本文選題：丙型肝炎病毒 + 抗體親和力�。� 參考：《大連醫(yī)科大學(xué)》2016年博士論文

【摘要】：背景:丙型肝炎病毒(Hepatitis C Virus,HCV)是輸血后以及散發(fā)性肝炎的主要病原,是世界性的公共衛(wèi)生難題。全世界約有1億7千萬(wàn)HCV血清學(xué)陽(yáng)性的患者,面臨著轉(zhuǎn)變成肝硬化、肝癌的風(fēng)險(xiǎn)。盡管HCV能刺激機(jī)體產(chǎn)生有效的免疫反應(yīng),但80%的HCV感染者會(huì)進(jìn)展成慢性丙肝患者,只有20%患者能有效清除病毒,自行恢復(fù)且不留任何后遺癥。大多數(shù)HCV慢性感染患者體內(nèi)能產(chǎn)生針對(duì)不同HCV病毒蛋白的抗體,而且在患者血清中能檢測(cè)到這些抗體的存在。顯然,HCV感染的宿主免疫反應(yīng)的類型和強(qiáng)度可能對(duì)其預(yù)后用著重要作用。HCV抗體檢測(cè)對(duì)HCV診斷有重要價(jià)值,中和抗體能直接作用于HCV病毒,但一般認(rèn)為通常在HCV感染者中所檢測(cè)到的抗體是針對(duì)HCr43蛋白(HCV非結(jié)構(gòu)區(qū)NS3及核心區(qū)的編碼產(chǎn)物)、c100-3抗原(HCV非結(jié)構(gòu)區(qū)NS3、NS4的編碼產(chǎn)物)的抗體,為非中和抗體,因此,不能通過(guò)檢測(cè)HCV抗體準(zhǔn)確判定HCV感染者的免疫狀態(tài)。我們?cè)趯?duì)乙型肝炎anti-HBc親和力與HBV感染的聯(lián)系中發(fā)現(xiàn)同為非中和抗體,但anti-HBc親和力與HBV感染的預(yù)后關(guān)系密切;也有研究證明抗體親和力高低能準(zhǔn)確反映巨細(xì)胞病毒感染的活動(dòng)狀況。測(cè)定HCV抗體親和力有可能較為準(zhǔn)確的反映HCV感染者的免疫狀況,對(duì)判定HCV感染的現(xiàn)狀和結(jié)局提供有價(jià)值的信息。抗體的總活性取決于抗體蛋白的含量及其與抗原間的結(jié)合活性(親和力)。而目前臨床實(shí)驗(yàn)室hcv抗體的檢測(cè)只檢測(cè)抗體的總活性,并未涉及抗體蛋白的含量和抗體親和力的檢測(cè),本研究將hcv抗體總活性解析成抗體蛋白量和抗體親和力,試圖利用常規(guī)的hcv抗體總活性的檢測(cè)系統(tǒng),參照乙型肝炎anti-hbc親和力的檢測(cè)原理來(lái)建立hcv抗體親和力的檢測(cè)方法,并探討丙型肝炎病毒抗體親和力、總活性及物質(zhì)量與病毒載量、機(jī)體損傷程度以及疾病不同階段變化的動(dòng)力學(xué)聯(lián)系。近十年對(duì)hla和hcv感染持續(xù)性及清除的研究非常多,機(jī)體對(duì)病毒表位的免疫反應(yīng)取決于抗原遞呈細(xì)胞加工和遞呈抗原表位的能力,以及免疫細(xì)胞識(shí)別這些抗原表位的能力,而這些功能是由hla分子遺傳決定的,因而推測(cè)hla類型可影響hcv感染結(jié)局。hla-i類等位基因與hcv感染的自限性轉(zhuǎn)歸之間存在很強(qiáng)的相關(guān)性,例如hla-i類等位基因a3、b27和cw*01均與病毒清除相關(guān),而b8則與病毒的持續(xù)性感染相關(guān)。ns3區(qū)域的一個(gè)表位對(duì)hla-dr具有高度親和性,提示hla-Ⅱ類分子也與病毒清除有關(guān)。某些hla-Ⅱ類等位基因也與hcv感染的結(jié)局相關(guān),與病毒清除最為高度相關(guān)的hla-Ⅱ類等位基因是dqb1*0301基因和drb1*1101。然而,這些研究結(jié)果并不完全一致,甚至相互矛盾。目的:采用抗體多維數(shù)據(jù)分析,建立hcv抗體親和力的檢測(cè)方法,并探討丙型肝炎病毒抗體親和力、物質(zhì)量及總活性動(dòng)力學(xué)變化及其與病毒量、機(jī)體損傷程度以及疾病不同階段的聯(lián)系。hcv感染患者h(yuǎn)la-a,hla-b,hla-drb1基因型別與疾病過(guò)程的聯(lián)系以及其作用機(jī)制。方法:1、采用重組乙型肝炎疫苗反復(fù)三次皮下注射免疫兔子,第一次注射一周后采集兔子血清,獲得低親和力抗體動(dòng)物血清;第三次注射兩周后采集兔子血清,獲得高親和力抗體動(dòng)物血清,倍比稀釋血清,采用雙抗原夾心酶聯(lián)免疫吸附實(shí)驗(yàn)測(cè)定anti-hbs。隨機(jī)收集臨床診斷為hcv感染患者血清106例,采用化學(xué)發(fā)光微粒子免疫檢測(cè)法測(cè)定hcv抗體,pcr-熒光探針?lè)z測(cè)hcv-rna,同時(shí)檢測(cè)alt、ast、alb等臨床常用檢測(cè)指標(biāo)。根據(jù)alt、ast水平以及hcv-rna水平各分三組,比較分析組間抗體親和力、抗體總活性及抗體物質(zhì)量的變化。2、隨機(jī)收集臨床診斷為hcv感染患者血清328例,采用化學(xué)發(fā)光微粒子免疫檢測(cè)法測(cè)定hcv抗體,pcr-熒光探針?lè)z測(cè)hcv-rna,同時(shí)檢測(cè)alb。根據(jù)疾病階段分為慢性肝炎組和肝硬化組,慢性肝炎組又根據(jù)患者alb和hcv-rna水平分為:alb正常hcv-rna陰性組(好轉(zhuǎn)恢復(fù)階段)和其他組(進(jìn)展階段)。分析比較組間抗體親和力、抗體物質(zhì)量及抗體總活性的變化。3、隨機(jī)收集臨床診斷為hcv感染患者血清104例及健康對(duì)照200例,采用化學(xué)發(fā)光微粒子免疫檢測(cè)法測(cè)定hcv抗體,pcr-熒光探針?lè)z測(cè)hcv-rna,同時(shí)檢測(cè)血清alb水平,采用測(cè)序方法(sequencebasedtyping,pcr-sbt)進(jìn)行hla基因型的鑒定。比較分析不同hla型別間alb水平、抗體親和力、抗體物質(zhì)量及抗體總活性的變化。4、采用網(wǎng)上搜索數(shù)據(jù)庫(kù)結(jié)合discoverystudio(ds)軟件來(lái)分析預(yù)測(cè)ns3和hla-drb1*09,hla-a*02,hla-a*33,hla-b*58,hla-drb1*07,hla-drb1*13這6種hla蛋白分子之間的相互作用。數(shù)據(jù)庫(kù)包括美國(guó)國(guó)立醫(yī)學(xué)圖書(shū)館文獻(xiàn)檢索系統(tǒng)ncbi,蛋白質(zhì)結(jié)構(gòu)數(shù)據(jù)庫(kù)pdb以及prosite數(shù)據(jù)庫(kù)。