Interferon regulatory factor 5 activation in monocytes of systemic lupus erythematosus patients is triggered by circulating autoantigens independent of type I interferons.
Interferon regulatory factor 5 activation in monocytes of systemic lupus erythematosus patients is triggered by circulating autoantigens independent of type I interferons.
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DOI：
10.1002/art.33395
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发表时间：
2012-03
影响因子：
--
通讯作者：
Barnes, Betsy J.
中科院分区：
文献类型：
--
作者：
Stone, Rivka C.;Feng, Di;Deng, Jing;Singh, Sukhwinder;Yang, Lisong;Fitzgerald-Bocarsly, Patricia;Eloranta, Maija-Leena;Ronnblom, Lars;Barnes, Betsy J.
干扰素调节因子5(IRF5)的遗传变异与系统性红斑狼疮(SLE)的易感性有关。IRF5调节促炎症细胞因子和I型干扰素的表达，I型干扰素被认为与SLE的发病有关。本研究的目的是通过评估IRF5在SLE患者和健康献血者免疫细胞中的核定位来确定IRF5的激活状态，并确定SLE激活IRF5的触发因素。应用流式细胞术检测14例分型SLE患者和11例健康对照外周血单个核细胞(PBMC)中IRF5的核定位。用SLE血清或SLE血清各组分体外刺激健康供者单核细胞，检测IRF5的活性和功能。细胞定位采用ImageStream法，细胞因子表达采用Q-PCR和ELISA法。IRF5以一种细胞类型特异性的方式被激活；SLE患者的单核细胞与NK和T细胞相比，其核IRF5水平明显升高。红斑狼疮血清是IRF5核聚集的触发因素，但干扰素α和红斑狼疮免疫复合物均不能诱导核定位。相反，由凋亡/坏死物质组成的自身抗原触发了单核细胞中IRF5的核积聚。单核细胞在系统性红斑狼疮血清或自身抗原刺激下产生细胞因子干扰素α、肿瘤坏死因子α和白介素6明显不同，但与IRF5核定位动力学有关。这项研究首次正式证明，SLE患者单核细胞中IRF5的激活发生了改变，这在一定程度上与SLE的血液环境有关。
Genetic variants of interferon regulatory factor 5 (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). IRF5 regulates the expression of proinflammatory cytokines and type I interferons (IFN) believed to be involved in SLE pathogenesis. The aim of this study was to determine the activation status of IRF5 by assessing its nuclear localization in immune cells of SLE patients and healthy donors, and to identify SLE triggers of IRF5 activation. IRF5 nuclear localization in subpopulations of peripheral blood mononuclear cells (PBMC) from 14 genotyped SLE patients and 11 healthy controls was assessed using imaging flow cytometry. IRF5 activation and function were examined after ex vivo stimulation of healthy donor monocytes with SLE serum or components of SLE serum. Cellular localization was determined by ImageStream and cytokine expression by Q-PCR and ELISA. IRF5 was activated in a cell type-specific manner; monocytes of SLE patients had constitutively elevated levels of nuclear IRF5 compared to NK and T cells. SLE serum was identified as a trigger for IRF5 nuclear accumulation; however, neither IFNα nor SLE immune complexes could induce nuclear localization. Instead, autoantigens comprised of apoptotic/necrotic material triggered IRF5 nuclear accumulation in monocytes. Production of cytokines IFNα, TNFα and IL6 in monocytes stimulated with SLE serum or autoantigens was distinct yet correlated with the kinetics of IRF5 nuclear localization. This study provides the first formal proof that IRF5 activation is altered in monocytes of SLE patients that is in part contributed by the SLE blood environment.
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影响因子：
4.4
作者：
Fanning, Stacey L.;George, Thaddeus C.;Fitzgerald-Bocarsly, Patricia
通讯作者：
Fitzgerald-Bocarsly, Patricia
影响因子：
27.4
作者：
Cairns, AP;Crockard, AD;Bell, AL
通讯作者：
Bell, AL
影响因子：
3.4
作者：
Ho, Vincent;Mclean, Anna;Terry, Shaughan
通讯作者：
Terry, Shaughan
影响因子：
4.4
作者：
Hornung, V;Rothenfusser, S;Hartmann, G
通讯作者：
Hartmann, G
影响因子：
4.8
作者：
Hu, Guodong;Barnes, Betsy J.
通讯作者：
Barnes, Betsy J.