本文選題：疾病特異性IgG + Fc��； 參考：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文

【摘要】：癌癥是僅次于心血管疾病的人類(lèi)健康第二大殺手,其中,胃癌和肺癌在癌癥相關(guān)的發(fā)生率與死亡率中排名前列。癌癥患者出現(xiàn)的早期癥狀如被誤診為相關(guān)炎癥,則可能導(dǎo)致錯(cuò)過(guò)最佳的治療時(shí)機(jī)而降低生存機(jī)會(huì),所以良性疾病與癌癥的診斷區(qū)分具有十分重要的臨床意義。免疫球蛋白G(Immunoglobulin G,IgG)是人體內(nèi)重要的免疫分子之一,其Fc N-糖基化修飾可以改變IgG分子與Fc受體之間的相互作用方式,從而影響IgG的促炎或抗炎活性,且與人類(lèi)生理病理狀態(tài)顯著相關(guān)。然而前期研究主要關(guān)注血液總IgG,這在一定程度上忽視了抗原特異性IgG的結(jié)構(gòu)變化。IgG作為外周血中豐度僅次于白蛋白的蛋白分子,并非所有IgG分子都與疾病發(fā)生、發(fā)展相關(guān);前期研究結(jié)果表明,疾病發(fā)展過(guò)程中抗原特異性IgG糖基化修飾與血液總IgG糖基化修飾的變化趨勢(shì)并不完全一致,所以研究抗原特異性IgG或疾病特異性IgG(Disease-specific IgG,DSIgG)能更精確反映病理狀態(tài)。本研究采用非變性丙烯酰胺凝膠電泳(Native-polyacrylamide gel electrophoresis,Native-PAGE)分離獲得個(gè)體化的體液免疫炎癥相關(guān)蛋白復(fù)合物(immunoinflammation-related protein complexes,ⅡRPCs),ⅡRPCs水平在健康人與慢性疾病患者中存在顯著差異。利用十二烷基磺酸鈉聚丙烯酰胺凝膠電泳(Sodium dodecyl sulfate-polyacrylamide gel electrophoresis,SDS-PAGE)從ⅡRPCs中分離得到的IgG,即為DSIgG。對(duì)DSIgG重鏈進(jìn)行膠內(nèi)酶解后,利用天然材料楊絮從酶解液中富集得到FcN-糖肽,再采用超高分辨率的基質(zhì)輔助激光解吸電離-傅里葉變換離子回旋共振質(zhì)譜儀(matrix-assisted laser desorption ionization-Fourier transform ion cyclotron resonance mass spectrometry,MALDI-FTICRMS)檢測(cè)FcN-糖肽,統(tǒng)計(jì)分析不同病理狀態(tài)下患者的糖肽差異,尋找可用于癌癥診斷和病情進(jìn)展監(jiān)測(cè)的個(gè)體化標(biāo)志物。本研究包括如下三個(gè)部分:1.DSIgG Fc N-糖基化修飾個(gè)體化標(biāo)志物區(qū)分胃癌與胃部良性疾病。本部分共研究了 1037例胃部疾病患者,其中包括525例胃部良性疾病患者和512例胃癌患者,共檢測(cè)到22種Fc N-糖肽,其中包括8種DSIgG1 N-糖肽(糖型為GOF、GOFN、G1、G1F、G1FN、G1S、G2F 和 G2FS)和 14 種 DSIgG2N-糖肽(糖型為 GOF、GOFN、G1、G1N、G1F、G1FN、G1S、G1FS、G2、G2S、G2N、G2F、G2FN和G2FS)。統(tǒng)計(jì)分析結(jié)果表明,胃部良性疾病與胃癌患者中具有G1、G1S、G2F、G1FN 糖型的 DSIgG1 N-糖肽和具有 GOF、GOFN、G1N、G1FS、G2、G2F、G2FN、G2FS糖型的DSIgG2N-糖肽具有顯著差異,糖肽相對(duì)強(qiáng)度比以及糖基化修飾水平與病理狀態(tài)相關(guān)。與胃部良性疾病患者相比,胃癌患者的唾液酸化修飾水平以及半乳糖基化修飾水平(特別是雙半乳糖基化修飾水平)均顯著降低,而平分型N-乙酰葡萄糖胺水平則顯著升高。在女性中,相差一個(gè)半乳糖殘基的糖肽相對(duì)強(qiáng)度比(G2FN/G1FN)可以顯著區(qū)分胃部良性疾病與胃癌,受試者工作特征(Receiver operating characteristic,ROC)分析表明,曲線下面積(Area under the curve,AUC)為0.872,特異度和靈敏度均為82.6%。在男性中,相差一個(gè)核心巖藻糖殘基的糖肽相對(duì)強(qiáng)度比(G2FN/G2N)和相差一個(gè)半乳糖殘基的糖肽相對(duì)強(qiáng)度比(G2F/G1F)的組合可用于60歲以下男性人群的胃部良性疾病與胃癌的區(qū)分,其AUC為0.846。DSIgG2 G1FS糖型、G2FN/G2N比值和DSIgG1相差兩個(gè)半乳糖殘基的糖肽相對(duì)強(qiáng)度比(G2F/G0F)的組合可以區(qū)分60歲以上男性人群的胃部良性疾病與胃癌,其AUC為0.777。本部分研究結(jié)果表明,Fc N-糖基化修飾類(lèi)型與患者胃部病理狀態(tài)顯著相關(guān),可作為一類(lèi)新型的胃癌個(gè)體化診斷的潛在標(biāo)志物。2.DSIgG Fc N-糖基化修飾個(gè)體化標(biāo)志物區(qū)分非小細(xì)胞肺癌與肺部良性疾病本部分共研究了 986例肺部疾病患者,其中包括509例肺部良性疾病患者和477例非小細(xì)胞肺癌患者,采用高分辨質(zhì)譜技術(shù)分析了 DSIgG Fc N-糖基化修飾。統(tǒng)計(jì)分析結(jié)果表明,糖基化修飾水平與年齡相關(guān)。與肺部良性疾病患者相比,非小細(xì)胞肺癌患者的核心巖藻糖基化修飾水平和唾液酸化修飾水平顯著升高,而半乳糖基化修飾水平則顯著降低。ROC分析結(jié)果表明,相差一個(gè)核心巖藻糖殘基的糖肽相對(duì)強(qiáng)度比(DSIgG2 G1F/G1G1F/G1、G1FS/G1S 和 DSIgG1 G1F/G1)的組合,可以區(qū)分 60歲以下年齡組肺部良性疾病與非小細(xì)胞肺癌,其AUC均優(yōu)于0.76,靈敏度優(yōu)于87%;而DSIgG2相差一個(gè)核心巖藻糖殘基的糖肽相對(duì)強(qiáng)度比(G2F/G2、G1FS/G1S)與相差一個(gè)唾液酸殘基的糖肽相對(duì)強(qiáng)度比(G1FS/G1F)的組合,可以區(qū)分60歲以上年齡組肺部良性疾病與非小細(xì)胞肺癌,其AUC均優(yōu)于0.78,靈敏度優(yōu)于91%。本部分研究表明,FcN-糖肽相對(duì)強(qiáng)度比水平與肺部病理狀態(tài)顯著相關(guān),可作為一類(lèi)新型的非小細(xì)胞肺癌個(gè)體化診斷的潛在標(biāo)志物。