本文選題：Toll樣受體3 + Toll樣受體4��； 參考：《新鄉(xiāng)醫(yī)學(xué)院》2017年碩士論文

【摘要】：背景特發(fā)性IgA腎病(IgA nephropathy,IgAN),是兒童常見的原發(fā)性腎小球腎炎,是一種以腎小球系膜區(qū)IgA沉積為主的臨床病理綜合征,常表現(xiàn)為急性上呼吸道或消化道感染后出現(xiàn)發(fā)作性肉眼血尿。早期研究學(xué)者認(rèn)為此病是良性疾病,臨床呈慢性進(jìn)展,預(yù)后良好,但目前眾多的資料顯示約20%-40%的患者在確診后的20年內(nèi)進(jìn)展到終末期腎臟病(ESRD),需要腎替代治療,對兒童的生活質(zhì)量及生命造成了嚴(yán)重威脅,故有必要對IgAN采取干預(yù)治療,然而目前由于IgAN發(fā)病機(jī)理尚未完全清楚,IgAN的治療方案有限,因此有必要探究IgAN的發(fā)病機(jī)制。研究表明,IgAN處理來自常見致病菌的共同外源性抗原失調(diào),可引起異常的免疫反應(yīng)、異常IgA的合成及腎損害,但具體通過何種途徑導(dǎo)致免疫失衡仍不清楚。Toll樣受體(Toll-like receptors,TLRs)是一種新型的、保守的模式識別受體,可表達(dá)于內(nèi)皮細(xì)胞、免疫細(xì)胞和腎臟固有細(xì)胞等,識別病原體相關(guān)分子模式和損傷相關(guān)分子模式等,通過髓樣分化因子-88(myeloid differentiation factor 88,MyD88)依賴信號傳導(dǎo)通路和MyD88非依賴信號傳導(dǎo)通路,激活核轉(zhuǎn)錄因子(nuclear factor,NF)-κB,引起細(xì)胞因子、趨化因子等表達(dá)增加,同時啟動天然免疫和適應(yīng)性免疫應(yīng)答與炎癥反應(yīng),成為感染性或非感染性腎臟病研究的熱點。我們前期研究了TLR4和TLR7在兒童原發(fā)性腎病綜合征患兒腎組織中的表達(dá)變化,證實了TLR4和TLR7參與兒童原發(fā)性腎病綜合征的發(fā)病。那么TLRs是否參與IgAN的發(fā)病過程?IgAN是否存在TLRs的異常變化?目的探討TLR3和TLR4在兒童特發(fā)性IgAN外周血單個核細(xì)胞及腎組織中的表達(dá),為兒童IgAN的發(fā)病機(jī)制提供實驗依據(jù),同時為IgAN的治療提供新靶點。方法收集2014年09月至2016年06月于我院兒科就診且經(jīng)腎穿刺活檢,最后確診的IgAN患者34例為IgAN組,同期在我院小兒外科行腎臟切除的腎腫瘤患兒7例為對照A組;以10例門診健康體檢兒童為對照B組。采用免疫組織化學(xué)法檢測IgAN組與對照A組腎組織中TLR3和TLR4的表達(dá)情況;同時采用流式細(xì)胞術(shù)檢測TLR3和TLR4在IgAN組與對照B組外周血單個核細(xì)胞中的陽性表達(dá)率。對TLR3和TLR4在IgAN組與對照組的陽性表達(dá)情況進(jìn)行分析,研究IgAN患者中TLR3和TLR4的表達(dá)情況。結(jié)果1.外周血單個核細(xì)胞中TLR3和TLR4的表達(dá):TLR3在對照B組外周血單個核細(xì)胞中幾乎沒有表達(dá),而在IgAN組則呈現(xiàn)出明顯的高表達(dá),TLR4在對照B組外周血單個核細(xì)胞中有少量的表達(dá),而在IgAN組的表達(dá)明顯升高。IgAN組外周血單個核細(xì)胞中TLR3和TLR4的陽性表達(dá)率分別為(17.62±8.33)%和(23.85±11.82)%,均明顯高于對照B組中TLR3(0.31±0.06)%和TLR4(3.02±0.09)%的表達(dá),差異有統(tǒng)計學(xué)意義(P0.05)。2.腎組織TLR3和TLR4表達(dá):TLR3、TLR4在腎組織的表達(dá)分別為胞核表達(dá)和胞漿表達(dá)。對照A組:腎小管上皮細(xì)胞有少量的TLR3表達(dá),而腎小球中幾乎無TLR3表達(dá),TLR4在腎小管及腎小球中均無明顯表達(dá)。IgAN組:TLR3和TLR4在腎小管上皮細(xì)胞均呈高表達(dá),而腎小球系膜細(xì)胞有不同程度TLR3和TLR4表達(dá)。IgAN組腎組織中TLR3和TLR4的表達(dá)分別為(68.28±6.37)%和(0.048±0.018),均明顯高于對照A組腎組織中TLR3(9.69±11.02)%和TLR4(0.003±0.001)的表達(dá),差異有統(tǒng)計學(xué)意義(P0.01)。結(jié)論1.TLR3和TLR4在IgAN腎組織及外周血單個核細(xì)胞中表達(dá)均增加,提示TLR3和TLR4異常活化可能參與了IgAN的發(fā)病過程。2.根據(jù)TLR3和TLR4兩種受體的主要識別配體類型,推斷病毒及細(xì)菌感染可能通過免疫作用引起IgAN的腎損害。
[Abstract]:Background idiopathic IgA nephropathy (IgA nephropathy, IgAN) is a common primary glomerulonephritis in children. It is a clinicopathological syndrome mainly in mesangial mesangial region IgA deposition, often manifested by acute upper respiratory tract or digestive tract infection with paroxysmal hematuria. The prognosis is good, but at present, many data show that about 20%-40% patients have progressed to end-stage renal disease (ESRD) within 20 years after diagnosis, which requires renal replacement therapy, which poses a serious threat to the quality of life and life of children. Therefore, it is necessary to take intervention treatment to IgAN, however, the pathogenesis of IgAN is not completely clear, Ig The treatment scheme of AN is limited, so it is necessary to explore the pathogenesis of IgAN. The study shows that IgAN treatment of common exogenous antigen disorders from common pathogenic bacteria can cause abnormal immune response, abnormal IgA synthesis and renal damage, but the specific way of immune imbalance is still unclear on the.Toll receptor (Toll-like receptors, TLRs). It is a new, conservative pattern recognition receptor that can be expressed in endothelial cells, immune cells and renal cells, identification of pathogen associated molecular patterns and damage related molecular patterns, and through the myeloid differentiation factor -88 (myeloid differentiation factor 88, MyD88) dependent signal transduction pathway and MyD88 non dependent signal transduction