血清sRAGE水平與系統(tǒng)性紅斑狼瘡疾病活動度相關(guān)性的研究
發(fā)布時間：2018-10-22 19:49
【摘要】：引言系統(tǒng)性紅斑狼瘡(SLE)是一種累及多器官、多系統(tǒng)的自身免疫性疾病,以產(chǎn)生針對自身核抗原如DNA、RNA及其他細(xì)胞核成分的多種自身抗體為特征,是自身免疫性疾病的原型。該病好發(fā)于育齡期女性,男女患病比例約為1:9。在SLE患者的病程中幾乎所有的器官(如皮膚黏膜、關(guān)節(jié)、腎臟、大腦、心血管及胃腸道等)均能累及,且緩解與復(fù)發(fā)交替的特點使得幾乎所有的狼瘡患者都需要接受終生抗狼瘡治療,對社會及患者本人帶來了巨大的經(jīng)濟負(fù)擔(dān)及精神心理壓力,具有嚴(yán)重的危害性。該病的發(fā)病機制十分復(fù)雜,至今尚未完全闡明。近年來各研究組從未停止對其發(fā)病機制的研究:研究表明大量分子或細(xì)胞因子參與到該病的發(fā)病過程中,且在該病的發(fā)病機制中發(fā)揮重要作用�？扇苄酝砥谔腔K產(chǎn)物受體(s RAGE)就是新近發(fā)現(xiàn)的可能在SLE發(fā)病機制中發(fā)揮重要作用的一種蛋白質(zhì)分子,它是細(xì)胞表面晚期糖基化終產(chǎn)物受體(RAGE)的可溶形式,可由RAGE的信使RNA經(jīng)過選擇性剪接[1-3]或經(jīng)基質(zhì)金屬蛋白酶MMP-9或ADAM10裂解產(chǎn)生[4,5],屬于免疫球蛋白超家族成員之一[6]。s RAGE是一種多配體受體,能夠與多種內(nèi)源性配體結(jié)合,如晚期糖基化終產(chǎn)物(AGEs)、S100/鈣粒蛋白家族、高遷移率族蛋白-1(HMGB1)、β淀粉樣蛋白、β2-整合素Mac-1等[7-10]。因其僅含有與RAGE相同的細(xì)胞外配體結(jié)合區(qū)域,缺乏跨膜區(qū)域和胞質(zhì)尾區(qū),因此s RAGE只具有配體結(jié)合功能,而不具有細(xì)胞內(nèi)信號傳導(dǎo)功能。由于這一特性,s RAGE被稱為“誘餌”受體,多數(shù)研究表明它能夠競爭性的拮抗RAGE的功能,在配體到達(dá)細(xì)胞表面與RAGE結(jié)合之前提前與其結(jié)合,阻斷NF-κB的核轉(zhuǎn)移以及下游效應(yīng)因子如腫瘤壞死因子α(TNF-α)、白介素6(IL-6)等細(xì)胞因子的活化,抑制細(xì)胞內(nèi)炎癥的級聯(lián)反應(yīng),從而保護易感細(xì)胞免于因受這些受體的活化而帶來的潛在毒害效應(yīng)[6]。然而,關(guān)于s RAGE的特性及其調(diào)節(jié)炎癥反應(yīng)的具體作用機制尚不清楚,仍需進一步闡明。目前關(guān)于s RAGE在SLE發(fā)病機制中的研究已成為各狼瘡研究小組的熱點,人們試圖探討s RAGE是否能夠成為評價狼瘡疾病活動度的新的生物標(biāo)志物。盡管如此,關(guān)于血清s RAGE濃度水平與SLE疾病活動度之間的相關(guān)研究仍舊是有限的,且不能形成統(tǒng)一認(rèn)識,仍需要大量多中心隨機雙盲對照研究進行證實。我們的研究納入大量樣本,旨在發(fā)現(xiàn)血清s RAGE濃度水平與SLE疾病活動度及其相關(guān)實驗室檢查指標(biāo)之間的相關(guān)性,評價其是否能夠成為一種評估SLE疾病活動度的新的生物標(biāo)志物,從而為進一步制定個體化治療方案提供一定的依據(jù)。目的探討血清s RAGE濃度水平是否與SLE疾病活動度之間存在相關(guān)性。方法1.收集2013年6月至2014年6月期間就診于鄭州大學(xué)第一附屬醫(yī)院風(fēng)濕免疫科和腎病科的SLE患者共104名,收集所有SLE患者的一般情況、臨床特征資料以及實驗室檢查結(jié)果,并采集所有患者的血標(biāo)本,離心后取上清置于-80℃冰箱中保存。2.應(yīng)用酶聯(lián)免疫吸附法(ELISA)檢測血清中s RAGE的濃度水平。按照SLEDAI評分將SLE患者分為兩組:SLEDIA評分0-4分為非活動性SLE患者組;SLEDIA評分≥5分為活動性SLE患者組,并分析血清s RAGE濃度水平在各組之間的差異以及血清s RAGE濃度水平與臨床各參數(shù)以及狼瘡疾病活動度之間的相關(guān)性;3.使用統(tǒng)計分析軟件SPSS 17.0(Chicago,Illinois,USA)進行統(tǒng)計學(xué)分析,定量資料使用均數(shù)±標(biāo)準(zhǔn)差(x±s)進行表示,定性資料使用百分比(%)進行表示。使用非參數(shù)檢驗Mann-Whitney U檢驗進行兩組間定量資料的比較,Spearman秩相關(guān)分析用來分析評價某一個參數(shù)與血清s RAGE濃度水平之間的相關(guān)性。P0.05被認(rèn)為具有統(tǒng)計學(xué)意義。結(jié)果1.血清s RAGE濃度水平在活動性SLE患者組中比在非活動性SLE患者組中顯著增高,差異具有統(tǒng)計學(xué)意義(Z=-2.673,p=0.008)。2.血清s RAGE濃度水平與臨床各參數(shù)之間的相關(guān)性分析:血清s RAGE濃度水平與抗ds-DNA抗體滴度(CI=0.268,p=0.008)、24小時尿總蛋白定量(CI=0.387,p=0.001)以及SLEDAI評分(CI=0.373,p=0.000)之間具有正相關(guān)關(guān)系;與血白細(xì)胞計數(shù)(CI=-0.230,p=0.020)、補體C3(CI=-0.371,p=0.000)及補體C4(CI=-0.280,p=0.000)之間具有負(fù)相關(guān)關(guān)系;結(jié)論血清s RAGE濃度水平與SLE疾病活動度之間呈正相關(guān),可能成為評價SLE患者疾病活動性的新的生物標(biāo)志物。
[Abstract]:Foreword systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs and multiple systems to produce a variety of autoantibodies against their nuclear antigens, such as DNA, RNA and other nuclear components, and is a prototype of autoimmune diseases. The morbidity of the disease is about 1: 9. Almost all organs (such as skin mucosa, joint, kidney, brain, cardiovascular and gastrointestinal tract, etc.) can be involved in the course of SLE patients, with the characteristics of alternating response and recurrence, so that almost all patients with lupus need to receive lifelong anti-lupus therapy, It brings huge economic burden and mental stress to society and patient, and has serious harm. The pathogenesis of the disease is very complicated and has not yet been fully elucidated. In recent years, research groups have never stopped studying the pathogenesis of the disease: research indicates that a large number of molecules or cytokines are involved in the pathogenesis of the disease and play an important role in the pathogenesis of the disease. Soluble late glycation end product receptor (s RAGE) is a newly discovered protein molecule which may play an important role in the pathogenesis of SLE, which is a soluble form of advanced glycation end product receptor (RAGE) in cell surface.