Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice
Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice
复制标题
CD2启动子控制下的RORγt过表达诱导转基因小鼠多克隆浆细胞增多和自身抗体产生
DOI：
10.1002/eji.201142250
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发表时间：
2012
期刊：
影响因子：
5.4
通讯作者：
Takahashi S
中科院分区：
文献类型：
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作者：
Yoh K;Morito N;Ojima M;Shibuya K;Yamashita Y;Morishima Y;Ishii Y;Kusakabe M;Nishikii H;Fujita A;Matsunaga E;Okamura M;Hamada M;Suto A;Nakajima H;Shibuya A;Yamagata K;Takahashi S
视黄酸相关孤儿受体γ t（RORγt）是Th 17细胞发育的主要调节因子。在这项研究中，我们产生了RORγt-过表达转基因（RORγt Tg）小鼠，其中转基因表达由CD 2启动子驱动，并发现这些小鼠发生了多克隆浆细胞增多症和自身抗体产生。RORγt Tg小鼠在C57 BL/6背景下产生，并且还与BALB/c小鼠杂交。BALB/c F1（BALB/F1）RORγt Tg小鼠出现大量多克隆浆细胞增多，寿命较短。观察到脾肿大和浆细胞浸润到肺中。在BALB/F1 RORγt Tg小鼠中检测到高球蛋白血症、抗双链DNA抗体、抗红细胞抗体和抗血小板抗体。在本研究中，BALB/F1 RORγt Tg小鼠中的多克隆浆细胞增多似乎是由于IL-17诱导过量IL-6产生所致。我们检测到产生IL-6的CD 11b+细胞数量增加。我们还产生了IL-6-缺陷型RORγt Tg BALB/F1背景小鼠，这些小鼠显示出高水平的血清IL-17，但没有出现严重的高球蛋白血症。在BALB/F1 RORγt Tg小鼠中，几种细胞类型（包括巨噬细胞）过度产生IL-6可能会影响浆细胞增多症的发生。这些结果提示RORγt在浆细胞增多症和自身抗体产生中起重要作用。
Retinoic acid related orphan receptor gamma‐t (RORγt) is known to be a master regulator of Th17‐cell development. In this study, we generated RORγt‐overexpressing transgenic (RORγt Tg) mice in which transgene expression was driven by the CD2 promoter, and found that these mice developed polyclonal plasmacytosis and autoantibody production. RORγt Tg mice were generated on a C57BL/6 background, and also were intercrossed with BALB/c mice. BALB/c F1 (BALB/F1) RORγt Tg mice developed massive polyclonal plasma‐cytosis, and had shorter life spans. Splenomegaly and infiltration of plasma cells into the lung were observed. Hyperglobulinemia, anti‐double‐stranded DNA antibodies, anti‐erythrocyte antibodies, and anti‐platelet antibodies were detected in BALB/F1 RORγt Tg mice. In the present study, polyclonal plasmacytosis in BALB/F1 RORγt Tg mice appeared to be due to the induction of excessive IL‐6 production by IL‐17. We detected increased numbers of CD11b+cells that produced IL‐6. We also generatedIL‐6‐deficient RORγt Tg BALB/F1 background mice, which displayed high levels of serum IL‐17, but did not develop severe hyperglobulinemia. Excessive IL‐6 production by several cell types, including macrophages, in BALB/F1 RORγt Tg mice, might effect the development of plasma‐cytosis. These results suggest that RORγt plays important roles in the development of plasmacytosis and autoantibody production.