pathway. Nuclear factor (NF) - kappa B activates the expression of cytokines, chemokines and other expressions. It also activates natural and adaptive immune responses and inflammatory responses. It has become a hot spot in the study of infectious or non infectious renal diseases. We studied TLR4 and TLR7 in the renal tissue of children with primary nephrotic syndrome. The expression changes have confirmed the involvement of TLR4 and TLR7 in the pathogenesis of primary nephrotic syndrome in children. Then does TLRs participate in the pathogenesis of IgAN? Is there an abnormal change in TLRs in IgAN? Objective to explore the expression of TLR3 and TLR4 in the peripheral blood mononuclear cells and renal tissues of children with idiopathic IgAN, and to provide an experimental basis for the pathogenesis of IgAN in children. At the same time, it provides new targets for the treatment of IgAN. Methods from 2014 09 months to 06 months in 2016, the pediatric patients in our hospital were treated with renal biopsy, 34 of the final confirmed IgAN patients were group IgAN. In the same period, 7 cases of renal tumor children with nephrectomy in our hospital were compared with the control group, and 10 cases of healthy physical examination children were compared with the B group. The expression of TLR3 and TLR4 in the renal tissue of group IgAN and control group A was detected by immunohistochemical method, and the positive expression rate of TLR3 and TLR4 in the peripheral blood mononuclear cells of group IgAN and control B group was detected by flow cytometry. The positive expression of TLR3 and TLR4 in the IgAN group and the control group was analyzed. Results the expression of TLR3 and TLR4 in 1. peripheral blood mononuclear cells: TLR3 was almost not expressed in the peripheral blood mononuclear cells of the control group B, but in the IgAN group, the expression of TLR4 was obviously expressed in the peripheral blood mononuclear cells of the control group of B group, and the expression of the peripheral blood mononuclear significantly increased in the group of IgAN. The positive expression rates of TLR3 and TLR4 in the cells were (17.62 + 8.33)% and (23.85 + 11.82)%, respectively, which were significantly higher than those of the control group B TLR3 (0.31 + 0.06)% and TLR4 (3.02 + 0.09)%. The difference was statistically significant (P0.05).2. renal tissue TLR3 and TLR4 expression: TLR3, TLR4 in the renal tissue expression and cytoplasm expression respectively. There was a small amount of TLR3 expression in the epithelial cells of the tubule, and there was almost no TLR3 expression in the glomeruli. There was no significant expression of TLR4 in the renal tubules and glomeruli. TLR3 and TLR4 were highly expressed in the renal tubular epithelial cells, while the expression of TLR3 and TLR4 in the glomerular mesangial cells expressed TLR3 and TLR4 in the.IgAN group of.IgAN group (68.28 + 6, respectively). .37)% and (0.048 + 0.018) were significantly higher than the expression of TLR3 (9.69 + 11.02)% and TLR4 (0.003 + 0.001) in the renal tissue of the control group A, and the difference was statistically significant (P0.01). Conclusion 1.TLR3 and TLR4 were increased in IgAN renal tissue and peripheral blood mononuclear cells, suggesting that the abnormal activation of TLR3 and TLR4 may be involved in IgAN pathogenesis. The main recognition ligand types of the two receptors of TLR4 and IgAN infer that the virus and bacterial infection may cause renal damage by immunization.

【學(xué)位授予單位】：新鄉(xiāng)醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R726.9

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