[4,5] can be produced by selective splicing of RAGE messenger RNA[1-3] or by matrix metalloproteinase-9 or ADAM10 cleavage[4, 5], belonging to one of the immunoglobulin members[6]. s RAGE is a multi-ligand receptor capable of binding to a variety of endogenous ligands, such as advanced glycation end products (AGEs), S100/ calcium particle protein family, high mobility group protein-1 (HMGB1), waxy starch-like protein, SO42-whole-element Mac-1, etc.[7-10]. Because they contain only the same extracellular ligand binding region as RAGE, there is a lack of transmembrane regions and cytoplasmic tail regions, so s RAGE only has ligand binding function without intracellular signal transduction. As a result of this feature, s RAGE is referred to as" bait "Most studies have shown that it can competitively antagonize RAGE's function, bind to it in advance before the ligand reaches the cell surface to bind RAGE, block the nuclear transfer of NF-Sepharose B and the activation of downstream effector factors such as tumor necrosis factor (TNF-gamma), interleukin 6 (IL-6) and other cytokines, Cascade responses that inhibit inflammation in cells, thereby protecting sensitive cells from potentially toxic effects due to activation of these receptors[6]. However, the specific mechanism of action regarding s RAGE and its regulatory inflammatory response is not yet clear and still need to be further elucidated. At present, the research on s RAGE in the pathogenesis of SLE has become the focus of the lupus research team, and people are trying to explore whether the s RAGE can be a new biomarker for evaluating the activity of lupus disease. Nevertheless, the study on serum s RAGE concentration level and SLE disease activity remains limited and does not form a unified understanding and requires a large number of multicenter randomized double-blind control studies. Our study included a large number of samples to detect the correlation between serum s RAGE concentration level and SLE disease activity and its associated laboratory test indices, and evaluate whether it could be a new biomarker for evaluating the activity of SLE disease, so as to provide a certain basis for further developing an individualized treatment plan. Objective To investigate the correlation between serum s RAGE concentration level and activity of SLE disease. Method 1. Collect 104 SLE patients who visited the First Affiliated Hospital of Zhengzhou University from June 2013 to June 2014 in the First Affiliated Hospital of Zhengzhou University, collected total of 104 SLE patients, clinical features and laboratory results, and collected blood samples from all patients. taking supernatant after centrifugation and placing the supernatant in a refrigerator at -80 DEG C for storage. Enzyme-linked immunosorbent assay (ELISA) was used to detect the concentration level of s RAGE in serum. SLE patients were divided into two groups according to SLEDAI score: SLEDIA score 0-4 was divided into inactive SLE patients group; SLEDIA score group 5 was divided into active SLE patients group. The correlation between serum s RAGE concentration level and serum s RAGE concentration level and clinical parameters as well as the activity of lupus disease was analyzed. Statistical analysis was performed using SPSS 17. 