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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus
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Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus

机译：肼苯哒嗪破坏了B淋巴细胞的耐受性，这是药物性狼疮的潜在机制

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摘要

Accumulating evidence indicates that epigenetic alterations contribute to exacerbated activation or deregulation of the mechanisms that maintain tolerance to self-antigens in patients with lupus, a systemic autoimmune disease that can be triggered by medications taken to treat a variety of conditions. Here, we tested the effect of hydralazine, an antihypertensive drug that triggers lupus, on receptor editing, a chief mechanism of B lymphocyte tolerance to self-antigens. Using mice expressing transgenic human Igs, we found that hydralazine impairs up-regulation of RAG-2 gene expression and reduces secondary Ig gene rearrangements. Receptor editing was also partially abolished in a dose-dependent manner by a specific inhibitor of MEK1/2. Adoptive transfer of bone marrow B cells pretreated with hydralazine or with a MEK inhibitor to naieve syngeneic mice resulted in autoantibody production. We conclude that, by disrupting receptor editing, hydralazine subverts B lymphocyte tolerance to self and contributes to generation of pathogenic autoreactivity. We also postulate that inhibition of the Erk signaling pathway contributes to the patho-genesis of hydralazine-induced lupus and idiopathic human lupus.
机译：越来越多的证据表明，表观遗传学改变有助于维持狼疮患者对自身抗原的耐受性的机制的加剧激活或失调，狼疮是一种系统性自身免疫疾病，可以通过治疗多种疾病的药物来触发。在这里，我们测试了肼苯哒嗪（一种触发狼疮的降压药）对受体编辑的作用，受体编辑是B淋巴细胞对自身抗原的耐受性的主要机制。使用表达转基因人Igs的小鼠，我们发现肼屈嗪损害RAG-2基因表达的上调并减少继发性Ig基因重排。受体编辑也被MEK1 / 2的特异性抑制剂以剂量依赖性方式部分消除。用肼苯哒嗪或MEK抑制剂预处理的骨髓B细胞过继转移至幼稚的同系小鼠，导致自身抗体的产生。我们得出的结论是，肼苯哒嗪通过破坏受体的编辑作用，使B淋巴细胞对自身的耐受性下降，并有助于致病性自身反应性的产生。我们还假定对Erk信号通路的抑制有助于肼苯哒嗪诱导的狼疮和特发性人类狼疮的发病机理。

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