本文選題：系統(tǒng)性紅斑狼瘡 + 狼瘡性腎炎��； 參考：《鄭州大學(xué)》2017年碩士論文

【摘要】：背景系統(tǒng)性紅斑狼瘡(systemic lupus erythematosus,SLE)是一種最常見的累及機(jī)體多系統(tǒng)、多器官的自身免疫性疾病,狼瘡性腎炎(Lupus nephritis,LN)是其最常見的并發(fā)癥。有關(guān)SLE的發(fā)病機(jī)制十分復(fù)雜,研究顯示遺傳、免疫紊亂、激素、感染和理化環(huán)境等均與SLE及LN的發(fā)生發(fā)展密切相關(guān)�；赟LE的特點(diǎn)之一產(chǎn)生以ANA、抗ds-DNA抗體為主的多種自身抗體及各型LN均有免疫復(fù)合物沉積,使得參與適應(yīng)性免疫反應(yīng)的T、B淋巴細(xì)胞在SLE的發(fā)病過(guò)程中最早受到關(guān)注并得到闡明,而有關(guān)NK細(xì)胞等固有免疫反應(yīng)細(xì)胞研究較少。自然殺傷細(xì)胞(natural killer cell,NK細(xì)胞)是固有免疫反應(yīng)中的主要細(xì)胞,可通過(guò)細(xì)胞-細(xì)胞之間的相互作用和分泌多種細(xì)胞因子和趨化因子來(lái)調(diào)節(jié)適應(yīng)性免疫反應(yīng)中的T、B淋巴細(xì)胞,被認(rèn)為是連接固有免疫反應(yīng)和適應(yīng)性免疫反應(yīng)的“橋梁”。越來(lái)越多的研究顯示NK細(xì)胞與器官特異性自身免疫性疾病有相關(guān)性。依據(jù)Yokoyama等提出的“l(fā)icensing”學(xué)說(shuō),可將NK細(xì)胞分為“l(fā)icensed”和“unlicensed”兩種亞群。有研究發(fā)現(xiàn)在骨髓移植急性排斥期,“unlicensed”NK細(xì)胞可促進(jìn)同種異體移植物細(xì)胞在宿主體內(nèi)的存活。本研究旨在使用Pristane(降植烷)誘導(dǎo)狼瘡腎模型,觀察“unlicensed”NK細(xì)胞在狼瘡鼠發(fā)病過(guò)程中的作用。目的采用Pristane(降植烷)誘導(dǎo)狼瘡小鼠模型,探討unlicensed NK細(xì)胞亞群在SLE及狼瘡性腎炎發(fā)病過(guò)程中的作用,為SLE的發(fā)病機(jī)制研究提供新思路。方法1.建立Pristane(降植烷)誘導(dǎo)的狼瘡小鼠模型:將18只雌性、SPF級(jí)、9-10周齡的BALB/c小鼠隨機(jī)分為兩組:(1)誘導(dǎo)組(9只):腹腔注射0.5ml Pristane;(2)對(duì)照組(9只):腹腔注射0.5ml PBS。觀察7個(gè)月,觀察指標(biāo)有小鼠外觀變化、體重、尿蛋白、自身抗體(ANA、抗ds-DNA抗體、抗nRNP/Sm抗體和抗ss-DNA抗體)水平、腎臟病理(普通光鏡和免疫熒光)等。比較兩組上述指標(biāo)間的變化。2.研究unlicensed NK細(xì)胞亞群與Pristane誘導(dǎo)的狼瘡小鼠發(fā)病機(jī)制的關(guān)系。將27只雌性、SPF級(jí)、9-10周齡的BALB/c小鼠隨機(jī)分為3組:(1)“U-NK”組:9只,實(shí)驗(yàn)開始前腹腔注射抗Ly49G2+的單克隆抗體4D11;(2)“non-NK”組:實(shí)驗(yàn)開始前腹腔注射Anti-asialoGM1;(3)“model”組:9只。實(shí)驗(yàn)開始當(dāng)天,3組小鼠均一次性腹腔注射0.5ml Pristane。實(shí)驗(yàn)觀察時(shí)間為7個(gè)月,指標(biāo)有:小鼠外觀變化、體重及尿蛋白情況,自身抗體(ANA、抗ds-DNA抗體、抗nRNP/Sm抗體和抗ss-DNA抗體)水平、腎臟病理改變(普通光鏡和免疫熒光)以及流式細(xì)胞儀檢測(cè)NK細(xì)胞亞群數(shù)量變化。結(jié)果1.誘導(dǎo)組部分小鼠出表現(xiàn)了紅斑和脫毛等狼瘡樣表現(xiàn),尿蛋白多為+1~+2,血清中出現(xiàn)四種自身抗體(ANA、抗ds-DNA抗體、抗nRNP/Sm抗體和抗ss-DNA抗體),腎臟組織病理光鏡下示部分腎小球體積增大,系膜細(xì)胞及內(nèi)皮細(xì)胞增生,腎間質(zhì)伴炎癥細(xì)胞浸潤(rùn);免疫熒光提示IgG和IgM延腎小球毛細(xì)管襻和系膜區(qū)沉積。對(duì)照組無(wú)上述變化。2.實(shí)驗(yàn)觀察結(jié)束后,3組間小鼠存活情況及外觀變化無(wú)差異;“U-NK”組尿蛋白、自身抗體水平及腎臟病理改變均較“non-NK”和“model”組明顯好轉(zhuǎn);而相對(duì)于“model”組,“non-NK”組抗nRNP/Sm抗體、抗ss-DNA抗體水平及IgG、IgM熒光強(qiáng)度均升高,情況較差。流式檢測(cè)小鼠脾臟NK細(xì)胞數(shù)量顯示,“U-NK”組unlicensed NK細(xì)胞數(shù)量較“model”組增多。結(jié)論P(yáng)ristane(降植烷)可以誘導(dǎo)雌性BALB/c小鼠形成狼瘡模型;unlicensed NK細(xì)胞在SLE及狼瘡性腎炎的發(fā)生發(fā)展過(guò)程中有抑制作用,為SLE的發(fā)病機(jī)制提供了新思路。
[Abstract]:Background systemic lupus erythematosus (systemic lupus erythematosus, SLE) is one of the most common autoimmune diseases involving multiple systems and multiple organs. Lupus nephritis (Lupus nephritis, LN) is the most common complication. The pathogenesis of SLE is very complex. The study shows heredity, immune disorder, hormone, infection, and physicochemical environment. All of them are closely related to the occurrence and development of SLE and LN. One of the characteristics of SLE based on the production of ANA, anti ds-DNA antibodies and various types of LN have immune complex deposition, making T, B lymphocytes involved in adaptive immune response to the earliest attention and clarified in the pathogenesis of SLE, and the inherent NK cells and other inherent There are few immunoreactive cells. Natural killer cells (natural killer cell, NK cells) are the main cells in the innate immune response. They can regulate the T, B lymphocytes in the adaptive immune response through the interaction between cells and cells and secreting a variety of cytokines and chemokines, which are considered to be linked to the inherent immune response and appropriate to the adaptive immune response. A growing number of studies have shown that NK