0 (Chicago, Illinois, USA) using the statistical analysis software, and the quantitative data were expressed using standard deviation (x/ s), and the qualitative data were expressed as a percentage (%). The comparison between the two sets of quantitative data was performed using a non-exponential test Mann-Whitney U test, and Spearman rank correlation analysis was used to analyze the correlation between the evaluation of a certain parameter and the serum s RAGE concentration level. P0. 05 was considered to be statistically significant. Result 1. Serum s RAGE concentration was significantly higher in active SLE patients than in inactive SLE patients (Z =-2.673, p = 0.0008). Correlation analysis between serum s RAGE concentration level and clinical parameters: serum s RAGE concentration level was positively correlated with anti ds-DNA antibody drop (CI = 0.268, p = 0.0008), 24-hour urinary total protein ration (CI = 0.387, p = 0.0001) and SLEDAI score (CI = 0.373, p = 0. 000); and blood white blood cell count (CI =-0.230, p = 0.020), There was a negative correlation between complement C3 (CI =-0.371, p = 0. 000) and complement C4 (CI =-0.280, p = 0. 000). Conclusion The level of serum s RAGE is positively correlated with the activity of SLE, and it may be a new biomarker to evaluate the disease activity of SLE patients.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R593.241
[Abstract]:Foreword systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs and multiple systems to produce a variety of autoantibodies against their nuclear antigens, such as DNA, RNA and other nuclear components, and is a prototype of autoimmune diseases. The morbidity of the disease is about 1: 9. Almost all organs (such as skin mucosa, joint, kidney, brain, cardiovascular and gastrointestinal tract, etc.) can be involved in the course of SLE patients, with the characteristics of alternating response and recurrence, so that almost all patients with lupus need to receive lifelong anti-lupus therapy, It brings huge economic burden and mental stress to society and patient, and has serious harm. The pathogenesis of the disease is very complicated and has not yet been fully elucidated. In recent years, research groups have never stopped studying the pathogenesis of the disease: research indicates that a large number of molecules or cytokines are involved in the pathogenesis of the disease and play an important role in the pathogenesis of the disease. Soluble late glycation end product receptor (s RAGE) is a newly discovered protein molecule which may play an important role in the pathogenesis of SLE, which is a soluble form of advanced glycation end product receptor (RAGE) in cell surface.[4,5] can be produced by selective splicing of RAGE messenger RNA[1-3] or by matrix metalloproteinase-9 or ADAM10 cleavage[4, 5], belonging to one of the immunoglobulin members[6]. s RAGE is a multi-ligand receptor capable of binding to a variety of endogenous ligands, such as advanced glycation end products (AGEs), S100/ calcium particle protein family, high mobility group protein-1 (HMGB1), waxy starch-like protein, SO42-whole-element Mac-1, etc.[7-10]. Because they contain only the same extracellular ligand binding region as RAGE, there is a lack of transmembrane regions and cytoplasmic tail regions, so s RAGE only has ligand binding function without intracellular signal transduction. As a result of this feature, s RAGE is referred to as" bait "Most studies have shown that it can competitively antagonize RAGE's function, bind to it in advance before the ligand reaches the cell surface to bind RAGE, block the nuclear transfer of NF-Sepharose B and the activation of downstream effector factors such as tumor necrosis factor (TNF-gamma), interleukin 6 (IL-6) and other