Increased arthritis susceptibility in cartilage proteoglycan-specific T cell receptor-transgenic mice
Increased arthritis susceptibility in cartilage proteoglycan-specific T cell receptor-transgenic mice
复制标题
DOI：
10.1002/art.22013
复制
发表时间：
2006-08-01
影响因子：
--
通讯作者：
Glant, Tibor T.
中科院分区：
文献类型：
--
作者：
Berlo, Suzanne E.;Guichelaar, Teun;Glant, Tibor T.
Objective.为了更好地了解抗原（致关节炎表位）特异性T细胞在自身免疫性关节炎发展中的作用。产生表达对人软骨蛋白聚糖（HuPG）聚集蛋白聚糖的显性致关节炎表位（指定为5/4 E8）特异性的T细胞受体（TCR）V（α）1.1和V（β）4链的转基因（Tg）小鼠。将该TCR-Tg小鼠品系与PG诱导的关节炎（PGIA）敏感的BALB/c品系回交，并测试关节炎的发病率和严重程度。CD 4 + TCR-Tg T细胞携带对HuPG（5/4 E8）的显性致关节炎表位具有特异性的功能活性TCR。初始TCR-Tg小鼠的T细胞处于活化阶段，因为对HuPG或肽刺激的体外应答诱导干扰素-γ和白细胞介素-4产生。即使没有佐剂，TCR-Tg小鼠也无一例外地发生严重和进行性多关节炎。发炎的关节表现出广泛的软骨退化和骨侵蚀，类似于在患有PGIA的野生型BALB/c小鼠的关节炎关节中观察到的。结论：TCR-Tg小鼠的脾细胞经HuPG免疫后，可过继性地将关节炎转移到BALB/c.SCID小鼠体内。TCR-Tg BALB/c小鼠显示关节炎易感性增加，并在体内抗原刺激后发生疾病加重。该模型使用TCR-Tg小鼠是一种新的和有价值的研究工具，用于研究抗原（致关节炎表位）驱动的关节炎调节机制，并了解T细胞如何识别关节中的自身抗原。这种类型的小鼠也可用于开发T细胞介导的自身免疫性疾病的新的免疫调节策略。
Objective. To better understand the role of antigen (arthritogenic epitope)-specific T cells in the development of autoimmune arthritis.Methods. A transgenic (Tg) mouse expressing the T cell receptor (TCR) V(alpha)1.1 and V(beta)4 chains specific for a dominant arthritogenic epitope (designated 5/4E8) of human cartilage proteoglycan (HuPG) aggrecan was generated. This TCR-Tg mouse strain was backcrossed into the PG-induced arthritis (PGIA)-susceptible BALB/c strain and tested for arthritis incidence and severity.Results. CD4+ TCR-Tg T cells carried functionally active TCR specific for a dominant arthritogenic epitope of HuPG (5/4E8). T cells of naive TCR-Tg mice were in an activated stage, since the in vitro response to HuPG or to peptide stimulation induced interferon-gamma and interleukin-4 production. TCR-Tg mice uniformly, without exception, developed severe and progressive polyarthritis, even without adjuvant. Inflamed joints showed extensive cartilage degradation and bone erosions, similar to that seen in the arthritic joints of wild-type BALB/c mice with PGIA. Spleen cells from both naive and HuPG-immunized arthritic TCR-Tg mice could adoptively transfer arthritis when injected into syngeneic BALB/c.SCID recipient mice.Conclusion. TCR-Tg BALB/c mice display increased arthritis susceptibility and develop aggravated disease upon in vivo antigen stimulation. This model using TCR-Tg mice is a novel and valuable research tool for studying mechanisms of antigen (arthritogenic epitope)-driven regulation of arthritis and understanding how T cells recognize autoantigen in the joints. This type of mouse could also be used to develop new immunomodulatory strategies in T cell-mediated autoimmune diseases.