cells are associated with organ specific autoimmune diseases. According to the "licensing" theory proposed by Yokoyama, NK cells can be divided into two subgroups of "licensed" and "unlicensed". Studies have found that "unlicensed" NK in the acute rejection period of bone marrow transplantation. Cells can promote the survival of allograft cells in the host. This study aims to use Pristane (descending) to induce lupus kidney model and observe the role of "unlicensed" NK cells in the pathogenesis of lupus mice. Objective to induce lupus mouse model with Pristane (descending alkane) and to explore the unlicensed NK cell subgroup in SLE and lupus. The role of the pathogenesis of sexual nephritis provides new ideas for the study of the pathogenesis of SLE. Method 1. a mouse model of lupus induced by Pristane was established: 18 female, SPF, and 9-10 week old BALB/c mice were randomly divided into two groups: (1) the induction group (9 rats): intraperitoneal injection of 0.5ml Pristane; (2) the control group (9): intraperitoneal injection 0.5ml PBS. observation 7 The changes of appearance, weight, urine protein, autoantibodies (ANA, anti ds-DNA, nRNP/Sm and ss-DNA), renal pathology (common light and immunofluorescence) were observed, and the changes between the two groups were compared with the.2. study on the pathogenesis of unlicensed NK cell subsets and Pristane induced lupus mice. 27 female, SPF, 9-10 weeks old BALB/c mice were randomly divided into 3 groups: (1) "U-NK" group: 9, before the experiment began to intraperitoneal injection of anti Ly49G2+ monoclonal antibody 4D11; (2) "non-NK" group: before the experiment began to intraperitoneal injection of Anti-asialoGM1; (3) "model" group: 9. The same day, 3 groups of mice were intraperitoneally injected 0.5ml Prista. Ne. experiment was observed for 7 months. The indexes were: changes in appearance of mice, body weight and urine protein, the level of autoantibodies (ANA, anti ds-DNA, anti nRNP/Sm and anti ss-DNA), renal pathological changes (common light and immunofluorescence) and the quantitative change of NK cell subsets by flow cytometry. Results the 1. induced mice were out of the table. Erythema and hair removal, such as lupus like manifestations, urinary protein is +1~+2, there are four kinds of autoantibodies (ANA, anti ds-DNA, anti nRNP/Sm, and anti ss-DNA) in serum. The renal tissue pathological light microscopy shows that partial glomerular volume increases, mesangial cells and endothelial cells increase, renal interstitium with inflammatory cells infiltration; immunofluorescence suggests IgG and I GM delayed glomerular capillary loop and mesangial region deposition. There was no difference in survival and appearance between the 3 groups without the above changes in the control group. The urine protein, autoantibody level and renal pathological changes in the "U-NK" group were significantly better than those in the "non-NK" and "model" group, while the "non-NK" group was resistant to the "model" group. NRNP/Sm antibody, anti ss-DNA antibody level and IgG, IgM fluorescence intensity increased, and the number of NK cells in splenic NK cells in flow test mice showed that the number of unlicensed NK cells in "U-NK" group was higher than that of the "model" group. Conclusion Pristane (descending alkanes) can induce female BALB/c mice to form lupus model. Glomerulonephritis has inhibitory effect in the course of occurrence and development, and provides a new idea for the pathogenesis of SLE.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R593.241
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本文編號(hào)：1923951