Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB x NZW)F1 mice
Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB x NZW)F1 mice
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DOI：
10.1038/sj.gene.6364458
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发表时间：
2008-03-01
影响因子：
5
通讯作者：
Gould, K. A.
中科院分区：
文献类型：
--
作者：
Bynote, K. K.;Hackenberg, J. M.;Gould, K. A.
雌激素在人类和这种疾病的一些小鼠模型中促进狼疮。然而，雌激素受体在狼疮发病机制中的作用知之甚少。在这里，我们报告说，在女性的狼疮倾向（NZB x NZW）F-1的背景下，雌激素受体α（ER α或Esr 1）的破坏减弱肾小球肾炎和增加生存。ER α缺乏也延缓了抗组蛋白/DNA抗体的产生，表明ER α促进了免疫耐受的丧失。此外，（NZB x NZW）F-1雌性中的ER α缺乏减弱了随后抗双链DNA（dsDNA）IgG抗体的产生，该抗体与该模型中的肾小球肾炎相关。我们提供的证据表明，雌激素受体α可能促进狼疮，至少部分，通过诱导干扰素-γ，雌激素调节的细胞因子，影响这种疾病。（NZB x NZW）F-1雄性的ER α缺乏增加了存活率并减少了抗dsDNA抗体，表明ER α也调节了雄性的狼疮。这些研究表明，ER α，而不是ER β，在调节（NZB x NZW）F-1小鼠的自身免疫中起着重要作用。此外，我们的研究结果首次表明，ER α促进狼疮，至少部分是通过影响最初的耐受性丧失。这些数据表明，靶向治疗破坏ER α，最有可能在免疫系统内，可能是有效的预防和/或治疗狼疮。
Estrogens promote lupus in humans and some mouse models of this disease. Nonetheless, little is known about the role of estrogen receptors in lupus pathogenesis. Here, we report that in females on the lupus-prone (NZB x NZW)F-1 background, disruption of estrogen receptor-alpha (ER alpha or Esr1) attenuated glomerulonephritis and increased survival. ER alpha deficiency also retarded development of anti-histone/DNA antibodies, suggesting that ER alpha promotes loss of immunologic tolerance. Furthermore, ER alpha deficiency in (NZB x NZW)F-1 females attenuated the subsequent development of anti-double-stranded DNA (dsDNA) IgG antibodies, which are associated with glomerulonephritis in this model. We provide evidence that ER alpha may promote lupus, at least in part, by inducing interferon-gamma, an estrogen-regulated cytokine that impacts this disease. ER alpha deficiency in (NZB x NZW)F-1 males increased survival and reduced anti-dsDNA antibodies, suggesting that ER alpha also modulates lupus in males. These studies demonstrate that ER alpha, rather than ER beta, plays a major role in regulating autoimmunity in (NZB x NZW)F-1 mice. Furthermore, our results suggest for the first time that ER alpha promotes lupus, at least in part, by impacting the initial loss of tolerance. These data suggest that targeted therapy disrupting ER alpha, most likely within the immune system, may be effective in the prevention and/or treatment of lupus.