結(jié)果:1、雌兔第1次免疫后血清抗體親和力為0.522,第2次為0.826,第3次為0.896;雄兔第1次免疫后血清抗體親和力為0.816,第2次為0.846,第3次為0.972,均呈逐漸升高趨勢(shì),與抗體親和力成熟規(guī)律一致。2、alt、ast正常組的抗體物質(zhì)量明顯低于任一異常組、均異常組(p0.05),而抗體親和力則明顯高于任一異常組、均異常組(p0.05)�？贵w總活性在三組中比較,均沒(méi)有顯著性差異(p0.05)。3、根據(jù)hcv-rna水平,將alt、ast均正常組(53例)進(jìn)一步分組為hcv-rna陰性組和hcv-rna陽(yáng)性組。hcv-rna陰性組的抗體總活性、抗體物質(zhì)量均明顯低于hcv-rna陽(yáng)性組(p0.05),而抗體親和力卻明顯高于hcv-rna陽(yáng)性組(p0.05)。4、hcv-rna陰性組的抗體總活性、抗體物質(zhì)量均明顯低于低病毒載量、高病毒載量組(p0.05),而抗體親和力則明顯高于低病毒載量、高病毒載量組(p0.05)。5、以hcv-rna陽(yáng)性為因變量,抗體親和力、抗體物質(zhì)量和抗體總活性為自變量,進(jìn)行l(wèi)ogistic回歸分析,hcv-rna水平與抗體親和力呈負(fù)相關(guān)(p0.05)。6、alb正常hcv-rna陰性組的抗體親和力明顯高于慢性肝炎其他組和肝硬化組(p0.05),而抗體物質(zhì)量明顯低于慢性肝炎其他組和肝硬化組(p0.05),抗體總活性在三組中比較沒(méi)有顯著性差異(p0.05)。7、抗體親和力和抗體物質(zhì)量的roc曲線下面積分別是0.816、0.811,均顯示了較高的診斷效能,明顯高于傳統(tǒng)的抗體檢測(cè)(roc曲線下面積為0.581)。抗體親和力對(duì)于區(qū)分丙肝感染進(jìn)展階段(hcv-rna陽(yáng)性)和好轉(zhuǎn)階段(hcv-rna陰性)的最佳診斷臨界點(diǎn)為0.873,抗體親和力越高,病毒復(fù)制越少。8、alb正常hcv-rna陰性組中,高抗體親和力(≥0.873)的比例明顯高于慢性肝炎其他組和肝硬化組(p0.05)。9、hcv-rna(+)的血清被含有高親和力抗體的血清中和后,lgrna明顯低于中和前的水平(p0.05)。10、在hcv患者和健康對(duì)照組中鑒定出8種hla型別具有顯著性差異(p0.05),分別是hla-a*02,hla-b*39,hla-drb1*09,hla-drb1*11,hla-a*33,hla-b*58,hla-drb1*07,hla-drb1*13。其中hla-a*02,hla-b*39,hla-drb1*09,hla-drb1*11在hcv患者中陽(yáng)性率明顯低于健康對(duì)照組,而hla-a*33,hla-b*58,hla-drb1*07,hla-drb1*13則明顯高于健康對(duì)照組(p0.05),提示hla-a*02,hla-b*39,hla-drb1*09,hla-drb1*11為丙肝感染的抵抗基因,而hla-a*33,hla-b*58,hla-drb1*07,hla-drb1*13則是丙肝感染的敏感基因。11、在上述8種hla型別中,血清alb水平在hla-a*02,hla-a*33,hla-b*39,hla-drb1*07,hla-drb1*11,hla-drb1*13基因攜帶者與非攜帶者間并無(wú)差異(p0.05),僅hla-b*58和hla-drb1*09攜帶者與非攜帶者的alb水平明顯不同,前者p=0.015,后者p=0.003,均0.05,但僅有hla-drb1*09在交叉驗(yàn)證中仍然具有顯著性差異,p=0.017,說(shuō)明hla-drb1*09不僅是丙肝感染的抵抗基因,還在阻礙alb水平下降及疾病進(jìn)展的過(guò)程中起到保護(hù)作用。12、hla-a位點(diǎn)基因頻率(高分辨)與抗體親和力呈正相關(guān),提示基因頻率越高,抗體親和力越強(qiáng)。13、對(duì)攜帶hla-a*02,hla-b*39,hla-drb1*09,hla-drb1*11,hla-a*33,hla-b*58,hla-drb1*07,hla-drb1*13基因型別的患者進(jìn)行抗體親和力、抗體物質(zhì)量以及抗體總活性的比較,由于hla-b*39僅有1例陽(yáng)性患者,hla-drb1*11只有4例陽(yáng)性患者,故不對(duì)此兩種基因型別進(jìn)行比較。結(jié)果顯示,按抗體親和力排序,hla-a*33hla-b*58hla-drb1*07hla-a*02hla-drb1*09hla-drb1*13。14、生物信息學(xué)角度的親和力分析結(jié)果是:hla對(duì)hcvns3的親和性排序?yàn)?hla-b*58hla-a*33hla-drb1*09hla-drb1*07hla-a*02hla-drb1*13。結(jié)論:1.hcv抗體多維數(shù)據(jù)解析方法成立,hcv感染患者抗體親和力、抗體總活性、抗體物質(zhì)量的變化有可能反應(yīng)肝細(xì)胞損傷及病毒載量的變化,具有一定的臨床應(yīng)用價(jià)值。2.hcv抗體多維數(shù)據(jù)解析發(fā)現(xiàn),抗體親和力與病情聯(lián)系密切,優(yōu)于傳統(tǒng)實(shí)驗(yàn)室僅檢測(cè)抗體總活性的方法�？贵w親和力在疾病轉(zhuǎn)歸中可能有一定的指示作用,具有較高的診斷效能,高親和力抗體可能有利于疾病的好轉(zhuǎn),測(cè)定抗體親和力將有助于臨床醫(yī)生判斷疾病的預(yù)后。3.HLA多態(tài)性與丙型肝炎發(fā)生發(fā)展過(guò)程及HCV抗體親和力高低有關(guān),基因頻率高(進(jìn)化保守),可能越有利于產(chǎn)生高親和力的抗體。
