Auret Jennifer, Abrahams Amaal, Prince Sharon, Heckmann Jeannine M
Neurology Research Group, Department of Medicine, University of Cape Town, Cape Town, South Africa; Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa.
Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa.
Neuromuscul Disord. 2014 Jun;24(6):499-508. doi: 10.1016/j.nmd.2014.02.010. Epub 2014 Mar 6.
Decay accelerating factor (DAF) expression at the muscle endplate is an important defence against complement-mediated damage in myasthenia gravis. Previously we implicated the c.-198C>G DAF polymorphism with the development of treatment-resistant myasthenia-associated ophthalmoplegia by showing that the C>G DAF polymorphism prevented lipopolysaccharide-induced upregulation of lymphoblast DAF. We postulated that drugs used in myasthenia gravis may increase the susceptibility of extraocular muscles to complement-mediated damage and studied their effects on endogenous DAF using patient-derived lymphoblasts as well as mouse myotubes. We show that prednisone repressed C>G DAF expression in lymphoblasts and increased their susceptibility to cytotoxicity. Methotrexate, but not azathioprine or cyclosporine, increased DAF in C>G lymphoblasts. In mouse myotubes expressing wild-type Daf, prednisone also repressed Daf expression. Although cyclosporine, azathioprine, and methotrexate increased muscle Daf levels when used alone, upon co-treatment with prednisone only azathioprine maintained myotube Daf levels close to basal. Therefore, prednisone negatively influences DAF expression in C>G lymphoblasts and in myotubes expressing wild-type Daf. We speculate that myasthenic individuals at risk of developing the ophthalmoplegic complication, such as those with C>G DAF, may have inadequate endogenous levels of complement regulatory protein protection in their extraocular muscle in response to prednisone, increasing their susceptibility to complement-mediated damage.
衰变加速因子（DAF）在肌肉终板的表达是重症肌无力中抵御补体介导损伤的重要防御机制。此前我们通过研究发现，c.-198C>G DAF基因多态性与难治性重症肌无力相关眼肌麻痹的发生有关，因为C>G DAF基因多态性可阻止脂多糖诱导的淋巴母细胞DAF上调。我们推测，重症肌无力治疗中使用的药物可能会增加眼外肌对补体介导损伤的易感性，并使用患者来源的淋巴母细胞和小鼠肌管研究了这些药物对内源性DAF的影响。我们发现泼尼松可抑制淋巴母细胞中C>G DAF的表达，并增加其对细胞毒性的易感性。甲氨蝶呤可增加C>G淋巴母细胞中的DAF表达，而硫唑嘌呤和环孢素则无此作用。在表达野生型Daf的小鼠肌管中，泼尼松也可抑制Daf的表达。虽然单独使用时环孢素、硫唑嘌呤和甲氨蝶呤均可增加肌肉Daf水平，但与泼尼松联合使用时，只有硫唑嘌呤能使肌管Daf水平维持在接近基础水平。因此，泼尼松对C>G淋巴母细胞和表达野生型Daf的肌管中的DAF表达有负面影响。我们推测，有发生眼肌麻痹并发症风险的重症肌无力患者，如携带C>G DAF的患者，其眼外肌中内源性补体调节蛋白保护水平可能不足，无法应对泼尼松的作用，从而增加了其对补体介导损伤的易感性。