3.DSIgG Fc N-糖基化修飾個(gè)體化標(biāo)志物監(jiān)測(cè)非小細(xì)胞肺癌疾病進(jìn)展耐藥性的產(chǎn)生可能造成非小細(xì)胞肺癌患者在靶向治療過(guò)程中出現(xiàn)疾病進(jìn)展,盡早發(fā)現(xiàn)疾病進(jìn)展有助于在癌癥復(fù)發(fā)甚至惡化早期及時(shí)采取有效的治療措施,提高患者的生存率與生存質(zhì)量。本部分采用高分辨質(zhì)譜技術(shù)共檢測(cè)36名非小細(xì)胞肺癌患者的413例隨訪血液樣本中的DSIgG Fc N-糖肽。Kaplan-Meier曲線表明相差一個(gè)半乳糖殘基的糖肽相對(duì)強(qiáng)度比(DSIgG1 G2F/G1F)以及相差一個(gè)核心巖藻糖殘基的糖肽相對(duì)強(qiáng)度比(DSIgG2 G1F/G1)與患者的無(wú)疾病進(jìn)展生存期顯著相關(guān)。隨訪樣本分析結(jié)果表明,利用DSIgG Fc N-糖基化修飾指標(biāo)(DSIgG1 G1F/G1、G1S/G1和DSIgG2G1S/G1、G1FN/G1N、G1FN/G0FN)可以個(gè)體化的監(jiān)測(cè)非小細(xì)胞肺癌的疾病進(jìn)展時(shí)間點(diǎn),比臨床影像學(xué)檢測(cè)的疾病進(jìn)展時(shí)間點(diǎn)平均提前29周(四分位數(shù)區(qū)間:16-34周)。本研究結(jié)果表明,DSIgG FcN-糖基化修飾水平與非小細(xì)胞肺癌的疾病進(jìn)程密切相關(guān),應(yīng)用DSIgG Fc N-糖基化修飾標(biāo)志物有助于評(píng)估靶向治療療效和調(diào)整治療策略,可作為個(gè)體化監(jiān)測(cè)非小細(xì)胞肺癌患者疾病進(jìn)展的潛在標(biāo)志物。
[Abstract]:Cancer is the second largest killer of human health after cardiovascular disease, among which, gastric cancer and lung cancer are in the forefront of the incidence and mortality of cancer. The early symptoms of cancer patients, if misdiagnosed as related inflammation, may lead to missing the best time for treatment and reduce the chances of survival, so the diagnosis of benign diseases and cancer G (Immunoglobulin G (IgG) is one of the most important immune molecules in the human body. Its Fc N- glycosylation modification can change the interaction between IgG molecules and Fc receptors, thus affecting the proinflammatory or anti-inflammatory activity of IgG, and is significantly related to the physiological and pathological state of human beings. The study mainly focused on the total IgG of blood, which, to some extent, ignored the structural change of antigen specific IgG as the protein molecule in the peripheral blood only inferior to albumin, not all IgG molecules were associated with the development of the disease. The previous study showed that the antigen specific IgG glycosylation modification and blood in the process of disease development The variation trend of total IgG glycosylation modification is not completely consistent, so the study of antigen specific IgG or disease specific IgG (Disease-specific IgG, DSIgG) can more accurately reflect the pathological state. This study uses non denaturated acrylamide gel electrophoresis (Native-polyacrylamide gel electrophoresis, Native-PAGE) to separate the individual body fluid The immune inflammatory related protein complex (immunoinflammation-related protein complexes, II RPCs), and the level of II RPCs in healthy people and chronic disease patients were significantly different. Twelve sodium alkyl sulfonate polyacrylamide gel electrophoresis (Sodium dodecyl sulfate-polyacrylamide gel electrophoresis, SDS-PAGE) was isolated from the second RPCs. The obtained IgG, that is, after the enzymatic hydrolysis of the DSIgG heavy chain by DSIgG., enriched the FcN- glycopeptide by the natural material poplar flocculation from the enzymolysis solution, and then used the ultra high resolution matrix assisted laser desorption ionization Fourier transform ion cyclotron