[Abstract]:Background: Hepatitis C Virus (HCV) is the main pathogen of post transfusion and sporadic hepatitis and is a worldwide public health problem. Around the world, about 170 million HCV serologically positive patients face the risk of transforming into liver cirrhosis and liver cancer. Although HCV can stimulate the body to produce an effective immune response, but a 80% HCV infection In patients with chronic hepatitis C, only 20% of the patients can effectively remove the virus, recover spontaneously and without any sequelae. Most of the patients with HCV chronic infection can produce antibodies against different HCV virus proteins and detect the presence of these antibodies in the patient's serum. Obviously, the type of host immune response to HCV infection and the type of host immune response are clearly defined. Strength may play an important role in its prognosis for its prognosis,.HCV antibody detection is of great value for the diagnosis of HCV. Neutralizing antibodies can directly act on HCV virus, but it is generally believed that the antibodies commonly detected in HCV infected persons are directed against the HCr43 protein (HCV unstructured region NS3 and core region), c100-3 antigen (HCV non structural NS3, NS4 coding). The antibody, as a non neutralizing antibody, can not determine the immune state of the HCV infected person by detecting the HCV antibody. We found the same non neutralizing antibody in the association of anti-HBc affinity with HBV infection, but the affinity of anti-HBc is closely related to the prognosis of HBV infection; and there are also studies showing that the affinity of antibodies is high and low. It is possible to accurately reflect the activity of cytomegalovirus infection. The determination of HCV antibody affinity may be more accurate to reflect the immune status of HCV infected people and provide valuable information for determining the status and outcome of HCV infection. The total activity of antibodies depends on the content of antibody protein and its binding activity with the anti primitive (affinity). The test of HCV antibody in bed laboratory only detected the total activity of antibody, and did not involve the detection of antibody protein content and antibody affinity. The total activity of HCV antibody was analyzed into antibody protein and antibody affinity, and the detection system of the general activity of HCV antibody was tried to refer to the detection principle of the affinity of hepatitis B anti-HBc. To establish a method to detect the affinity of HCV antibody, and to explore the relationship between the antibody affinity of HCV, the total activity and the quality of the virus, the degree of body damage and the dynamics of the changes in different stages of the disease. The study on the persistence and clearance of HLA and HCV infection in the last ten years is not much, and the immune response of the body to the epitopes of the virus depends on the immune response of the body. Antigen presenting cells are capable of processing and presenting antigen epitopes, and the ability of immune cells to identify these epitopes, which are genetically determined by HLA molecules. Therefore, it is speculated that the HLA type can affect the.Hla-i allele of HCV infection and the self limiting transformation of HCV infection, such as the HLA-I class, etc. The gene