淋巴细胞JAM-A在类风湿关节炎的作用研究

发布时间：2018-05-20 10:05

本文选题：自身免疫疾病 + 类风湿关节炎　；参考：《云南大学》2015年博士论文

【摘要】：类风湿关节炎(Rheumatoid Arthritis,RA)属于自身免疫性疾病,滑膜炎是其病理基本类型。可以出现关节红肿、疼痛,随病情发展滑膜和骨质被破坏,严重者则出现关节变形。RA确切的病因不清楚,多因素参与发病。JAM-A是一种细胞膜表面的蛋白分子,分布于内皮细胞间的紧密连接,协助形成完整的物理屏障,防止水和大分子物质自由穿过细胞间缝隙。在白细胞也有JAM-A蛋白表达,在细胞迁移过程中可以重新分布,保持细胞极性。既往的研究多关注于紧密连接的JAM-A蛋白在维持免疫屏障方面的作用,而对于它在RA淋巴细胞的功能的报道尚不多见,本研究从临床RA患者、胶原诱导性关节炎小鼠动物模型以及细胞分子生物学等角度对淋巴细胞的JAM-A蛋白在RA这一自身免疫性疾病中的功能进行探讨。 JAMs蛋白家族在健康人淋巴细胞广谱表达,JAM-A的mRNA水平和蛋白水平都很高,在B淋巴细胞中,只检测到.Jam-a的]mRNA高表达,JAM-A的蛋白表达水平很低,表明生理条件下T淋巴细胞可能是JAM-A基因和蛋白水平表达的主要淋巴细胞类型。与健康人相比,RA患者淋巴细胞的JAM-A增高,但是未接受规范药物治疗患者的JAM-A蛋白水平却无明显改变,而MTX可以升高RA的淋巴细胞(尤其是T淋巴细胞)JAM-A蛋白水平,并与疾病活动评分成负相关,对淋巴细胞的JAM-A蛋白水平调控可能是MTX治疗RA的药物机制之一。关节炎小鼠淋巴细胞JAM-A蛋白水平与正常组比较无差异,而甲氨喋呤可以升高关节炎小鼠外周血总淋巴细胞、T淋巴细胞和B淋巴细胞膜的JAM-A蛋白水平并减轻关节炎小鼠的关节肿胀程度。为了进一步研究淋巴细胞JAM-A在RA中的作用,体外培养淋巴细胞开展实验。RA患者淋巴细胞的迁移能力高于健康人。MTX能够抑制RA患者淋巴细胞的迁移能力,而这种作用可被JAM-A的抗体J10.4所拮抗。0.01μg/mL的MTX对Jam-a基因和.JAM-A蛋白具有上调作用。这些结果也表明淋巴细胞膜上的JAM-A在RA疾病发生中发挥了作用。本研究结果表明,JAM-A可能通过调节淋巴细胞的迁移过程参与RA发病。提示淋巴细胞的JAM-A可能成为将来临床治疗RA的一个靶点,本研究可为探索RA的发病机制以及新的治疗药物的筛选提供参考。
[Abstract]:Rheumatoid arthritis (RA) belongs to autoimmune disease, synovitis is the basic pathological type. Joint redness and swelling, pain, destruction of synovium and bone with the development of the disease, and in severe cases, the exact cause of joint deformation.RA is not clear, and many factors are involved in the pathogenesis. JAM-A is a protein molecule on the surface of cell membrane. Tight junctions distributed among endothelial cells help to form a complete physical barrier to prevent water and macromolecular substances from freely passing through intercellular gaps. JAM-A protein is also expressed in leukocytes and can be redistributed during cell migration to maintain cell polarity. Previous studies have focused on the role of tightly connected JAM-A protein in maintaining the immune barrier, but there have been few reports of its function in RA lymphocytes. The function of lymphocyte JAM-A protein in RA, an autoimmune disease, was studied from the animal model of collagen-induced arthritis and from the perspective of cellular and molecular biology. The mRNA level and protein level of JAMs protein family were very high in the lymphocytes of healthy people. In B lymphocytes, only mRNA of. Jam-a was detected. The expression level of JAM-A protein was very low. It is suggested that T lymphocytes may be the main type of lymphocytes expressing JAM-A gene and protein under physiological conditions. The level of JAM-A in RA patients was higher than that in healthy controls, but there was no significant change in JAM-A protein level in patients without regular drug therapy. However, MTX could increase the level of JAM-A protein in RA lymphocytes (especially T lymphocytes). The regulation of JAM-A protein level in lymphocytes may be one of the drug mechanisms of MTX in the treatment of RA. The level of lymphocyte JAM-A protein in arthritis mice was not different from that in normal group. Methotrexate could increase the JAM-A protein level of T lymphocyte and B lymphocyte membrane in the peripheral blood of arthritis mice and reduce the degree of joint swelling in arthritis mice. In order to further study the role of lymphocyte JAM-A in RA, lymphocyte migration ability of RA patients was higher than that of healthy controls. This effect could be antagonized by JAM-A antibody J10.4. MTX with 0.01 渭 g/mL could up-regulate Jam-a gene and .JAM-A protein. These results also suggest that JAM-A on lymphocyte membrane plays an important role in the pathogenesis of RA. The results suggest that JAM-A may be involved in the pathogenesis of RA by regulating the migration of lymphocytes. The results suggest that the JAM-A of lymphocytes may be a target for the treatment of RA in the future. This study may provide a reference for exploring the pathogenesis of RA and screening new therapeutic drugs.
【学位授予单位】：云南大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R593.22

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