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From Influenza Virus Infections to Lupus: Synchronous Estrogen Receptor α and RNA Polymerase II Binding Within the Immunoglobulin Heavy Chain Locus.
Viral Immunology ( IF 2.2 ) Pub Date : 2020-05-13 , DOI: 10.1089/vim.2019.0144
Bart G Jones 1 , Robert E Sealy 1 , Rhiannon R Penkert 1 , Sherri L Surman 1 , Barbara K Birshtein 2 , Beisi Xu 3 , Geoffrey Neale 4 , Robert W Maul 5 , Patricia J Gearhart 5 , Julia L Hurwitz 1, 6
Affiliation  

Males and females respond to pathogens differently and exhibit significantly different frequencies of autoimmune disease. For example, vaccinated adult females control influenza virus better than males, but females suffer systemic lupus erythematosus at a 9:1 frequency compared to males. Numerous explanations have been offered for these sex differences, but most have involved indirect mechanisms by which estrogen, a nuclear hormone, modifies cell barriers or immunity. In search of a direct mechanism, we examined the binding of estrogen receptor α (ERα), a class I nuclear hormone receptor, to the immunoglobulin heavy chain locus. Here, we show that in purified murine B cells, ERα and RNA polymerase II (RNA Pol II) exhibit extraordinarily similar DNA binding patterns. We further demonstrate that ERα preferentially binds adenosine–cytidine (AC)-repeats in the immunoglobulin heavy chain locus when supplemental estrogen is added to purified, lipopolysaccharide-activated B cells. Based on these and previous data, we hypothesize that (i) estrogen guides the binding of ERα and its RNA Pol II partner within the locus, which in turn instructs sterile transcription and class switch recombination (CSR), (ii) ERα binding to AC-repeats modifies the DNA architecture and loops associated with CSR, and (iii) by these mechanisms, estrogen instructs antibody expression. By targeting ERα-DNA interactions in the immunoglobulin heavy chain locus, clinicians may ultimately enhance antibody responses in the context of infectious diseases and reduce antibody responses in the context of allergic or autoimmune reactions.

中文翻译:

从流感病毒感染到狼疮:免疫球蛋白重链基因座内的同步雌激素受体α和RNA聚合酶II结合。

男性和女性对病原体的反应不同,自身免疫疾病的发生频率也明显不同。例如,接种疫苗的成年女性对流感病毒的控制要好于男性,但是女性与男性相比,系统性红斑狼疮的发病率为9:1。对于这些性别差异已经提供了许多解释,但是大多数解释都涉及间接机制,通过这种机制雌激素(一种核激素)可以改变细胞屏障或免疫力。在搜索的直接机制,我们研究了雌激素受体结合α(ER α),I类核激素受体,免疫球蛋白重链基因座。在这里,我们表明,在纯化的鼠B细胞,ER αRNA聚合酶II(RNA Pol II)表现出非常相似的DNA结合模式。我们进一步证明ER α优先结合腺苷-胞苷(AC)在免疫球蛋白重链基因座-repeats当补充雌激素添加到提纯,脂多糖活化的B细胞。基于这些和以前的数据,我们假设其(i)雌激素引导ER的结合α和轨迹内的RNA聚合酶II的伙伴,这又指示无菌转录和类别转换重组(CSR),(ⅱ)ER α的结合AC重复序列的修饰修饰与CSR相关的DNA结构和环,并且(iii)通过这些机制,雌激素指示抗体表达。通过针对ER α-在免疫球蛋白重链基因座中的DNA相互作用,临床医生可能最终会在传染性疾病中增强抗体反应,而在变态反应或自身免疫反应中降低抗体反应。
更新日期:2020-05-13
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