Estrogen contributes to females' strong antibody response to microbial vaccines and proneness to autoimmunity, particularly antibody-mediated systemic autoimmunity, in females. We have hypothesized that this is due to estrogen-mediated potentiation of class switch DNA recombination (CSR) and somatic hypermutation (SHM). As we have shown, estrogen boosts AID expression, which is critical for both CSR and SHM, through upregulation of HoxC4, which together with NF-κB critically mediates Aicda (AID gene) promoter activation. We contend here that additional regulation of Aicda expression by estrogen occurs through epigenetic mechanisms. As we have shown, histone deacetylase inhibitors (HDIs) short-chain fatty acid (SCFA) butyrate and propionate as well as the pharmacologic HDI valproic acid upregulate miRNAs that silence AID expression, thereby modulating specific antibody responses in C57BL/6 mice and autoantibody responses in lupus-prone MRL/Fas lpr/lpr mice. Here, using constitutive knockout Esr1 -/- mice and B cells as well as conditional knockout Aicda cre/cre Esr1 flox/flox mice and B cells, we showed that the HDI-mediated downregulation of Aicda expression as well as the maturation of antibody and autoantibody responses is reversed by estrogen and enhanced by deletion of ERα or E2 inhibition. Estrogen's reversion of HDI-mediated inhibition of Aicda and CSR in antibody and autoantibody responses occurred through downregulation of B cell miR-26a, which, as we showed, targets Aicda mRNA 3'UTR. miR-26a was significantly upregulated by HDIs. Accordingly, enforced expression of miR-26a reduced Aicda expression and CSR, while miR-26a-sponges (competitive inhibitors of miR-26a) increased Aicda expression and CSR. Thus, our findings show that estrogen reverses the HDI-mediated downregulation of AID expression and CSR through selective modulation of miR-26a. They also provide mechanistic insights into the immunomodulatory activity of this hormone and a proof-of-principle for using combined ER inhibitor-HDI as a potential therapeutic approach.

中文翻译：

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雌激素通过下调 miR-26a 逆转 HDAC 抑制剂介导的 Aicda 抑制以及抗体和自身抗体反应中的类别转换。


雌激素有助于女性对微生物疫苗产生强烈的抗体反应，并导致女性容易发生自身免疫，特别是抗体介导的全身性自身免疫。我们假设这是由于雌激素介导的 DNA 类别转换重组 (CSR) 和体细胞超突变 (SHM) 增强所致。正如我们所表明的，雌激素通过上调 HoxC4 来增强 AID 表达，这对于 CSR 和 SHM 都至关重要，HoxC4 与 NF-κB 一起关键介导 Aicda（AID 基因）启动子激活。我们认为雌激素对 Aicda 表达的额外调节是通过表观遗传机制发生的。正如我们所表明的，组蛋白脱乙酰酶抑制剂 (HDI) 短链脂肪酸 (SCFA) 丁酸盐和丙酸盐以及药理学 HDI 丙戊酸上调沉默 AID 表达的 miRNA，从而调节 C57BL/6 小鼠的特异性抗体反应和自身抗体反应在狼疮倾向 MRL/Fas lpr/lpr 小鼠中。在这里，使用组成型敲除 Esr1 -/- 小鼠和 B 细胞以及条件性敲除 Aicda cre/cre Esr1 flox/flox 小鼠和 B 细胞，我们发现 HDI 介导的 Aicda 表达下调以及抗体和成熟蛋白的成熟。自身抗体反应可被雌激素逆转，并通过删除 ERα 或 E2 抑制而增强。雌激素通过下调 B 细胞 miR-26a 来逆转 HDI 介导的抗体和自身抗体反应中的 Aicda 和 CSR 抑制，正如我们所表明的，miR-26a 靶向 Aicda mRNA 3'UTR。 HDIs 显着上调 miR-26a。因此，miR-26a的强制表达降低了Aicda表达和CSR，而miR-26a-sponges（miR-26a的竞争性抑制剂）增加了Aicda表达和CSR。 因此，我们的研究结果表明，雌激素通过选择性调节 miR-26a 逆转 HDI 介导的 AID 表达和 CSR 下调。他们还提供了对该激素免疫调节活性的机制见解，以及使用 ER 抑制剂-HDI 组合作为潜在治疗方法的原理验证。