSK) is characterized by fluctuating fatigable weakness. In MuSK MG, involvement of bulbar muscles, neck, and shoulder and respiratory weakness are more prominent than in acetylcholine receptor (AChR) MG. MuSK autoantibodies are mainly of the IgG4 subclass, and as such are unable to activate complement, have low affinity for Fc receptors, and are functionally monovalent. Therefore, the pathogenicity of IgG4 MuSK autoantibodies was initially questioned. A broad collection of in vitro active immunization and passive transfer models has been developed that have shed light on the pathogenicity of MuSK autoantibodies. Passive transfer studies with purified IgG4 from MuSK MG patients confirmed that IgG4 is sufficient to reproduce clear clinical, electrophysiological, and histological signs of myasthenia. In vitro experiments revealed that MuSK IgG4 autoantibodies preferably bind the first Ig-like domain of MuSK, correlate with disease severity, and interfere with the association between MuSK and low-density lipoprotein receptor-related protein 4 and collagen Q. Some patients have additional IgG1 MuSK autoantibodies, but their role in the disease is unclear. Altogether, this provides a rationale for epitope-specific or IgG4-specific treatment strategies for MuSK MG and emphasizes the importance of the development of different experimental models.
抗肌肉特异性激酶（MuSK）抗体阳性的重症肌无力（MG）以波动性、易疲劳性无力为特征。在 MuSK MG 中，延髓肌肉、颈部、肩部和呼吸肌无力比乙酰胆碱受体（AChR）MG 更明显。MuSK 自身抗体主要为 IgG4 亚类，因此不能激活补体，与 Fc 受体亲和力低，功能单价。因此，最初对 IgG4 MuSK 自身抗体的致病性提出了质疑。已经开发了广泛的体外主动免疫和被动转移模型，这些模型阐明了 MuSK 自身抗体的致病性。来自 MuSK MG 患者的纯化 IgG4 的被动转移研究证实，IgG4 足以重现明显的临床、电生理和组织学重症肌无力迹象。体外实验表明，MuSK IgG4 自身抗体优先结合 MuSK 的第一个免疫球蛋白样结构域，与疾病严重程度相关，并干扰 MuSK 与低密度脂蛋白受体相关蛋白 4 和胶原蛋白 Q 的结合。一些患者还有额外的 IgG1 MuSK 自身抗体，但它们在疾病中的作用尚不清楚。总之，这为 MuSK MG 的表位特异性或 IgG4 特异性治疗策略提供了依据，并强调了开发不同实验模型的重要性。
