Toll-like receptor 2 is required for autoantibody production and development of renal disease in pristane-induced lupus.
Toll-like receptor 2 is required for autoantibody production and development of renal disease in pristane-induced lupus.
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DOI：
10.1002/art.37914
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发表时间：
2013-06
影响因子：
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通讯作者：
V. Urbonaviciute;Charlotte Starke;Wiebke Pirschel;S. Pohle;S. Frey;C. Daniel;K. Amann;G. Schett;M. Herrmann;R. Voll
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文献类型：
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作者：
V. Urbonaviciute;Charlotte Starke;Wiebke Pirschel;S. Pohle;S. Frey;C. Daniel;K. Amann;G. Schett;M. Herrmann;R. Voll
目的系统性红斑狼疮(SLE)打破自身核抗原免疫耐受的机制尚不完全清楚。我们最近在非自身免疫小鼠中的研究为Toll样受体2(TLR-2)在高迁移率族蛋白1-核小体复合体诱导抗染色质自身抗体中的重要作用提供了证据。这项研究的目的是调查TLR-2信号是否在诱导自身抗体和狼疮样疾病的发生发展中起作用。方法采用泼尼松诱导C57BL/6和TLR-2(-/-)小鼠狼疮样病模型。用流式细胞仪检测免疫细胞数和血清细胞因子浓度。肾脏疾病通过尿蛋白定量、组织学分析和酶联免疫斑点法进行评估。结果与野生型对照相比，注射Pristane的TLR2(-/-)小鼠产生的CD138+/胞浆κL/λL链阳性浆细胞数量减少，对双链DNA、组蛋白、核小体、某些可提取的核自身抗原和心磷脂的免疫应答减弱。TLR-2缺乏抑制了Pristane诱导的全身IL-6和IL-10的释放。TLR-2的缺失减少了CD11c+细胞的腹膜募集和脂肪肉芽肿的形成。重要的是，Pristane治疗的TLR-2(-/-)小鼠发生的肾脏疾病没有对照组小鼠严重，这反映在蛋白尿较轻，肾小球内免疫球蛋白和补体的沉积减少，肾脏自身抗体分泌细胞的渗透减少。结论在Pristane诱导的小鼠狼疮模型中，TLR-2在狼疮自身抗体的产生和肾脏疾病的发生中是必需的。干扰TLR-2信号通路可能是治疗SLE的一种有前景的新策略。
OBJECTIVE The mechanisms involved in breaking immunologic tolerance against nuclear autoantigens in systemic lupus erythematosus (SLE) are not fully understood. Our recent studies in nonautoimmune mice provided evidence of an important role of Toll-like receptor 2 (TLR-2) in antichromatin autoantibody induction by high mobility group box chromosomal protein 1-nucleosome complexes derived from apoptotic cells. The objective of this study was to investigate whether TLR-2 signaling is required for the induction of autoantibodies and the development of SLE-like disease in murine pristane-induced lupus. METHODS Lupus-like disease in C57BL/6 and TLR-2(-/-) mice was induced by pristane injection. The numbers of immune cells and serum cytokine concentrations were determined by flow cytometry. Renal disease was assessed by quantification of proteinuria, histologic analyses, and enzyme-linked immunospot assay. RESULTS Pristane-injected TLR-2(-/-) mice generated reduced numbers of splenic CD138+/cytoplasmic κL/λL chain-positive plasma cells and displayed diminished IgG responses against double-stranded DNA, histones, nucleosomes, some extractable nuclear autoantigens, and cardiolipin when compared with wild- type controls. TLR-2 deficiency prevented the pristane-induced systemic release of interleukin-6 (IL-6) and IL-10. The absence of TLR-2 attenuated peritoneal recruitment of CD11c+ cells and formation of lipogranulomas. Importantly, the renal disease that developed in pristane-treated TLR-2(-/-) mice was less severe than that in control mice, as reflected by milder proteinuria, reduced glomerular deposition of IgG and complement, and decreased renal infiltration of autoantibody-secreting cells. CONCLUSION TLR-2 is required for the production of prototypical lupus autoantibodies and the development of renal disease in pristane-induced murine lupus. Interference with TLR-2 signaling may be a promising novel strategy for the treatment of SLE.