本文選題：T細胞免疫球蛋白域黏蛋白域蛋白-1水相逢 + 腎病綜合征��； 參考：《南方醫(yī)科大學》2016年博士論文

【摘要】：第一部分背景和目的：兒童原發(fā)性腎病綜合征發(fā)病率占兒童泌尿系統第二位,發(fā)病率逐年提高,但發(fā)病機制目前仍不清楚,從最初發(fā)現白細胞介素-4等在腎病綜合征患者表達異常到發(fā)現TH1/TH2免疫平衡紊亂可能參與該發(fā)病機制,再到TIM基因家族在調控人類效應T細胞活化及分化為TH1/TH2可能的作用,實現了從宏觀到微觀,從分子水平到基因水平研究的重大進展,這與前人所做的研究努力及科學技術水平的提升密不可分。研究表明,遺傳因素參與原發(fā)性腎病綜合征的發(fā)生、發(fā)展過程,且具有遺傳易感性,不同地區(qū)、不同種族,其基因多態(tài)性變異也具有差異。越來越多的研究表明,T細胞免疫球蛋白域黏蛋白域蛋白-1(T-cell immunoglobulin domain and mucin domain-1, TIM-1)基因存在多態(tài)性,并且基因多態(tài)性可能與某些疾病如自身免疫性疾病、糖尿病、支氣管哮喘、類風濕性關節(jié)炎的發(fā)病存在關聯,甚至與某些疾病的遺傳易感性相關。研究指出PNS可能的發(fā)病機制與T淋巴細胞免疫失衡有關,往往涉及Thl與Th2數量及功能紊亂。TIM基因家族被發(fā)現其在調控T淋巴細胞活化及細胞因子分泌等方面具有重要作用,而這些均與PNS的尿蛋白形成有關。目前國內外對TIM基因家族的研究也越來越多。由于單核苷酸多態(tài)性的存在,使得疾病的發(fā)病機制非單一因素所決定,遺傳因素也參與疾病的發(fā)生、發(fā)展過程,不同地區(qū)、不同種族,其基因多態(tài)性變異也具有差異。因此,TIM-1基因多態(tài)性研究為探討PNS的易感性,疾病的進展、預后,甚至通過干預TH1/TH2之間的平衡來治療該疾病成為一種可能具有重大意義。本實驗目的在探討內蒙地區(qū)蒙漢兩族TIM-1基因多態(tài)性差異及其與兒童原發(fā)性腎病綜合征的關系；探索IL-13與PNS之間的關聯,為PNS的治療提供新思路。方法1.樣本：病例組的選擇：2014-10至2015-12期間,在內蒙古醫(yī)科大學附屬醫(yī)院兒內科和國際蒙醫(yī)院住院的確診為初發(fā)PNS的患兒21例；對照組：于內蒙古醫(yī)科大學附屬醫(yī)院及國際蒙醫(yī)院同一時期同地區(qū)的健康體檢漢族兒童20例、蒙古族兒童20例作為漢族及蒙古族正常對照。2.納入標準：病例組依照我國兒童PNS診斷標準,確診為PNS；對照組除外變應性疾病、腎臟病史及腎臟病家族史、近期免疫抑制劑應用史。3.采集受試對象外周靜脈血液標本2m1各2管,均取自于清晨空腹,按要求妥善存放,將所提取的血液標本按步驟提取DNA及檢測IL-13濃度。4.實驗方法：TIM-1-1454G/A位點多態(tài)性檢測用到的方法包括聚合酶鏈反應和限制性內切酶片段長度多態(tài)性(PCR-RFLP)、瓊脂糖凝膠電泳和基因測序等方法。IL-13檢測采用酶聯免疫吸附試驗完成。5.數據分析：將所得數據運用正確的統計學方法,采用統計學相關軟件,得出各組的基因型以及頻率等結果,將數據結果進行統計學比較,檢驗水準為α=0.05,當P0.05,差異有統計學意義,反之則為無意義。結果1、PNS患兒啟動子-1454G/A基因型GG、AG、AA的頻率為0.905,0.095,0.0；漢族對照組基因型GG、AA、AG頻率為0.55、0.4、0.05；蒙古族對照組基因型GG、AA、AG頻率為0.6,0.35,0.05。2.漢族PNS組與漢族正常組的基因頻率比較差異有統計學意義(χ2=5.64,P0.025)；蒙古族與漢族對照組基因型頻率相比較,差異無統計學意義(χ2=0.11,P0.05)。3.PNS組與健康對照組基因型頻率分布比較,差異有統計學意義(χ2=7.09 P=0.030.05)。4.PNS患兒中TIM-1-1454G等位基因頻率較正常組頻率明顯增高(OR=6.23, 95%CI=1.38-28.22,P=0.01)。5.PNS患兒急性期的IL-13含量較健康對照組相比差異有統計學意義。6.蒙古族與漢族正常對照組中IL-13的水平相比較,兩者無明顯差異。結論1.TIM-1-1454G/A位點的基因多態(tài)性可能與內蒙地區(qū)漢族兒童PNS的發(fā)病相關；-1454G等位基因可能是內蒙地區(qū)漢族兒童PNS發(fā)病的危險因素,或者說TIM-1--1454G等位基因與PNS的易感性相關。2.雖然本實驗不能說明漢族與蒙古族正常兒童的TIM-1基因多態(tài)性存在差異,但在未擴大樣本及對TIM-1其它基因位點進行進一步研究的前提下,并不能認為TIM-1在蒙古族與漢族對照組間不存在基因多態(tài)性。3.IL-13的水平異常與PNS的發(fā)病密切相關,IL-13參與PNS的發(fā)病。4.TIM-1基因多態(tài)性和IL-13水平參與了兒童PNS的發(fā)病,兩者之間具體的調控途徑仍然有待進一步研究。第二部分背景和目的：TIM(T細胞免疫球蛋白黏蛋白分子)是一組由TIM基因編碼的T細胞表面分子。TIM蛋白家族各成員在T細胞亞群上的選擇性表達使之成為區(qū)分Thl和Th2細胞亞群的重要標志,同時它們在T細胞分化、T細胞效應功能、巨噬細胞活化等方面的作用被認為參與了多種自身免疫性疾病的發(fā)生、發(fā)展,從而引起了人們的關注。TIM家族是新近研究的與臨床疾病密切相關的基因家族,其中TIM-3是備受關注的重要成員,其具有多重生物學效應,同時是區(qū)分Th1/Th2細胞特異性的表面標志分子,有研究其同時表達于Th17分子表面,參與機體的各項免疫應答調節(jié),如調節(jié)IFN-r的表達,與臨床疾病的發(fā)病有密切聯系。Th1和Th2是效應性T細胞,但同時也具有免疫調節(jié)作用,Th1主要介導細胞免疫和炎癥反應,抗病毒和抗胞內寄生菌感染,參與移植物排斥；Th2主要涉及B細胞增殖,抗體產生、超敏反應和抗寄生蟲免疫。兩群細胞分泌的細胞因子不同,其中關鍵性細胞因子是Th1分泌IFN-γ,Th2分泌IL-4.然而,Th1/Th2又顯示免疫調節(jié)作用。Th1產生的IFN-γ可激活胞內一種稱為T-bet的亞群專一性轉錄因子,T-bet可促進IFNG基因轉錄而抑制IL4基因轉錄；相反,Th2產生的IL-4可激活Th2亞群專一性轉錄因子Gata-3,后者促進IL4基因而抑制IFNG基因的轉錄。其結果,Thl和Th2成為一類各自以對方及相關疾病為調節(jié)對象的細胞亞群。IFN-γ能誘導Mφ及APC上調MHCⅡ類分子,增強抗原處理機提呈作用。IFN-γ自身及其誘導的Mφ產生的IL-12可誘導Thl細胞功能,增強遲發(fā)型超敏反應及效應CTL產生。兒童原發(fā)性腎病綜合征據目前研究分析,是一種以免疫介導為主的,以部分免疫沉著為主,損害腎小球組織的疾病。很多研究提示,該疾病的發(fā)生發(fā)展存在免疫紊亂的表現,主要是以Th1/Th2平衡紊亂為主[2,15,28]；在該疾病的研究中,我們考慮加強對TIM家族的有關基因進行試驗對比研究。