A3, B27 and cw*01 are all associated with virus clearance, while B8 is highly compatible to HLA-DR in the.Ns3 region associated with the persistent infection of the virus, suggesting that the hla- class II molecules are also related to the virus clearance. Some hla- class II alleles are also related to the outcome of HCV infection, and the most highly related hla- II class of the virus clearance. The allele is dqb1*0301 gene and drb1*1101., however, the results of these studies are not entirely consistent and even contradictory. Objective: to establish a detection method for affinity of HCV antibodies with antibody multidimensional data analysis, and to explore the changes in the affinity, mass and total activity of HCV antibody, the amount of the virus and the damage process of the body. The relationship between.Hcv and HLA-A, HLA-B, HLA-DRB1 genotypes and the process of disease and its mechanism of action. Methods: 1, the three subcutaneous injection of Recombinant Hepatitis B Vaccine was used to immunize rabbits repeatedly, and the rabbit blood was collected for the first week after the first injection, and the low affinity antibody animal serum was obtained; the third injection was given. After two weeks, rabbit serum was collected to obtain high affinity antibody animal serum, double dilution sera, and double antigen sandwich enzyme-linked immunosorbent assay was used to detect anti-hbs. in 106 cases of HCV infected patients, and HCV antibody was determined by chemiluminescent particle immunization assay, and HCV-RNA was detected by pcr- fluorescence probe. Detection of alt, AST, ALB and other clinical indicators. According to alt, AST level and HCV-RNA level in three groups, the affinity of antibody, the total activity of antibody and the change of the quality of antibody were compared and analyzed, and 328 cases of HCV infected patients were randomly collected, and the HCV antibody and pcr- fluorescence were measured by the chemiluminescent particle immunoassay. HCV-RNA was detected by probe, and alb. was divided into chronic hepatitis group and liver cirrhosis group according to the disease stage. The chronic hepatitis group was divided into ALB normal HCV-RNA negative group (improvement recovery stage) and other group (progressive stage) according to the level of ALB and HCV-RNA, and the changes of antibody affinity, antibody quality and total antibody activity were analyzed and compared. 3, 104 patients with HCV infection and 200 healthy controls were randomly collected. HCV antibody was measured by chemiluminescent particle immunoassay, HCV-RNA was detected by pcr- fluorescence probe, and serum ALB level was detected. The identification of HLA genotypes was carried out by sequencebasedtyping (PCR-SBT). The different HLA types were compared and analyzed. ALB level, antibody affinity, antibody quality and antibody total activity change.4, using online search database combined with discoverystudio (DS) software to analyze and