Accelerated pathological and clinical nephritis in systemic lupus erythematosus-prone New Zealand Mixed 2328 mice doubly deficient in TNF receptor 1 and TNF receptor 2 via a Th17-associated pathway.
Accelerated pathological and clinical nephritis in systemic lupus erythematosus-prone New Zealand Mixed 2328 mice doubly deficient in TNF receptor 1 and TNF receptor 2 via a Th17-associated pathway.
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DOI：
10.4049/jimmunol.0802948
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发表时间：
2009-02-15
期刊：
影响因子：
--
通讯作者：
Jacob CO
中科院分区：
文献类型：
--
作者：
Jacob N;Yang H;Pricop L;Liu Y;Gao X;Zheng SG;Wang J;Gao HX;Putterman C;Koss MN;Stohl W;Jacob CO
TNF-α具有促炎和免疫调节功能。虽然TNF给药对系统性红斑狼疮（SLE）易发（新西兰黑×新西兰白）F1小鼠具有保护作用，但仍不确定这种作用是否在个体TNFR上分离。我们培育了2328只TNFR1、TNFR2或两种受体基因缺陷的易患sled的新西兰混血小鼠。双缺陷小鼠出现病理性和临床肾炎加速，循环IgG抗dsdna自身抗体水平升高，CD4+ T淋巴细胞数量增加，尤其是激活记忆（cd44highcd62low） CD4+ T细胞。我们发现这些细胞表达Th17基因谱，流式细胞术细胞内IL-17染色呈阳性，并在培养中产生外源性IL-17。相比之下，单独缺乏TNFR的小鼠的免疫学、病理学和临床特征与其他小鼠或野生型对照小鼠没有差异。因此，在新西兰混合2328 SLE模型中，TNF-α-介导的信号通路的完全消融对宿主是高度有害的。这些观察结果可能对TNF和TNFR拮抗剂在人类SLE和相关自身免疫性疾病中的应用产生深远的影响，并首次证明Th17途径与SLE动物模型的关联。
TNF-α has both proinflammatory and immunoregulatory functions. Whereas a protective role for TNF administration in systemic lupus erythematosus (SLE)-prone (New Zealand Black × New Zealand White)F1 mice has been established, it remains uncertain whether this effect segregates at the individual TNFR. We generated SLE-prone New Zealand Mixed 2328 mice genetically deficient in TNFR1, in TNFR2, or in both receptors. Doubly-deficient mice developed accelerated pathological and clinical nephritis with elevated levels of circulating IgG anti-dsDNA autoantibodies and increased numbers of CD4+ T lymphocytes, especially activated memory (CD44highCD62Llow) CD4+ T cells. We show that these cells expressed a Th17 gene profile, were positive for IL-17 intracellular staining by FACS, and produced exogenous IL-17 in culture. In contrast, immunological, pathological, and clinical profiles of mice deficient in either TNFR alone did not differ from those in each other or from those in wild-type controls. Thus, total ablation of TNF-α-mediated signaling was highly deleterious to the host in the New Zealand Mixed 2328 SLE model. These observations may have profound ramifications for the use of TNF and TNFR antagonists in human SLE and related autoimmune disorders, as well as demonstrate, for the first time, the association of the Th17 pathway with an animal model of SLE.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
DOI：
10.1084/jem.179.1.305
发表时间：
1994-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ishida H;Muchamuel T;Sakaguchi S;Andrade S;Menon S;Howard M
通讯作者：
Howard M
影响因子：
4.9
作者：
Aringer M;Smolen JS
通讯作者：
Smolen JS
DOI：
10.1084/jem.193.4.427
发表时间：
2001-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kassiotis G;Kollias G
通讯作者：
Kollias G
影响因子：
4.4
作者：
Jacob, Chaim O.;Pricop, Luminita;Stohl, William
通讯作者：
Stohl, William