Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans
Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans
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DOI：
10.1172/jci44583
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发表时间：
2011-04-01
影响因子：
15.9
通讯作者：
Lipes, Myra A.
中科院分区：
文献类型：
--
作者：
Lv, HuiJuan;Havari, Evis;Lipes, Myra A.
长期以来，自身免疫与心肌炎及其后遗症扩张型心肌病有关，扩张型心肌病是年轻患者心力衰竭的主要原因。然而，潜在的机制是不明确的，与大多数临床研究集中在体液自身免疫作为干预的目标。在此，我们发现肌球蛋白重链α亚型（α-MyHC，由Myh 6基因编码）是自发性心肌炎小鼠模型中CD 4（+）T细胞的致病性自身抗原。此外，我们发现，Myh 6的成绩单是不存在的小鼠胸腺髓质上皮细胞（mTECs）和外周淋巴基质细胞，这已涉及在介导中央和外周T细胞耐受，分别。在胸腺上皮中转基因表达α-MyHC赋予对心肌肌球蛋白的耐受性并预防心肌炎，表明α-MyHC是这种疾病过程中的主要自身抗原。值得注意的是，我们发现人类mTEC中也缺乏α-MyHC，外周血中α-MyHC特异性T细胞的频率很高，心肌炎患者对α-MyHC的T细胞反应明显增强。由于α-MyHC构成了人类心脏中MyHC的一小部分，这些发现挑战了MyHC的自身免疫靶向是由于其心脏丰度的长期概念，而是表明它是由于受损的T细胞耐受机制而被靶向的。因此，这些结果支持T细胞特异性治疗心肌炎的作用。
Autoimmunity has long been linked to myocarditis and its sequela, dilated cardiomyopathy, the leading causes of heart failure in young patients. However, the underlying mechanisms are poorly defined, with most clinical investigations focused on humoral autoimmunity as the target for intervention. Here, we show that the alpha-isoform of myosin heavy chain (alpha-MyHC, which is encoded by the gene Myh6) is the pathogenic autoantigen for CD4(+) T cells in a spontaneous mouse model of myocarditis. Further, we found that Myh6 transcripts were absent in mouse medullary thymic epithelial cells (mTECs) and peripheral lymphoid stromal cells, which have been implicated in mediating central and peripheral T cell tolerance, respectively. Transgenic expression of alpha-MyHC in thymic epithelium conferred tolerance to cardiac myosin and prevented myocarditis, demonstrating that alpha-MyHC is a primary autoantigen in this disease process. Remarkably, we found that humans also lacked alpha-MyHC in mTECs and had high frequencies of alpha-MyHC-specific T cells in peripheral blood, with markedly augmented T cell responses to alpha-MyHC in patients with myocarditis. Since alpha-MyHC constitutes a small fraction of MyHC in human heart, these findings challenge the longstanding notion that autoimmune targeting of MyHC is due to its cardiac abundance and instead suggest that it is targeted as a result of impaired T cell tolerance mechanisms. These results thus support a role for T cell-specific therapies for myocarditis.