Deletion of the Antiphospholipid Syndrome Autoantigen β2-Glycoprotein I Potentiates the Lupus Autoimmune Phenotype in a Toll-like Receptor 7-Mediated Murine Model
Deletion of the Antiphospholipid Syndrome Autoantigen β2-Glycoprotein I Potentiates the Lupus Autoimmune Phenotype in a Toll-like Receptor 7-Mediated Murine Model
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DOI：
10.1002/art.38646
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发表时间：
2014-08-01
影响因子：
13.3
通讯作者：
Krilis, Steven A.
中科院分区：
文献类型：
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作者：
Giannakopoulos, Bill;Mirarabshahi, Peyman;Krilis, Steven A.
目标。BXSB.Yaa小鼠品系是一种依赖于Toll样受体7基因复制的系统性红斑狼疮模型。本研究旨在系统描述雄性BXSB.Yaa小鼠血浆可溶性蛋白β(2)-糖蛋白I(beta(2)GPI)基因缺失后所观察到的自身免疫表型。我们用野生型品系与C57BL/6β(2)GPI(-/-)小鼠回交10代，获得了BXSB.Yaa和NZW小鼠品系，其中β(2)GPI基因已被敲除。不同品系的性别和年龄匹配的小鼠被关在相同的条件下，并在固定的时间间隔内被杀死。在不同时间点采集血清和组织标本。检测狼疮相关自身抗体、炎性细胞因子和I型干扰素基因特征。对淋巴细胞进行流式细胞仪分析。肾小球肾炎的严重程度由2位独立的肾组织病理学专家进行分级。男性BXSB。与年龄匹配的对照组相比，YaAβ(2)GPI(-/-)小鼠出现了显著的淋巴结病和脾肿大。男性BXSB。YaAβ(2)GPI(-/-)小鼠的自身抗体水平也显著升高，包括肿瘤坏死因子α、白介素6和BAFF在内的炎性细胞因子水平增加，肾小球肾炎也更严重。男性BXSB的I型干扰素基因特征。Yaaβ(2)GPI(-/-)小鼠显著高于对照组小鼠。男性BXSB。YaAβ(2)GPI(-/-)小鼠还存在明显的B细胞和T细胞群在脾和淋巴结中的失调，以及细胞凋亡的清除障碍。β(2)GPI的缺失加速并增强了男性BXSB的自身免疫表型。亚阿老鼠。
Objective. The BXSB.Yaa mouse strain is a model of systemic lupus erythematosus that is dependent on duplication of the Toll-like receptor 7 gene. The objective of this study was to systematically describe the amplified autoimmune phenotype observed when the soluble plasma protein beta(2)-glycoprotein I (beta(2)GPI) gene was deleted in male BXSB.Yaa mice.Methods. We generated BXSB.Yaa and NZW mouse strains in which the beta(2)GPI gene had been knocked out by backcrossing the wild-type strains with C57BL/6 beta(2)GPI(-/-) mice for 10 generations. Sex-and age-matched mice of the various strains were housed under identical conditions and were killed at fixed time intervals. Serum and tissue specimens were collected at various time points. Lupus-associated autoantibodies, inflammatory cytokines, and the type I interferon (IFN) gene signature were measured. Flow cytometric analyses of lymphocyte populations were performed. The severity of glomerulonephritis was graded by 2 independent renal histopathologists.Results. Male BXSB. Yaa beta(2)GPI(-/-) mice developed significant lymphadenopathy and splenomegaly compared with age-matched controls. Male BXSB. Yaa beta(2)GPI(-/-) mice also had significantly higher levels of autoantibodies, increased levels of inflammatory cytokines including tumor necrosis factor alpha, interleukin-6, and BAFF, and more severe glomerulonephritis. The type I IFN gene signature in male BXSB. Yaa beta(2)GPI(-/-) mice was significantly higher than that in control mice. Male BXSB. Yaa beta(2)GPI(-/-) mice also had marked dysregulation of various B cell and T cell populations in the spleens and lymph nodes and a disturbance in apoptotic cell clearance.Conclusion. Deletion of beta(2)GPI accelerates and potentiates the autoimmune phenotype in male BXSB. Yaa mice.