Deficiency of the type I interferon receptor protects mice from experimental lupus
Deficiency of the type I interferon receptor protects mice from experimental lupus
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DOI：
10.1002/art.23023
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发表时间：
2007-11-01
影响因子：
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通讯作者：
Reeves, Westley H.
中科院分区：
文献类型：
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作者：
Nacionales, Dina C.;Kelly-Scumpia, Kindra M.;Reeves, Westley H.
目标。系统性红斑狼疮（SLE）是根据一系列临床表现和与I型干扰素（IFN-I）刺激基因（ISGs）异常表达相关的自身抗体来诊断的。ifn - 1在SLE发病机制中的作用仍不确定，部分原因是缺乏合适的动物模型。本研究的目的是探讨IFN-I信号在2,6,10,14-四甲基戊烷（TMPD）诱导的小鼠狼疮发病机制中的作用。IFN-I受体缺陷（IFNAR(-/-)） 129Sv小鼠和野生型（WT） 129Sv对照小鼠腹腔注射TMPD。实时聚合酶链反应检测ISGs的表达。通过免疫荧光和酶联免疫吸附试验评估自身抗体的产生。测定蛋白尿和肾小球细胞量，免疫荧光法检测肾免疫复合物。在tmpd处理的WT小鼠外周血中观察到ISG表达增加，而在tmpd处理的IFNAR（-/-）小鼠外周血中则没有。TMPD在IFNAR（-/-）小鼠中没有诱导狼疮特异性自身抗体（抗rnp，抗sm，抗双链DNA），而129Sv对照组则产生了这些特异性。尽管在IFNAR（-/-）小鼠中存在肾小球免疫复合物，但没有发生蛋白尿和肾小球高细胞性增生，而在tmpd治疗的WT对照组中发现了肾小球肾炎的这些特征。tmpd治疗小鼠的临床和血清学表现强烈依赖IFNAR信号，这与isg表达增加与狼疮特异性自身抗体和人类肾炎的相关性一致。类似于其在人类SLE中的作用，通过IFNAR的信号传导是tmpd诱导狼疮自身抗体和肾小球肾炎发病机制的核心。这个狼疮模型是第一个在外周血中显示“干扰素特征”的动物模型。
Objective. Systemic lupus erythematosus (SLE) is diagnosed according to a spectrum of clinical manifestations and autoantibodies associated with abnormal expression of type I interferon (IFN-I)-stimulated genes (ISGs). The role of IFN-I in the pathogenesis of SLE remains uncertain, partly due to the lack of suitable animal models. The objective of this study was to examine the role of IFN-I signaling in the pathogenesis of murine lupus induced by 2,6,10,14-tetramethylpentadecane (TMPD).Methods. IFN-I receptor-deficient (IFNAR(-/-)) 129Sv mice and wild-type (WT) 129Sv control mice were treated intraperitoneally with TMPD. The expression of ISGs was measured by real-time polymerase chain reaction. Autoantibody production was evaluated by immunofluorescence and enzyme-linked immunosorbent assay. Proteinuria and renal glomerular cellularity were measured and renal immune complexes were examined by immunofluorescence.Results. Increased ISG expression was observed in the peripheral blood of TMPD-treated WT mice, but not in the peripheral blood of TMPD-treated IFNAR(-/-) mice. TMPD did not induce lupus-specific autoantibodies (anti-RNP, anti-Sm, anti-double-stranded DNA) in IFNAR(-/-) mice, whereas 129Sv controls developed these specificities. Although glomerular immune complexes were present in IFNAR(-/-) mice, proteinuria and glomerular hypercellularity did not develop, whereas these features of glomerulonephritis were found in the TMPD-treated WT controls. The clinical and serologic manifestations observed in TMPD-treated mice were strongly dependent on IFNAR signaling, which is consistent with the association of increased expression of ISGs with lupus-specific autoantibodies and nephritis in humans.Conclusion. Similar to its proposed role in human SLE, signaling via the IFNAR is central to the pathogenesis of autoantibodies and glomerulonephritis in TMPD-induced lupus. This lupus model is the first animal model shown to recapitulate the "interferon signature" in peripheral blood.