Histone deacetylase inhibitors upregulate B cell microRNAs that silence AID and Blimp-1 expression for epigenetic modulation of antibody and autoantibody responses.
Histone deacetylase inhibitors upregulate B cell microRNAs that silence AID and Blimp-1 expression for epigenetic modulation of antibody and autoantibody responses.
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DOI：
10.4049/jimmunol.1401702
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发表时间：
2014-12-15
期刊：
影响因子：
--
通讯作者：
Casali P
中科院分区：
文献类型：
--
作者：
White CA;Pone EJ;Lam T;Tat C;Hayama KL;Li G;Zan H;Casali P
类转换DNA重组（CSR）和体细胞超突变（SHM）需要AID，而浆细胞分化需要Blimp-1，这对于类转换和超突变（成熟）抗体和自身抗体反应的产生至关重要。我们在这里发现，在人和小鼠B细胞中，组蛋白去乙酰化酶（HDAC）抑制剂（HDI）丙戊酸（VPA）和丁酸上调miR-155、miR-181b和miR-361，从而沉默AICDA/ AICDA (AID) mRNA，以及miR-23b、miR-30a和miR-125b，从而沉默PRDM1/ PRDM1 (Blimp-1) mRNA。这导致AID、Blimp-1和Xbp-1表达下调，从而抑制CSR、SHM和浆细胞分化，但不改变B细胞的活力和增殖。hdi介导的AICDA/ AICDA和PRDM1/ PRDM1沉默的选择性通过HoxC4和Irf4 （AICDA/ AICDA的重要诱导剂/调节剂），Rev1和Ung （CSR/SHM的核心元件），Bcl6， Bach2或Pax5 （PRDM1/ PRDM1表达的抑制因子）的表达不变，以及miR-19a/b， miR-20a和miR-25的表达不变而得到强调，miR-19a/b， miR-20a和miR-25是未知的调节AICDA/ AICDA或PRDM1/ PRDM1。通过这些B细胞内在的表观遗传机制，VPA减弱了C57BL/6小鼠的类别切换和超突变t依赖性和t依赖性抗体反应。此外，在狼疮MRL/Faslpr/lpr小鼠中，它还能降低类转换和超突变自身抗体，改善疾病并延长生存期。我们的研究结果概述了调节酶（AID）和转录因子（Blimp-1和Xbp-1）表达的表观遗传机制，这些转录因子对B细胞分化过程至关重要，支持抗体和自身抗体反应。它们还为自身抗体介导的自身免疫提供了治疗原理证明。
Class-switch DNA recombination (CSR) and somatic hypermutation (SHM), which require AID, and plasma cell differentiation, which requires Blimp-1, are critical for the generation of class-switched and hypermutated (mature) antibody and autoantibody responses. We showed here that the histone deacetylase (HDAC) inhibitors (HDI) valproic acid (VPA) and butyrate upregulated miR-155, miR-181b and miR-361, which silenced AICDA/Aicda (AID) mRNA, and miR-23b, miR-30a and miR-125b, which silenced PRDM1/Prdm1 (Blimp-1) mRNA, in human and mouse B cells. This led to downregulation of AID, Blimp-1 and Xbp-1 expression, thereby dampening CSR, SHM and plasma cell differentiation without altering B cell viability or proliferation. The selectivity of HDI-mediated silencing of AICDA/Aicda and PRDM1/Prdm1 was emphasized by unchanged expression of HoxC4 and Irf4 (important inducers/modulators of AICDA/Aicda), Rev1 and Ung (central elements for CSR/SHM), and Bcl6, Bach2 or Pax5 (repressors of PRDM1/Prdm1 expression), as well as unchanged expression of miR-19a/b, miR-20a and miR-25, which are not known to regulate AICDA/Aicda or PRDM1/Prdm1. Through these B cell intrinsic epigenetic mechanisms, VPA blunted class-switched and hypermutated T-dependent and T-independent antibody responses in C57BL/6 mice. In addition, it decreased class-switched and hypermutated autoantibodies, ameliorated disease and extended survival in lupus MRL/Faslpr/lpr mice. Our findings outline epigenetic mechanisms that modulate expression of an enzyme (AID) and transcription factors (Blimp-1 and Xbp-1) that critical to the B cell differentiation processes that underpin antibody and autoantibody responses. They also provide therapeutics proof-of-principle in autoantibody-mediated autoimmunity.
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