predict the interaction between the 6 kinds of HLA protein fractions of NS3 and hla-drb1*09, hla-a*02, hla-a*33, hla-b*58, hla-drb1*07, hla-drb1*13. The database includes national national medical books Library literature retrieval system NCBI, protein structure database PDB and PROSITE database. Results: 1, the serum antibody affinity of female rabbits after first times immunization is 0.522, second times 0.826 and third times 0.896. The affinity of serum antibody after first immunization of male rabbits is 0.816, second is 0.846 and third is 0.972, which are all gradually increasing and affinity with antibody. The antibody quality of.2, alt, AST normal group was significantly lower than any abnormal group (P0.05), and the antibody affinity was significantly higher than any abnormal group (P0.05). The total antibody activity in the three groups was not significantly different (P0.05).3. According to HCV-RNA level, the normal group of ALT and AST (53 cases) were further divided into two groups. In the group of HCV-RNA negative group and HCV-RNA positive group, the total antibody activity of.Hcv-rna negative group was significantly lower than that of HCV-RNA positive group (P0.05), but the antibody affinity was significantly higher than that of HCV-RNA positive group (P0.05).4, the total antibody activity of the HCV-RNA negative group was significantly lower than the low viral load, and the high virus load group (P0.05), The antibody affinity was significantly higher than the low viral load, high viral load group (P0.05).5, HCV-RNA positive as the dependent variable, antibody affinity, antibody quality and antibody total activity as independent variables, logistic regression analysis, HCV-RNA level with antibody affinity was negatively correlated (P0.05).6, ALB normal HCV-RNA negative group antibody affinity obviously Higher than the other groups of chronic hepatitis and liver cirrhosis (P0.05), the quality of antibody was significantly lower than that of other groups of chronic hepatitis and liver cirrhosis (P0.05). The total antibody activity was not significantly different in the three groups (P0.05).7, and the area of antibody affinity and antibody mass was 0.816,0.811, respectively, which showed high diagnostic efficiency. It was significantly higher than the traditional antibody test (the area under the ROC curve was 0.581). The antibody affinity was 0.873 for the best diagnostic critical point for differentiating the progression of hepatitis C infection (HCV-RNA positive) and the good turn phase (HCV-RNA negative). The higher the antibody affinity, the less the virus replication was.8, and the ratio of the high antibody affinity (> 0.873) in the alb normal HCV-RNA negative group. The cases were significantly higher than the other groups of chronic hepatitis and liver cirrhosis (P0.05).9, the serum of HCV-RNA (+) was neutralized with high affinity antibody, and the lgrna was significantly lower than that before the neutralization