TIM-3有多重的生物學效應,以調節(jié)免疫反應為主,其與特異性受體相結合,產生特定的細胞信號,在某些特殊細胞因子的刺激作用下,出現Th1類細胞的活化或增殖受到抑制,程度較為顯著。從而導致出現T細胞為主的免疫朝向現負方調節(jié)的現象。增強或抑制TIM-3與其特異性配體的結合,對有關TH1/Th2失衡相關的疾病可起到改變其導向的作用.在各類臨床疾病中均有其獨特的治療思路研究意義。因此在臨床疾病的研究過程中對TIM-3分子的深入研究,對相關疾病的治療及臨床癥狀的緩解會起到不可估量的作用。且IFN-γ在PNS患兒體內表達降低,提示Th1細胞的失活有可能參與PNS的發(fā)病過程。TIM-3基因的轉錄發(fā)生在機體受抗原刺激的初始階段,該階段對T細胞分化及定型為THI或TH2有至關重要的作用。對TIM-3基因關于腎臟疾病的研究才剛剛開始,其分子調節(jié)功能的許多機制仍然需要大量研究。TIM-3可能成為Th細胞上免疫調節(jié)治療的靶向分子。本實驗目的是研究TIM-3基因多態(tài)性及IFN-γ水平與兒童原發(fā)性腎病綜合征(PNS)發(fā)病機制的相關性。方法：采用病例對照研究,選取居住于內蒙古自治區(qū)漢族PNS患兒21例,正常蒙古族(祖籍三代以上均為蒙古族,居住于錫盟地區(qū)的蒙古族)、漢族(祖籍三代以上均為漢族,家族中無蒙漢通婚史)對照組各為20例,采用PCR-限制性片段多態(tài)性分析、PCR-聚丙烯酰胺凝膠電泳分析和毛細管電泳分析,基因測序技術檢測PNS患兒和40例健康兒童(健康對照組)的TIM-3基因外顯子-574A/C的SNP的多態(tài)性,計算基因型及等位基因頻率的統計。采用酶聯免疫吸附實驗檢測血IFN-γ水平,分析其與原發(fā)性腎病綜合征發(fā)生發(fā)展中的作用及檢測IFN-γ的臨床診斷意義。結果：(1)健康漢族對照組TIM-3外顯子區(qū)-574位A/A,A/C, C/C基因型頻率分別為：30%,45%,25%,蒙古族該位點的出現頻率為：20%,55%,25%；蒙古族與漢族的正常對照組比較差異無統計學的意義(χ2=0.6,P0.05,)而PNS組頻率分別為9.5%,28.6%,61.9%；該數據統計的基因型頻率與漢族健康對照組比較出現的差異統計學有意義。(χ2=7.08,P=0.05)；將總體正常對照組與病例組比較差異具有顯著性,有統計學意義(χ2=7.16, P=0.05); PNS患兒攜帶-574C/C等位基因的頻率增高(OR=4.875, ORL=1.58, ORu=14.1;P=0.05);(2)由于TIM-3對IFN-γ的轉錄翻譯有一定的調控作用,我們在進一步對其細胞因子水平進行研究。21例PNS患兒及40例正常對照組血清IFN-γ的水平進行檢測,分析其與PNS臨床指標的關系。PNS組與正常對照組相比,血清IFN-γ的水平無明顯差異性。各組間差異無統計學意義(P0.05)。結論：TIM-3基因外顯子-574A/C的單核苷酸多態(tài)性可能與兒童腎病綜合征的發(fā)病機制相關。但在細胞因子水平,IFN-γ無明顯的差異性變化。
[Abstract]:Background and objective: the incidence of primary nephrotic syndrome in children is second of the urinary system in children. The incidence of the disease is increasing year by year, but the pathogenesis is still unclear. From the initial discovery of the abnormal expression of interleukin -4 in patients with nephrotic syndrome to the discovery of TH1/TH2 immune balance disorder may be involved in the pathogenesis, and then to TIM The gene family plays an important role in regulating the activation and differentiation of human effect T cells into TH1/TH2. It has achieved great progress from macro to microcosmic, from molecular level to gene level. This is inseparable from the previous research efforts and the advancement of science and technology. The genetic polymorphisms of the T cell immunoglobulin domain protein -1 (T-cell immunoglobulin domain and mucin domain-1, TIM-1) gene are polymorphic, and the genetic polymorphism may be associated with some diseases. Diseases such as autoimmune diseases, diabetes, bronchial asthma, and rheumatoid arthritis are associated, and even related to genetic susceptibility to certain diseases. The study indicates that the possible pathogenesis of PNS is related to the imbalance of T lymphocyte immunity, which often involves the number and dysfunction of the.TIM gene family of Thl and Th2 and is found to be in the control of T drenching. The activation of the cells and the secretion of cytokine are important, and these are related to the formation of PNS's urinary protein. There are more and more studies on the TIM gene family at home and abroad. The existence of single nucleotide polymorphisms makes the pathogenesis of the disease determined by no single factor, and the genetic factors