本文選題：類風濕關(guān)節(jié)炎 + 類風濕關(guān)節(jié)炎動物模型　； 參考：《錦州醫(yī)科大學》2017年碩士論文

【摘要】：目的類風濕關(guān)節(jié)炎(rheumatoid athritis,RA)是一種全身性自身免疫疾病,主要特征表現(xiàn)為慢性炎性關(guān)節(jié)病變,并伴全身多個系統(tǒng)受累。究其受多重因素的影響,發(fā)病機制目前尚不明確。隨著Th17細胞亞群的發(fā)現(xiàn),Th17細胞對RA的發(fā)病機制有了新的考究,同時也有研究表明Wnt/β-catenin信號也參與RA的炎正反應,具體機制仍不清楚。故本研究目的是探討β-連環(huán)蛋白(β-catenin)在RA動物模型中對Th17細胞分化的影響。方法將8-10周的雄性C57BL/6小鼠分為三組:對照組,CIA組(類風濕關(guān)節(jié)炎模型組),CIA+β-catenin激動劑組(即注射LICL組)。疾病高峰期處死小鼠后,取小鼠血清,檢測血清中的炎癥因子(IL17、IL1β、IL6、IL23)。踝關(guān)節(jié)、膝關(guān)節(jié)、脾臟和淋巴結(jié)經(jīng)固定石蠟包埋后用于HE染色、免疫}D化染色和免疫熒光染色,比較各組間病理改變、炎癥細胞分布和蛋白分布(β-catenin、IL17和CD68)。脾臟和淋巴結(jié)中的AKT以及轉(zhuǎn)錄因子(TCF1、TCF4、RORγT,c-Jun)則用免疫印跡法(western blot)檢測。結(jié)果1、比較CIA組和LICL組小鼠臨床評分和發(fā)病率發(fā)現(xiàn),LICL組評分較CIA組明顯降低,發(fā)病時間較CIA組延遲,而且發(fā)病率較CIA組降低。2、HE染色顯示,CIA組小鼠踝關(guān)節(jié)和膝關(guān)節(jié)的滑膜組織明顯增厚,淋巴細胞、粒細胞等炎癥細胞的浸潤明顯增加,膝關(guān)節(jié)的軟骨組織可見滑膜組織中炎性細胞的浸潤和侵蝕的現(xiàn)象,LICL組這些現(xiàn)象則明顯好轉(zhuǎn)。同時,血清中炎癥因子結(jié)果顯示;CIA組炎癥因子顯著增加,而LICL組則明顯降低。3、LICL組血清中的炎癥因子(IL1β,IL23,IL6,IL17)較CIA組明顯降低;LICL的滑膜組織、軟骨關(guān)節(jié)組織以及的IL17的浸潤明顯較CIA組減少4、CIA組的脾臟和淋巴結(jié)中IL17+Th細胞、CD68+巨噬細胞明顯增加;而LICL處理后可以降低上兩種細胞。免疫熒光雙重染色結(jié)果顯示,β-catenin可以表達在Th細胞和巨噬細胞。5、CIA脾臟和淋巴結(jié)中AKT、RORγT、c-Jun明顯增加,而LICL組上述蛋白明顯降低。CIA組脾臟中TCF1明顯降低;LICL組脾臟中TCF1增加;而CIA組淋巴結(jié)中的TCF1增加,LICL組則降低。TCF4則只在LICL組的脾臟中顯著增加。結(jié)論β-catenin降低是類風濕關(guān)節(jié)炎發(fā)病的重要因素。在類風濕關(guān)節(jié)中,β-catenin不僅通過抑制巨噬細胞活性而影響Th17分化,還可以直接影響其活性。在CIA的脾臟和淋巴結(jié)中,AKT可以通過影響c-Jun而促進Th17的分化。而β-catenin/TCF1在CIA的不同臟器可能通過不同機制參與Th17的分化。
[Abstract]:Objective rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammatory joint disease and multiple systemic involvement. It is affected by many factors, the pathogenesis is not clear. With the discovery of Th17 cell subsets, Th17 cells have a new understanding of the pathogenesis of RA, and some studies have also shown that Wnt/ 尾 -catenin signal is also involved in the positive response of RA, but the specific mechanism is still unclear. The aim of this study was to investigate the effect of 尾 -catenin on the differentiation of Th17 cells in RA animal model. Methods male C57BL/6 mice aged 8 to 10 weeks were divided into three groups: control group (rheumatoid arthritis model group) and 尾 -catenin agonist group (LICL group). After the mice were killed in the peak period of disease, the serum of mice was taken and the inflammatory factor IL17, IL1 尾, IL6 and IL23 were detected. The ankle joint, knee joint, spleen and lymph nodes were embedded with fixed paraffin wax for HE staining, immunological} D staining and immunofluorescence staining. The pathological changes, distribution of inflammatory cells and protein distribution (尾 -cateninine IL-17 and CD68) were compared among the three groups. The AKT in spleen and lymph nodes and the transcription factor TCF1, TCF4, ROR 緯 -Tnc-Jun) were detected by Western blot (Western blot). Results 1.Compared with the clinical score and incidence rate of CIA group and LICL group, the score of LICL group was significantly lower than that of CIA group, and the onset time was longer than that of CIA group. Compared with CIA group, the incidence of the disease was lower than that of CIA group. The results of HE staining showed that the synovial tissue of ankle and knee joint was thickened, and the infiltration of inflammatory cells such as lymphocytes and granulocytes was obviously increased in the CIA group. The infiltration and erosion of inflammatory cells in synovial tissue were observed in cartilage tissue of knee joint. At the same time, the results of inflammatory cytokines in serum showed that the inflammatory factors in the CIA group were significantly increased, while the inflammatory cytokines in the serum of the LICL group were significantly lower than those in the CIA group, and that in the LICL group was significantly lower than that in the CIA group. Compared with CIA group, the infiltration of IL17 Th cells and CD68 macrophages in IL17 Th cells in spleen and lymph nodes were significantly decreased in the chondroarticular tissue and IL17 group, but the CD68 macrophages in the IL17 Th cells in the spleen and lymph nodes were decreased after LICL treatment. The results of double immunofluorescence staining showed that 尾 -catenin could be expressed in the spleen and lymph nodes of Th cells and macrophages. The expression of AK Tor 緯 Tnc-Jun in spleen and lymph nodes was significantly increased, while the expression of TCF1 in spleen of LICL group was significantly lower than that of control group. The increase of TCF1 in spleen of LICL group was significantly lower than that of control group. However, the increase of TCF1 in lymph nodes in CIA group and the decrease of TCF4 in LICL group were only significantly increased in spleen of LICL group. Conclusion the decrease of 尾-catenin is an important factor in the pathogenesis of rheumatoid arthritis. In rheumatoid joints, 尾 -catenin not only affects Th17 differentiation by inhibiting macrophage activity, but also directly affects its activity. In the spleen and lymph nodes of CIA, AK T can promote the differentiation of Th17 by affecting c-Jun. 尾 -catenin / TCF1 may participate in the differentiation of Th17 in different organs of CIA through different mechanisms.
【學位授予單位】：錦州醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R593.22;R-332

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