level (P0.05).10. In HCV patients and the healthy control group, the 8 HLA types were identified with significant difference (P0.05), hla-a*02, hla-b*39, hla-drb1*09, respectively. Drb1*11, hla-a*33, hla-b*58, hla-drb1*07, hla-drb1*13., hla-a*02, hla-b*39, hla-drb1*09, hla-drb1*11 in HCV patients were significantly lower than those in the healthy control group. Anti gene, while hla-a*33, hla-b*58, hla-drb1*07, and hla-drb1*13 are the sensitive gene.11 of hepatitis C infection. In these 8 HLA types, serum ALB levels are in hla-a*02, hla-a*33, hla-b*39, hla-drb1*07, hla-drb1*11, carriers and non carriers. The level of Alb is obviously different, the former p=0.015 and the latter p=0.003, all 0.05, but only hla-drb1*09 in cross validation still have significant differences, p=0.017, indicating that hla-drb1*09 is not only the resistance gene of hepatitis C infection, but also hinders the decline of ALB and the progression of the disease, which plays a protective role.12, the frequency of the HLA-A site gene (high resolution). There was a positive correlation with antibody affinity, suggesting that the higher the frequency of the gene, the stronger the antibody affinity.13, the antibody affinity, the quality of the antibody and the total activity of the antibody in patients carrying hla-a*02, hla-b*39, hla-drb1*09, hla-drb1*11, hla-a*33, hla-b*58, hla-drb1*07, and hla-drb1*13, because hla-b*39 only had 1 positive patients. Hla-drb1*11 only 4 positive patients did not compare the two genotypes. The results showed that according to the affinity sequencing of antibody, the affinity analysis of hla-a*33hla-b*58hla-drb1*07hla-a*02hla-drb1*09hla-drb1*13.14 and bioinformatics was: the affinity of HLA to hcvns3 was: hla-b*58hla-a*33hla-drb1*09hla-drb1*07hl A-a*02hla-drb1*13. conclusion: the multi-dimensional data analysis method of 1.hcv antibody was established. The antibody affinity, the total activity of the antibody and the change of the quality of the antibody may reflect the changes of the liver cell damage and the viral load. It has certain clinical application value of the.2.hcv antibody multidimensional data analysis, and the affinity of the antibody is closely related to the condition of the disease. It is better than the traditional laboratory to detect the total activity of antibody only. The antibody affinity may have a certain indicator in the outcome of the disease. It has a high diagnostic efficiency. The high affinity antibody may be beneficial to the improvement of the disease. The determination of antibody affinity will help clinicians to judge the prognosis of the.3.HLA polymorphism and the incidence of hepatitis C The development process is related to the high affinity of HCV antibody. The high gene frequency (evolutionary conservatism) may help to produce high affinity antibodies.
【學(xué)位授予單位】：大連醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R512.63;R446.6

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