resonance mass spectrometer (matrix-assisted laser desorption ionization-Fourier transform ion cyclotron). Resonance mass spectrometry, MALDI-FTICRMS) detection of FcN- glycopeptides, statistically analyzing the glycopeptide differences in patients with different pathological conditions, looking for individual markers that can be used for cancer diagnosis and progression monitoring. This study includes the following three parts: 1.DSIgG Fc N- glycosylated individualized markers distinguish gastric cancer and gastric benign disease. A total of 1037 patients with gastric diseases, including 525 patients with benign gastric diseases and 512 cases of gastric cancer, were studied, and 22 Fc N- glycopeptides were detected, including 8 DSIgG1 N- glycopeptides (GOF, GOFN, G1, G1F, G1FN, G1S, G2F and G2FS) and 14 kinds of glycopeptides N, G2F, G2FN and G2FS). The statistical analysis showed that the gastric benign disease and gastric cancer patients have G1, G1S, G2F, G1FN sugar DSIgG1 N- glycopeptides and GOF, the relative intensity ratio of glycosylated peptide and the level of glycosylated modification related to the pathological state. Compared with the patients with disease, the level of acidification modification and the level of galactoylation modification (especially the level of double galactoylation) in the patients with gastric cancer were significantly reduced, while the level of the N- acetyl glucosamine was significantly increased. In women, the relative intensity ratio of a galactopeptide with a different galactose residue (G2FN/G1FN) could significantly distinguish the stomach from the stomach. The Receiver operating characteristic (ROC) analysis showed that the area under the curve (Area under the curve, AUC) was 0.872, and the specificity and sensitivity were 82.6%. in men, and the relative intensity ratio (G2FN/G2N) and the difference of a galactose residue from a core fucose residue were different. The combination of peptide relative intensity ratio (G2F/G1F) can be used to distinguish between benign gastric disease and gastric cancer in male population under 60 years of age. The combination of AUC is 0.846.DSIgG2 G1FS sugar, and the relative intensity ratio (G2F/G0F) of two galactose residues of G2FN/G2N ratio and DSIgG1 can be divided into benign gastric disease and gastric cancer in male population over 60 years old. The results of its AUC 0.777. study show that the type of Fc N- glycosylation modification is significantly related to the pathological state of the stomach. It can be used as a potential marker for a new type of individualized diagnosis of gastric cancer,.2.DSIgG Fc N- glycosylated individualized markers to distinguish between non small cell lung cancer and benign lung diseases in this part, 986 cases of lung were studied. DSIgG Fc N- glycosylation modification was analyzed by high resolution mass spectrometry, including 509 patients with benign lung disease and 477 patients with non-small cell lung cancer. Statistical analysis showed that the glycosylation level