Type I interferon receptor controls B-cell expression of nucleic acid-sensing Toll-like receptors and autoantibody production in a murine model of lupus.
Type I interferon receptor controls B-cell expression of nucleic acid-sensing Toll-like receptors and autoantibody production in a murine model of lupus.
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DOI：
10.1186/ar2771
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发表时间：
2009
影响因子：
4.9
通讯作者：
Utz PJ
中科院分区：
文献类型：
--
作者：
Thibault DL;Graham KL;Lee LY;Balboni I;Hertzog PJ;Utz PJ
系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，其特征是产生针对核自身抗原的高滴度IgG自身抗体。I型干扰素（IFN-I）已被证明在这种疾病中起致病性作用。在本研究中，我们表征了I型IFN （IFN-I）受体的IFNAR2链在狼疮pristane模型中靶向核酸相关自身抗原和核酸敏感toll样受体（TLRs） TLR7和TLR9的b细胞表达中的作用。野生型（WT）和IFNAR2-/-小鼠接受普里斯坦治疗，每月监测蛋白尿情况。用自身抗原芯片检测自身抗体的产生，并用酶联免疫吸附试验（ELISA）和免疫沉淀法确认。血清免疫球蛋白同型水平，以及体外b细胞细胞因子的产生，通过ELISA定量。胸腺嘧啶掺入法检测b细胞增殖。自身抗原微阵列分析显示，经普里斯坦处理的IFNAR2-/-小鼠缺乏针对rna相关自身抗原复合物史密斯抗原/核糖核蛋白（Sm/RNP）和核糖体磷酸化蛋白P0 （RiboP）成分的自身抗体。与朊蛋白酶处理的WT小鼠相比，朊蛋白酶处理的IFNAR2-/-小鼠抗单链DNA IgG和抗组蛋白自身抗体水平降低。在IFNAR2-/-小鼠B细胞中，TLR7的表达和TLR7激动剂的激活显著降低。IFNAR2-/- B细胞在IFN- i的作用下未能上调TLR7和TLR9的表达，与IFN-α处理后的WT小鼠B细胞相比，对TLR7和TLR9激动剂的效应反应显著降低。我们的研究在小鼠SLE模型中提供了IFN-I通路与tlr特异性b细胞反应调节之间的关键联系。
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of high-titer IgG autoantibodies directed against nuclear autoantigens. Type I interferon (IFN-I) has been shown to play a pathogenic role in this disease. In the current study, we characterized the role of the IFNAR2 chain of the type I IFN (IFN-I) receptor in the targeting of nucleic acid-associated autoantigens and in B-cell expression of the nucleic acid-sensing Toll-like receptors (TLRs), TLR7 and TLR9, in the pristane model of lupus. Wild-type (WT) and IFNAR2-/- mice were treated with pristane and monitored for proteinuria on a monthly basis. Autoantibody production was determined by autoantigen microarrays and confirmed using enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation. Serum immunoglobulin isotype levels, as well as B-cell cytokine production in vitro, were quantified by ELISA. B-cell proliferation was measured by thymidine incorporation assay. Autoantigen microarray profiling revealed that pristane-treated IFNAR2-/- mice lacked autoantibodies directed against components of the RNA-associated autoantigen complexes Smith antigen/ribonucleoprotein (Sm/RNP) and ribosomal phosphoprotein P0 (RiboP). The level of IgG anti-single-stranded DNA and anti-histone autoantibodies in pristane-treated IFNAR2-/- mice was decreased compared to pristane-treated WT mice. TLR7 expression and activation by a TLR7 agonist were dramatically reduced in B cells from IFNAR2-/- mice. IFNAR2-/- B cells failed to upregulate TLR7 as well as TLR9 expression in response to IFN-I, and effector responses to TLR7 and TLR9 agonists were significantly decreased as compared to B cells from WT mice following treatment with IFN-α. Our studies provide a critical link between the IFN-I pathway and the regulation of TLR-specific B-cell responses in a murine model of SLE.
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影响因子：
32.4
作者：
Jego, G;Palucka, AK;Banchereau, J
通讯作者：
Banchereau, J
DOI：
10.1084/jem.20021553
发表时间：
2003-03-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bennett L;Palucka AK;Arce E;Cantrell V;Borvak J;Banchereau J;Pascual V
通讯作者：
Pascual V
影响因子：
30.5
作者：
Fenner, JE;Starr, R;Hertzog, PJ
通讯作者：
Hertzog, PJ
影响因子：
4.4
作者：
Lee, Pui Y.;Weinstein, Jason S.;Reeves, Westley H.
通讯作者：
Reeves, Westley H.
影响因子：
--
作者：
Hoffman, RW;Gazitt, T;Greidinger, EL
通讯作者：
Greidinger, EL