Ogawa Yoko, Morikawa Satoru, Okano Hideyuki, Mabuchi Yo, Suzuki Sadafumi, Yaguchi Tomonori, Sato Yukio, Mukai Shin, Yaguchi Saori, Inaba Takaaki, Okamoto Shinichiro, Kawakami Yutaka, Tsubota Kazuo, Matsuzaki Yumi, Shimmura Shigeto
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
Department of Dentistry and Oral Surgery, Keio University School of Medicine, Tokyo, Japan.
Elife. 2016 Jan 26;5:e09394. doi: 10.7554/eLife.09394.
Fibrosis of organs is observed in systemic autoimmune disease. Using a scleroderma mouse, we show that transplantation of MHC compatible, minor antigen mismatched bone marrow stromal/stem cells (BMSCs) play a role in the pathogenesis of fibrosis. Removal of donor BMSCs rescued mice from disease. Freshly isolated PDGFRα(+) Sca-1(+) BMSCs expressed MHC class II following transplantation and activated host T cells. A decrease in FOXP3(+) CD25(+) Treg population was observed. T cells proliferated and secreted IL-6 when stimulated with mismatched BMSCs in vitro. Donor T cells were not involved in fibrosis because transplanting T cell-deficient RAG2 knock out mice bone marrow still caused disease. Once initially triggered by mismatched BMSCs, the autoimmune phenotype was not donor BMSC dependent as the phenotype was observed after effector T cells were adoptively transferred into naïve syngeneic mice. Our data suggest that minor antigen mismatched BMSCs trigger systemic fibrosis in this autoimmune scleroderma model.
在系统性自身免疫性疾病中可观察到器官纤维化。利用硬皮病小鼠模型，我们发现移植主要组织相容性复合体（MHC）相容、次要抗原不匹配的骨髓基质/干细胞（BMSCs）在纤维化发病机制中起作用。去除供体BMSCs可使小鼠免于患病。新鲜分离的血小板衍生生长因子受体α（PDGFRα）阳性、干细胞抗原-1（Sca-1）阳性的BMSCs在移植后表达II类MHC并激活宿主T细胞。观察到叉头框蛋白3（FOXP3）阳性、CD25阳性调节性T细胞群体减少。体外使用不匹配的BMSCs刺激时，T细胞增殖并分泌白细胞介素-6（IL-6）。供体T细胞不参与纤维化，因为移植T细胞缺陷的重组激活基因2（RAG2）敲除小鼠骨髓仍会引发疾病。一旦最初由不匹配的BMSCs触发，自身免疫表型就不依赖于供体BMSCs，因为在效应T细胞过继转移到同基因幼稚小鼠后仍可观察到该表型。我们的数据表明，在这种自身免疫性硬皮病模型中，次要抗原不匹配的BMSCs会引发系统性纤维化。
