Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy.
Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy.
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DOI：
10.1084/jem.20041367
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发表时间：
2005-02-21
期刊：
影响因子：
--
通讯作者：
Rosen A
中科院分区：
文献类型：
--
作者：
Casciola-Rosen L;Nagaraju K;Plotz P;Wang K;Levine S;Gabrielson E;Corse A;Rosen A
独特的自身抗体特异性与不同的临床表型密切相关，使自身抗体对诊断和预后有用。为了研究这种显著关联的机制，我们检测了自身抗原在正常肌肉和自身免疫性肌炎患者肌肉中的表达。虽然肌炎自身抗原在对照肌肉中的表达水平很低，但在肌炎肌肉中的表达水平很高。此外，自身抗原表达的增加与分化状态相关，因此肌炎自身抗原的表达在具有再生肌肉细胞特征的细胞中增加。与此一致，我们发现培养的成肌细胞表达高水平的自身抗原，当细胞在体外分化为肌管时，这些自身抗原被显著下调。这些数据强烈表明，自身免疫性肌炎持续抗原供应的来源是再生的肌细胞，而不是成熟的肌管。肌炎自身抗原的表达在几种已知与自身免疫性肌炎相关的癌症中也显著增加，但在相关的正常组织中不表达，这表明肿瘤细胞和未分化的成肌细胞在抗原性上是相似的。我们认为，在癌症相关性肌炎中，针对癌症的自身免疫反应与再生的肌肉细胞发生交叉反应，从而实现了组织损伤和抗原选择的前馈循环。调节抗原表达的途径可能为自身免疫性疾病提供未知的治疗机会。
Unique autoantibody specificities are strongly associated with distinct clinical phenotypes, making autoantibodies useful for diagnosis and prognosis. To investigate the mechanisms underlying this striking association, we examined autoantigen expression in normal muscle and in muscle from patients with autoimmune myositis. Although myositis autoantigens are expressed at very low levels in control muscle, they are found at high levels in myositis muscle. Furthermore, increased autoantigen expression correlates with differentiation state, such that myositis autoantigen expression is increased in cells that have features of regenerating muscle cells. Consistent with this, we found that cultured myoblasts express high levels of autoantigens, which are strikingly down-regulated as cells differentiate into myotubes in vitro. These data strongly implicate regenerating muscle cells rather than mature myotubes as the source of ongoing antigen supply in autoimmune myositis. Myositis autoantigen expression is also markedly increased in several cancers known to be associated with autoimmune myositis, but not in their related normal tissues, demonstrating that tumor cells and undifferentiated myoblasts are antigenically similar. We propose that in cancer-associated myositis, an autoimmune response directed against cancer cross-reacts with regenerating muscle cells, enabling a feed-forward loop of tissue damage and antigen selection. Regulating pathways of antigen expression may provide unrecognized therapeutic opportunities in autoimmune diseases.
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