MHC-compatible bone marrow stromal/stem cells trigger fibrosis by activating host T cells in a scleroderma mouse model.
MHC-compatible bone marrow stromal/stem cells trigger fibrosis by activating host T cells in a scleroderma mouse model.
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DOI：
10.7554/elife.09394
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发表时间：
2016-01-26
期刊：
影响因子：
7.7
通讯作者：
Shimmura S
中科院分区：
文献类型：
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作者：
Ogawa Y;Morikawa S;Okano H;Mabuchi Y;Suzuki S;Yaguchi T;Sato Y;Mukai S;Yaguchi S;Inaba T;Okamoto S;Kawakami Y;Tsubota K;Matsuzaki Y;Shimmura S
在系统性自身免疫性疾病中观察到器官纤维化。使用硬皮病小鼠，我们证明 MHC 相容、次要抗原不匹配的骨髓基质/干细胞 (BMSC) 移植在纤维化的发病机制中发挥作用。移除供体骨髓间充质干细胞使小鼠摆脱了疾病。新鲜分离的 PDGFRα+ Sca-1+ BMSC 在移植后表达 MHC II 类并激活宿主 T 细胞。观察到 FOXP3+ CD25+ Treg 群体减少。当体外用不匹配的 BMSC 刺激时，T 细胞增殖并分泌 IL-6。供体 T 细胞不参与纤维化，因为移植 T 细胞缺陷的 RAG2 敲除小鼠骨髓仍然会引起疾病。一旦最初由不匹配的 BMSC 触发，自身免疫表型就不再依赖于供体 BMSC，因为该表型是在效应 T 细胞过继转移至幼稚同系小鼠体内后观察到的。我们的数据表明，在这种自身免疫性硬皮病模型中，轻微抗原不匹配的 BMSC 会引发系统性纤维化。 DOI：http://dx.doi.org/10.7554/eLife.09394.001 系统性硬皮病是一种自身免疫性疾病，由免疫系统攻击身体的结缔组织引起，结缔组织为身体提供结构支持。称为 T 细胞的免疫细胞在结缔组织中积聚，导致皮肤硬化，还可能损害心脏、肺和其他内脏器官。然而，尚不清楚是什么促使 T 细胞在这些个体的结缔组织中积聚。当免疫系统错误地将宿主细胞识别为对身体的威胁时，就会出现自身免疫性疾病。通常，免疫系统通过细胞表面特定蛋白质的存在来识别健康的身体细胞。一组称为主要组织相容性复合物 (MHC) 的表面蛋白在此过程中发挥着重要作用，但还有许多其他表面蛋白发挥着更次要的作用。 2002年，研究人员开发了一种可以引发小鼠系统性硬皮病症状的方法。这种方法涉及将一只小鼠的骨髓移植到另一只小鼠体内。两只小鼠的细胞表面都有相同的 MHC 蛋白，但其他细胞表面蛋白有一些差异，因此供体小鼠的骨髓会触发受体小鼠的免疫反应。为了更好地了解这种系统性硬皮病小鼠“模型”的工作原理，Okawa、Morikawa 等人。改进了该方法，以便他们可以将特定类型的骨髓细胞移植到受体小鼠体内。实验表明，来自供体小鼠的骨髓基质干细胞，而不是所谓的“造血干细胞”，负责触发受体的免疫反应和疾病症状。 Okawa、Morikawa 等人的研究结果表明，骨髓基质干细胞上不匹配的小细胞表面蛋白可引发小鼠系统性硬皮病的症状。需要进一步的研究来了解这些细胞如何促进 T 细胞触发自身免疫反应。 DOI：http://dx.doi.org/10.7554/eLife.09394.002
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. DOI: http://dx.doi.org/10.7554/eLife.09394.001 Systemic scleroderma is an autoimmune disease caused by the immune system attacking the body’s connective tissues, which provide the body with structural support. Immune cells called T cells accumulate in connective tissue, which leads to the hardening of the skin and may also damage the heart, lungs and other internal organs. However, it is not clear what prompts the T cells to accumulate in the connective tissues of these individuals. Autoimmune diseases develop when the immune system mistakenly identifies host cells as being a threat to the body. Normally, the immune system recognizes healthy body cells by the presence of particular proteins on the surface of the cells. A set of surface proteins called the major histocompatibility complexes (MHCs) play a major role in this process, but there are also many other surface proteins that play more minor roles. In 2002, researchers developed a method that can trigger the symptoms of systemic scleroderma in mice. This method involves transplanting bone marrow from one mouse into another mouse. Both mice have identical MHC proteins on the surfaces of their cells, but have some differences in other cell surface proteins, and so the bone marrow from the donor mouse triggers an immune response in the recipient. To better understand how this mouse “model” of systemic scleroderma works, Ogawa, Morikawa et al. refined the method so that they could just transplant specific types of bone marrow cells into the recipient mice. The experiments reveal that bone marrow stromal stem cells, but not so-called “hematopoietic stem cells”, from a donor mouse are responsible for triggering the immune response and disease symptoms in the recipients. Ogawa, Morikawa et al.’s findings show that mismatched minor cell surface proteins on bone marrow stromal stem cells can trigger symptoms of systemic scleroderma in mice. Further studies are required to find out how these cells encourage T cells to trigger an autoimmune response. DOI: http://dx.doi.org/10.7554/eLife.09394.002