Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy.
Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy.
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DOI：
10.1002/art.30156
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发表时间：
2011-03
影响因子：
--
通讯作者：
Casciola-Rosen, Livia A.
中科院分区：
文献类型：
--
作者：
Mammen, Andrew L.;Chung, Tae;Christopher-Stine, Lisa;Rosen, Paul;Rosen, Antony;Doering, Kimberly R.;Casciola-Rosen, Livia A.
除了诱导自限性肌病外，他汀类药物的使用与免疫介导的坏死性（IMNM）肌病有关，其自身抗体识别~ 200和~100 kDa的自身抗原。识别这些分子将有助于阐明疾病的发病机制，促进诊断。他汀类药物治疗对自身抗原表达的影响通过患者血清免疫沉淀来解决。通过体外翻译HMGCR蛋白的免疫沉淀证实了~100 kDa自身抗原的身份。免疫荧光法分析HMGCR在肌肉组织中的表达。一组肌病患者通过ELISA筛选抗hmgcr自身抗体，并对rs4149056 C等位基因进行基因分型，rs4149056 C等位基因是自限性他汀类肌病的预测因子。他汀暴露诱导培养细胞表达~200/~100 kDa自身抗原。HMGCR鉴定为~100 kDa的自身抗原。竞争实验表明，没有明显的自身抗体识别~ 200kda蛋白。在抗HMGCR阳性患者的肌肉活检中，表达NCAM（肌肉再生标志物）的细胞中HMGCR表达上调。到约翰霍普金斯肌炎中心就诊的750例患者中有45例（6%）发现抗hmgcr自身抗体。在50岁及以上的患者中，92%的患者暴露于他汀类药物。抗hmgcr受试者中rs4149056 C等位基因的患病率未增加。他汀类药物上调HMGCR的表达，HMGCR是他汀相关IMNM中自身抗体的主要靶点。再生的肌肉细胞表达高水平的HMGCR，这可能在他汀类药物停用后维持免疫反应。这些研究证明了环境触发与持续自身免疫发展之间的机制联系。检测抗hmgcr自身抗体有助于诊断和指导治疗。
In addition to inducing a self-limited myopathy, statin use is associated with an immune-mediated necrotizing (IMNM) myopathy with autoantibodies recognizing ~ 200 and ~100 kDa autoantigens. Identifying these molecules will clarify disease mechanism and facilitate diagnosis. The effect of statin treatment on autoantigen expression was addressed by immunoprecipitation using patient sera. The identity of the ~100 kDa autoantigen was confirmed by immunoprecipitating in vitro-translated HMGCR protein. HMGCR expression in muscle was analyzed by immunofluorescence. A cohort of myopathy patients was screened for anti-HMGCR autoantibodies by ELISA and genotyped for the rs4149056 C allele, a predictor of self-limited statin myopathy. Statin exposure induced expression of the ~200/~100 kDa autoantigens in cultured cells. HMGCR was identified as the ~100 kDa autoantigen. Competition experiments demonstrated no distinct autoantibodies recognizing the ~200 kDa protein. In muscle biopsies from anti-HMGCR positive patients, HMGCR expression was up-regulated in cells expressing NCAM, a marker of muscle regeneration. Anti-HMGCR autoantibodies were found in 45 of 750 patients presenting to the Johns Hopkins Myositis Center (6%). Among patients age 50 or older, 92% were exposed to statins. The prevalence of the rs4149056 C allele was not increased in anti-HMGCR subjects. Statins up-regulate expression of HMGCR, the major target of autoantibodies in statin-associated IMNM. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response even after statins are discontinued. These studies demonstrate a mechanistic link between an environmental trigger and the development of sustained autoimmunity. Detection of anti-HMGCR autoantibodies may facilitate diagnosis and direct therapy.
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影响因子：
2.8
作者：
Needham, Merrilee;Fabian, Victoria;Mastaglia, Frank L.
通讯作者：
Mastaglia, Frank L.
DOI：
10.1111/j.1742-7843.2006.pto_193.x
发表时间：
2006-01-01
影响因子：
3.1
作者：
Soininen, K;Niemi, M;Kivistö, KT
通讯作者：
Kivistö, KT
影响因子：
3.5
作者：
Sarkar, K;Miller, FW
通讯作者：
Miller, FW
影响因子：
--
作者：
Mammen, Andrew L.;Casciola-Rosen, Livia A.;Hall, John C.;Christopher-Stine, Lisa;Corse, Andrea M.;Rosen, Antony
通讯作者：
Rosen, Antony
影响因子：
158.5
作者：
BOHAN, A;PETER, JB
通讯作者：
PETER, JB