are also involved in the development of the disease. The genetic polymorphisms of different regions and different races are also different. Therefore, the study of TIM-1 gene polymorphism is of great significance to explore the susceptibility of PNS, the progress of the disease, the prognosis, and even the balance between the TH1/TH2 and the treatment of the disease. The purpose of this experiment is to explore the two ethnic TI of Mongolian and Han nationality in Inner Mongolia region. M-1 gene polymorphism and its relationship with children's primary nephrotic syndrome; explore the association between IL-13 and PNS to provide new ideas for the treatment of PNS. Method 1.: the selection of the case group: 2014-10 to 2015-12, in the hospital of the Affiliated Hospital of Inner Mongolia Medical University and the international Mongolian Hospital of the Inner Mongolia Medical University, the primary PNS patients were diagnosed. 21 children in the control group: 20 cases of Han children in the same area of Inner Mongolia Medical University Affiliated to Inner Mongolia Medical University and international Mongolian hospital, and 20 cases of Mongolian children as the normal control of Han and Mongolian. The case group was diagnosed as PNS according to the diagnostic standard of Chinese children's PNS; the control group except the allergic disease, kidney The history of the disease and family history of kidney disease and the history of the application of immunosuppressive agents in the recent history of immunosuppressive agents.3. collected 2 tubes of 2M1 from the peripheral venous blood specimens of the subjects, which were taken from the early morning empty stomach and properly stored in accordance with the requirements. The extracted blood specimens were extracted according to the steps of DNA and the IL-13 concentration.4. test method: the method package used for the TIM-1-1454G/A locus polymorphism detection. .IL-13 detection, including polymerase chain reaction and restriction endonuclease fragment length polymorphism (PCR-RFLP), agarose gel electrophoresis and gene sequencing, used enzyme linked immunosorbent assay to complete the analysis of.5. data: using the correct statistical method and using statistical software to obtain the genotype and frequency of each group. The results were compared statistically, the test level was alpha =0.05, when P0.05, the difference was statistically significant, and on the contrary, it was meaningless. Results 1, the frequency of -1454G/A genotype GG, AG, AA in PNS children was 0.905,0.095,0.0, and the genotype GG, AA, AG frequency of the Han control group was 0.55,0.4,0.05; Mongolian control group genotype, frequency, frequency There was a significant difference in the frequency of gene frequency between the PNS group of 0.6,0.35,0.05.2. Han and the normal Han group (x 2=5.64, P0.025), and there was no statistical difference between the Mongolian and the Han control group (x 2=0.11, P0.05), and the difference was statistically significant (x 2=7.09 P) between the.3.PNS group and the healthy control group (x 2=7.09 P). =0.030.05) the frequency of TIM-1-1454G allele in children with.4.PNS was significantly higher than that of the normal group (OR=6.23, 95%CI=1.38-28.22, P=0.01), the IL-13 content in the acute phase of children with.5.PNS was significantly higher than that of the healthy control group. There was no significant difference in the level of IL-13 in the normal control group between the Mongolian and the Han people. The genetic polymorphism of the -1454G/A loci may be associated with the incidence of PNS in Han children in Inner Mongolia. The -1454G allele may be a risk factor for the incidence of PNS in Han children in Inner Mongolia, or the TIM-1--1454G allele is associated with the susceptibility of PNS to.2. although this experiment does not explain the TIM-1 gene polymorphism of the Han and Mongolian normal children. There is a difference in sex, but on the premise of no enlargement of the sample and the further study of other TIM-1 gene loci, it is not considered that the abnormal level of genetic polymorphism of TIM-1 between the Mongolian and the Han control groups is closely related to the incidence of PNS, and IL-13 participates in the polymorphism of the.4.TIM-1 gene and IL-13 level in the pathogenesis of PNS. The specific regulatory pathway between PNS and children remains to be further studied. Second background and purpose: TIM (T cell immunoglobulin mucin molecule) is a group of T cell surface molecules encoded by TIM gene.TIM protein family members in the T cell subgroup selectively expressed to differentiate Thl and Th2 cell subgroups The important markers of group, and their role in T cell differentiation, T cell effect function, macrophage activation and so on, are considered to be involved in the occurrence and development of a variety of autoimmune diseases, which have aroused the concern that the.TIM family is a recently studied gene family closely related to clinical diseases, of which TIM-3 is the most important concern. As a member, it has multiple biological effects and is a surface marker to distinguish the specific Th1/Th2 cells. It is expressed on the surface of the Th17 molecule and participates in the regulation of the immune response of the body, such as regulating the expression of IFN-r, and closely related to the pathogenesis of clinical diseases:.Th1 and Th2 are effector T cells, but they also have immune response. Pestilence, Th1 mainly mediates cell immunity and inflammatory reaction, antiviral and anti cytosolic infection, and participates in graft rejection; Th2 mainly involves B cell proliferation, antibody production, hypersensitivity and anti parasitic immunity. The cytokines secreted by two groups are different, and the key cytokines are Th1 secreting IFN- gamma, Th2 secretes IL-4. ran. In addition, Th1/Th2 also shows that IFN- gamma produced by immunoregulatory action.Th1 activates a subgroup specific transcription factor called T-bet. T-bet can promote the transcription of IFNG gene and inhibit the transcription of IL4 gene. On the contrary, IL-4 activates Th2 subgroup specific