Mechanism of Mitochondrial Transcription Factor A Attenuation of CpG-Induced Antibody Production.
Mechanism of Mitochondrial Transcription Factor A Attenuation of CpG-Induced Antibody Production.
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DOI：
10.1371/journal.pone.0157157
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Janoff EN
中科院分区：
文献类型：
--
作者：
Malarkey CS;Gustafson CE;Saifee JF;Torres RM;Churchill ME;Janoff EN
线粒体转录因子A（TFAM）先前已被证明是一种损伤相关的分子模式，能够增强CpG-A硫代磷酸寡脱氧核苷酸（ODN）介导的刺激人浆细胞样树突状细胞产生IFNα的能力。TFAM可能影响CpG ODN介导的先天性免疫应答的机制的检查揭示TFAM直接、紧密和选择性地结合结构相关的CpG-A、-B和-C ODN。TFAM还调节CpG-B或-C刺激人B细胞产生抗体的能力。TFAM对体外人B细胞中CpG-B和-C诱导的抗体产生具有剂量依赖性调节，高剂量的CpG刺激增强，低剂量的CpG刺激抑制。这种作用与TFAM直接抑制CpG ODN与B细胞结合的能力有关，其方式与TFAM对ODN的相对结合亲和力一致。这些数据表明TFAM通过将该ODN隔离在TFAM-CpG复合物中来改变可用于刺激B细胞的CpG的游离浓度。因此，TFAM有可能降低体内暴露于天然CpG样低甲基化DNA的致病后果，以及诸如在创伤性损伤、感染、自身免疫性疾病和妊娠期间发现的致病后果。
Mitochondrial transcription factor A (TFAM) had previously been shown to act as a damage associated molecular pattern with the ability to enhance CpG-A phosphorothioate oligodeoxynucleotide (ODN)-mediated stimulation of IFNα production from human plasmacytoid dendritic cells. Examination of the mechanism by which TFAM might influence CpG ODN mediated innate immune responses revealed that TFAM binds directly, tightly and selectively to the structurally related CpG-A, -B, and -C ODN. TFAM also modulated the ability of the CpG-B or -C to stimulate the production of antibodies from human B cells. TFAM showed a dose-dependent modulation of CpG-B, and -C -induced antibody production from human B cells in vitro, with enhancement of high dose and inhibition of low doses of CpG stimulation. This effect was linked to the ability of TFAM to directly inhibit the binding of CpG ODNs to B cells, in a manner consistent with the relative binding affinities of TFAM for the ODNs. These data suggest that TFAM alters the free concentration of the CpG available to stimulate B cells by sequestering this ODN in a TFAM-CpG complex. Thus, TFAM has the potential to decrease the pathogenic consequences of exposure to natural CpG-like hypomethylated DNA in vivo, as well as such as that found in traumatic injury, infection, autoimmune disease and during pregnancy.