cytokines, Cascade responses that inhibit inflammation in cells, thereby protecting sensitive cells from potentially toxic effects due to activation of these receptors[6]. However, the specific mechanism of action regarding s RAGE and its regulatory inflammatory response is not yet clear and still need to be further elucidated. At present, the research on s RAGE in the pathogenesis of SLE has become the focus of the lupus research team, and people are trying to explore whether the s RAGE can be a new biomarker for evaluating the activity of lupus disease. Nevertheless, the study on serum s RAGE concentration level and SLE disease activity remains limited and does not form a unified understanding and requires a large number of multicenter randomized double-blind control studies. Our study included a large number of samples to detect the correlation between serum s RAGE concentration level and SLE disease activity and its associated laboratory test indices, and evaluate whether it could be a new biomarker for evaluating the activity of SLE disease, so as to provide a certain basis for further developing an individualized treatment plan. Objective To investigate the correlation between serum s RAGE concentration level and activity of SLE disease. Method 1. Collect 104 SLE patients who visited the First Affiliated Hospital of Zhengzhou University from June 2013 to June 2014 in the First Affiliated Hospital of Zhengzhou University, collected total of 104 SLE patients, clinical features and laboratory results, and collected blood samples from all patients. taking supernatant after centrifugation and placing the supernatant in a refrigerator at -80 DEG C for storage. Enzyme-linked immunosorbent assay (ELISA) was used to detect the concentration level of s RAGE in serum. SLE patients were divided into two groups according to SLEDAI score: SLEDIA score 0-4 was divided into inactive SLE patients group; SLEDIA score group 5 was divided into active SLE patients group. The correlation between serum s RAGE concentration level and serum s RAGE concentration level and clinical parameters as well as the activity of lupus disease was analyzed. Statistical analysis was performed using SPSS 17. 0 (Chicago, Illinois, USA) using the statistical analysis software, and the quantitative data were expressed using standard deviation (x/ s), and the qualitative data were expressed as a percentage (%). The comparison between the two sets of quantitative data was performed using a non-exponential test Mann-Whitney U test, and Spearman rank correlation analysis was used to analyze the correlation between the evaluation of a certain parameter and the serum s RAGE concentration level. P0. 05 was considered to be statistically significant. Result 1. Serum s RAGE concentration was significantly higher in active SLE patients than in inactive SLE patients (Z =-2.673, p = 0.0008). Correlation analysis between serum s RAGE concentration level and clinical parameters: serum s RAGE concentration level was positively correlated with anti ds-DNA antibody drop (CI = 0.268, p = 0.0008), 24-hour urinary total protein ration (CI = 0.387, p = 0.0001) and SLEDAI score (CI = 0.373, p = 0. 000); and blood white blood cell count (CI =-0.230, p = 0.020), There was a negative correlation between complement C3 (CI =-0.371, p = 0. 000) and complement C4 (CI =-0.280, p = 0. 000). Conclusion The level of serum s RAGE is positively correlated with the activity of SLE, and it may be a new biomarker to evaluate the disease activity of SLE patients.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R593.241
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