was related to age. Compared with the benign lung disease patients, the core fucoylation of non small cell lung cancer patients was compared with those of the patients with benign lung disease. The level of modification and acidification of saliva increased significantly, while the level of galactin modification was significantly reduced by.ROC analysis. The relative intensity ratio of a core fucose residue (DSIgG2 G1F/G1G1F/G1, G1FS/G1S and DSIgG1 G1F/G1) could be divided into benign and non small lung diseases in the age group under 60 years of age. The AUC of cell lung cancer is better than 0.76 and the sensitivity is better than 87%, while the relative intensity of the glycopeptide relative intensity of a core fucose residue (G2F/G2, G1FS/G1S) and the difference of the relative intensity ratio (G1FS/G1F) of one sialic acid residue (G1FS/G1F) can distinguish between the 60 years old age group and the non small cell lung cancer in the age group over 60 years old, and the AUC is better than 0.78. The sensitivity is better than the 91%. part of this study. The relative intensity ratio of FcN- glycopeptide is significantly related to the pulmonary pathological state. It can be used as a new type of potential marker for individual diagnosis of non-small cell lung cancer,.3.DSIgG Fc N- glycosylated individualized marker monitoring the development of non small cell lung cancer disease development resistance may cause non Patients with small cell lung cancer have developed disease in the course of targeted therapy. The early discovery of disease progress helps to take effective treatment measures in the early stage of cancer recurrence and even worsening, and improves the survival rate and quality of life of the patients. This part uses high resolution mass spectrometry to detect 413 cases of 36 patients with non-small cell lung cancer. The DSIgG Fc N- glycopeptide.Kaplan-Meier curve in the sample indicates that the relative intensity ratio of the glycopeptide relative intensity ratio (DSIgG1 G2F/G1F) and the difference of a core fucose residue (DSIgG2 G1F/G1) is significantly related to the patient's disease progression survival period (DSIgG2 G1F/G1). The follow-up sample analysis shows that DSIgG Fc N- sugar is used. DSIgG1 G1F/G1, G1S/G1 and DSIgG2G1S/G1, G1FN/G1N, G1FN/G0FN) can monitor the progression of non small cell lung cancer at a time point, 29 weeks earlier than the time point of the disease progression by clinical imaging (four quantile interval: 16-34 weeks). The results of this study showed that the level of glycosylation of DSIgG FcN- and non small The process of cell lung cancer is closely related. The application of DSIgG Fc N- glycosylation markers can help to evaluate the therapeutic effect and adjust the therapeutic strategy, which can be used as a potential marker for individual monitoring of the disease progression in non small cell lung cancer patients.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R735.2;R734.2

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