Lin Feng, Kaminski Henry J, Conti-Fine Bianca M, Wang Wei, Richmonds Chelliah, Medof M Edward
Institute of Pathology, Case Western Reserve University, University Hospitals of Cleveland, and Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 44106, USA.
J Clin Invest. 2002 Nov;110(9):1269-74. doi: 10.1172/JCI16086.
Myasthenia gravis (MG) is an autoimmune neuromuscular transmission disorder characterized by loss of acetylcholine receptors (AChR's) due primarily to the production of anti-AChR autoantibodies. In this study we investigated whether the presence of decay-accelerating factor (DAF or CD55), an intrinsic complement regulator, protects against the development of disease. Experimental autoimmune MG was induced in Daf1(-/-) mice (devoid of neuromuscular DAF protein) and their Daf1(+/+) littermates by injection of rat anti-AChR mAb McAb-3. After twenty-four hours, grip strength assessment revealed that Daf1(-/-) mice exhibited hold times of less than 30 seconds, compared with more than 8 minutes for the Daf1(+/+) controls. The weakness was reversed by edrophonium, consistent with a myasthenic disorder. Immunohistochemistry revealed greatly augmented C3b deposition localized at postsynaptic junctions, and radioimmunoassays showed more profound reductions in AChR levels. Electron microscopy demonstrated markedly greater junctional damage in the Daf1(-/-) mice compared with the Daf1(+/+) littermates. Control studies showed equivalent levels of other cell surface regulators, i.e., Crry and CD59. The results demonstrate that mice that lack DAF are markedly more susceptible to anti-AChR-induced MG, which simulates the primary mechanism in the human disease, and strongly suggest that in disease flares complement inhibitors might have therapeutic value.
重症肌无力（MG）是一种自身免疫性神经肌肉传递障碍疾病，主要特征是由于抗乙酰胆碱受体（AChR）自身抗体的产生导致乙酰胆碱受体丧失。在本研究中，我们调查了内源性补体调节因子衰变加速因子（DAF或CD55）的存在是否能预防疾病的发生。通过注射大鼠抗AChR单克隆抗体McAb-3，在Daf1(-/-)小鼠（缺乏神经肌肉DAF蛋白）及其Daf1(+/+)同窝小鼠中诱导实验性自身免疫性MG。24小时后，握力评估显示，Daf1(-/-)小鼠的抓握时间少于30秒，而Daf1(+/+)对照小鼠的抓握时间超过8分钟。依酚氯铵可逆转肌无力症状，这与重症肌无力疾病相符。免疫组织化学显示，突触后连接处的C3b沉积显著增加，放射免疫分析显示AChR水平下降更为明显。电子显微镜显示，与Daf1(+/+)同窝小鼠相比，Daf1(-/-)小鼠的突触损伤明显更严重。对照研究表明，其他细胞表面调节因子，即Crry和CD59的水平相当。结果表明，缺乏DAF的小鼠对抗AChR诱导的MG明显更易感，这模拟了人类疾病的主要机制，并强烈提示在疾病发作时补体抑制剂可能具有治疗价值。
