Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis
Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis
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DOI：
10.1007/s00415-011-6194-7
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发表时间：
2012-03-01
影响因子：
6
通讯作者：
Kroeger, Stephan
中科院分区：
文献类型：
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作者：
Pevzner, Alexandra;Schoser, Benedikt;Kroeger, Stephan
重症肌无力（MG）是一种自身免疫性疾病，其特征是神经肌肉接头处的突触传递缺陷，导致波动性肌无力，对重复神经刺激的反应减弱或单纤维肌电图（EMG）中的抖动改变。大约80%的重症肌无力患者血清中存在抗烟碱乙酰胆碱受体的自身抗体。针对酪氨酸激酶肌肉特异性激酶（MuSK）的自身抗体是所有重症肌无力病例的5-10%的原因。其余病例的自身免疫靶点未知。最近，低密度脂蛋白受体相关蛋白4（LRP 4）已被确定为聚集蛋白受体。LRP 4与聚集蛋白相互作用，聚集蛋白的结合激活MuSK，这导致形成大多数（如果不是全部）突触后特化，包括在接合质膜中含有乙酰胆碱受体（AChR）的聚集体。在本研究中，我们测试了是否在重症肌无力患者中可检测到针对LRP 4的自身抗体。为此，我们分析了13例全身性重症肌无力患者的血清，但没有AChR或MuSK抗体。结果显示，13份来自双血清阴性MG患者的抗血清中有12份与浓缩在成年小鼠骨骼肌神经肌肉接头处的蛋白质结合，约50%的测试血清特异性结合人LRP 4转染的HEK 293细胞。此外，这13个血清中的4个抑制聚集蛋白诱导的AChRs在培养的肌管中聚集超过50%，这表明关于神经肌肉终板功能障碍的致病作用。这些结果表明，LRP 4是自身抗体的新靶标，并且是血清阴性MG患者的诊断标志物。
Myasthenia gravis (MG) is an autoimmune disorder characterized by a defect in synaptic transmission at the neuromuscular junction causing fluctuating muscle weakness with a decremental response to repetitive nerve stimulation or altered jitter in single-fiber electromyography (EMG). Approximately 80% of all myasthenia gravis patients have autoantibodies against the nicotinic acetylcholine receptor in their serum. Autoantibodies against the tyrosine kinase muscle-specific kinase (MuSK) are responsible for 5-10% of all myasthenia gravis cases. The autoimmune target in the remaining cases is unknown. Recently, low-density lipoprotein receptor-related protein 4 (LRP4) has been identified as the agrin receptor. LRP4 interacts with agrin, and the binding of agrin activates MuSK, which leads to the formation of most if not all postsynaptic specializations, including aggregates containing acetylcholine receptors (AChRs) in the junctional plasma membrane. In the present study we tested if autoantibodies against LRP4 are detectable in patients with myasthenia gravis. To this end we analyzed 13 sera from patients with generalized myasthenia gravis but without antibodies against AChR or MuSK. The results showed that 12 out of 13 antisera from double-seronegative MG patients bound to proteins concentrated at the neuromuscular junction of adult mouse skeletal muscle and that approximately 50% of the tested sera specifically bound to HEK293 cells transfected with human LRP4. Moreover, 4 out of these 13 sera inhibited agrin-induced aggregation of AChRs in cultured myotubes by more than 50%, suggesting a pathogenic role regarding the dysfunction of the neuromuscular endplate. These results indicate that LRP4 is a novel target for autoantibodies and is a diagnostic marker in seronegative MG patients.