Nephritogenic autoantibodies but absence of nephritis in Il-12p35-deficient mice with pristane-induced lupus
Nephritogenic autoantibodies but absence of nephritis in Il-12p35-deficient mice with pristane-induced lupus
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DOI：
10.1046/j.1523-1755.2003.00178.x
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发表时间：
2003-09-01
影响因子：
19.6
通讯作者：
Richards, HB
中科院分区：
文献类型：
--
作者：
Calvani, N;Satoh, M;Richards, HB
背景有强有力的证据表明，Th 1细胞因子是必不可少的疾病在狼疮鼠模型。白细胞介素-12（IL-12）是Th 1细胞分化所必需的，并诱导干扰素-γ（IFN-γ）产生。奇怪的是，已经表明IL-12缺陷驱动狼疮的发病机制，尽管其确切作用仍不清楚。我们研究了IL-12在降植烷诱导的狼疮样疾病中的作用。用降植烷或磷酸盐缓冲盐水（PBS）处理IL-12 p35缺陷（-/-）和对照（+/+）BALB/c小鼠。治疗后10个月，测量蛋白尿并进行肾脏病理学评价。分析血清的自身抗体和总免疫球蛋白水平。分析细胞因子的表达和产生。降植烷在IL-12 -/-和+/+小鼠中诱导致肾炎自身抗体和肾免疫球蛋白和补体沉积。然而，IL-12-/-小鼠中不存在增殖性病理和蛋白尿，而降植烷在三分之一的+/+小鼠中诱导了严重的肾炎。正如预期的那样，降植烷处理的IL-12 -/-小鼠的细胞因子平衡偏向于Th 2应答。这些数据表明，肾免疫复合物沉积可以在不存在IL-12 p35的情况下发生，但是结构性肾损伤需要IL-12 p35或由该分子诱导的介质（例如IFN-γ）的存在。与缺乏IFN-γ导致的致肾炎自身抗体的消除相反，IL-12 p35缺陷型小鼠中的降植烷诱导了这种抗体。尽管降植烷处理的IL-12-/-小鼠中存在致肾炎性自身抗体，但无结构性肾病，表明在该模型中单独的抗体沉积不足以发展狼疮性肾炎。
Background. There is strong evidence that Th1 cytokines are essential for disease in murine models of lupus. Interleukin-12 (IL-12) is essential for Th1 cell differentiation and induces interferon-gamma (IFN-gamma) production. Paradoxically, it has been suggested that an IL-12 defect drives the pathogenesis of lupus, although its precise role remains unclear. We investigated the role of IL-12 for lupus-like disease induced by pristane. IL-12p35-deficient (-/-) and control (+/+) BALB/c mice were treated with pristane or phosphate-buffered saline (PBS).Methods. Proteinuria was measured and renal pathology evaluated 10 months after treatment. Sera were analyzed for autoantibodies and total immunoglobulin levels. Cytokine expression and production was analyzed.Results. Pristane induced nephritogenic autoantibodies and renal immunoglobulin and complement deposition in both IL-12 -/- and +/+ mice. However, proliferative pathology and proteinuria were absent in IL-12-/- mice, whereas pristane induced severe nephritis in one third of the +/+ mice. As expected, cytokine balance was skewed toward a Th2 response in pristane-treated IL-12 -/- mice.Conclusion. These data indicate that renal immune complex deposition can occur in the absence of IL-12p35, but that structural renal damage requires the presence of IL-12p35 or mediators induced by this molecule, such as IFN-gamma. In contrast to the abrogation of nephritogenic autoantibodies by the lack of IFN-gamma, such antibodies are induced by pristane in IL-12p35-deficient mice. Absence of structural renal disease, despite the presence of nephritogenic autoantibodies in pristane-treated IL-12-/- mice, indicates that antibody deposition alone is not sufficient for the development of lupus nephritis in this model.