本文選題：自身免疫疾病 + 類風(fēng)濕關(guān)節(jié)炎��； 參考：《云南大學(xué)》2015年博士論文

【摘要】：類風(fēng)濕關(guān)節(jié)炎(Rheumatoid Arthritis,RA)屬于自身免疫性疾病,滑膜炎是其病理基本類型�？梢猿霈F(xiàn)關(guān)節(jié)紅腫、疼痛,隨病情發(fā)展滑膜和骨質(zhì)被破壞,嚴(yán)重者則出現(xiàn)關(guān)節(jié)變形。RA確切的病因不清楚,多因素參與發(fā)病。JAM-A是一種細(xì)胞膜表面的蛋白分子,分布于內(nèi)皮細(xì)胞間的緊密連接,協(xié)助形成完整的物理屏障,防止水和大分子物質(zhì)自由穿過細(xì)胞間縫隙。在白細(xì)胞也有JAM-A蛋白表達(dá),在細(xì)胞遷移過程中可以重新分布,保持細(xì)胞極性。既往的研究多關(guān)注于緊密連接的JAM-A蛋白在維持免疫屏障方面的作用,而對于它在RA淋巴細(xì)胞的功能的報(bào)道尚不多見,本研究從臨床RA患者、膠原誘導(dǎo)性關(guān)節(jié)炎小鼠動物模型以及細(xì)胞分子生物學(xué)等角度對淋巴細(xì)胞的JAM-A蛋白在RA這一自身免疫性疾病中的功能進(jìn)行探討。 JAMs蛋白家族在健康人淋巴細(xì)胞廣譜表達(dá),JAM-A的mRNA水平和蛋白水平都很高,在B淋巴細(xì)胞中,只檢測到.Jam-a的]mRNA高表達(dá),JAM-A的蛋白表達(dá)水平很低,表明生理?xiàng)l件下T淋巴細(xì)胞可能是JAM-A基因和蛋白水平表達(dá)的主要淋巴細(xì)胞類型。 與健康人相比,RA患者淋巴細(xì)胞的JAM-A增高,但是未接受規(guī)范藥物治療患者的JAM-A蛋白水平卻無明顯改變,而MTX可以升高RA的淋巴細(xì)胞(尤其是T淋巴細(xì)胞)JAM-A蛋白水平,并與疾病活動評分成負(fù)相關(guān),對淋巴細(xì)胞的JAM-A蛋白水平調(diào)控可能是MTX治療RA的藥物機(jī)制之一。 關(guān)節(jié)炎小鼠淋巴細(xì)胞JAM-A蛋白水平與正常組比較無差異,而甲氨喋呤可以升高關(guān)節(jié)炎小鼠外周血總淋巴細(xì)胞、T淋巴細(xì)胞和B淋巴細(xì)胞膜的JAM-A蛋白水平并減輕關(guān)節(jié)炎小鼠的關(guān)節(jié)腫脹程度。 為了進(jìn)一步研究淋巴細(xì)胞JAM-A在RA中的作用,體外培養(yǎng)淋巴細(xì)胞開展實(shí)驗(yàn)。RA患者淋巴細(xì)胞的遷移能力高于健康人。MTX能夠抑制RA患者淋巴細(xì)胞的遷移能力,而這種作用可被JAM-A的抗體J10.4所拮抗。0.01μg/mL的MTX對Jam-a基因和.JAM-A蛋白具有上調(diào)作用。這些結(jié)果也表明淋巴細(xì)胞膜上的JAM-A在RA疾病發(fā)生中發(fā)揮了作用。 本研究結(jié)果表明,JAM-A可能通過調(diào)節(jié)淋巴細(xì)胞的遷移過程參與RA發(fā)病。提示淋巴細(xì)胞的JAM-A可能成為將來臨床治療RA的一個靶點(diǎn),本研究可為探索RA的發(fā)病機(jī)制以及新的治療藥物的篩選提供參考。
[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.
【學(xué)位授予單位】：云南大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R593.22

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1 Lili Magyari;Dalma Varszegi;Erzsebet Kovesdi;Patricia Sarlos;Bernadett Farago;Andras Javorhazy;Katalin Sumegi;Zsolt Banfai;Bela Melegh;;Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications[J];World Journal of Orthopedics;2014年04期

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本文編號：1914193