transcription factor Gata-3, which promotes the IL4 gene to inhibit the transcription of the gene. As a result, Thl and Th2 become a class of cell subgroups, each of which are regulated by each other and related diseases,.IFN- gamma can induce M phi and APC up regulation of MHC II molecules, enhance the function of.IFN- y and its induced M Phi induced IL-12 inducible Thl cells, enhance late hypersensitivity and effect CTL production. Nephrotic syndrome, according to current research and analysis, is an immune mediated disease which is mainly mediated by immunization and damages glomerular tissue. Many studies suggest that the development of the disease is manifested in the presence of immune disorders, mainly based on Th1/Th2 balance disorder [2,15,28]; in the study of the disease, we consider strengthening TIM A comparative study of the related genes in the family,.TIM-3 has multiple biological effects, which regulates the immune response mainly. It combines with the specific receptor to produce specific cell signals. Under the stimulation of certain specific cytokines, the activation or proliferation of Th1 like cells is inhibited, which leads to the emergence of T. Cell based immunization toward negative side regulation. Enhancing or inhibiting the binding of TIM-3 to its specific ligands can change its guiding role for diseases related to TH1/Th2 imbalance. It has its unique therapeutic significance in all kinds of clinical diseases. Therefore, the TIM-3 molecule in the study of the disease of the bed. In depth study, it can play an inestimable role in the treatment of related diseases and the relief of clinical symptoms. And the expression of IFN- gamma is reduced in PNS children, suggesting that the inactivation of Th1 cells may participate in the pathogenesis of PNS, and the transcription of.TIM-3 gene occurs at the initial stage of the body being stimulated by antigen, and the differentiation and stereotype of T cells is THI or TH2 has a crucial role to play. The study of the TIM-3 gene about kidney disease has just begun. Many mechanisms of its molecular modulating function still require a lot of study of.TIM-3 as a target for immunomodulatory therapy on Th cells. The purpose of this experiment is to study the TIM-3 gene polymorphism and the level of IFN- gamma in children with primary nephrotic synthesis. The correlation of the pathogenesis (PNS). Methods: a case control study was used to select 21 cases of PNS children living in the Han nationality in the Inner Mongolia Autonomous Region, the normal Mongolian nationality (all over three generations of the ancestors are Mongolian, the Mongolian people living in Xilong area), the Han nationality (all of the three generations of the ancestors were Han, and the family without the marriage history of the Mongolian Han Tong) in the control group, each of the 20 cases, used in the control group. PCR- restriction fragment polymorphism analysis, PCR- polyacrylamide gel electrophoresis analysis and capillary electrophoresis analysis, gene sequencing technique to detect the SNP polymorphism of TIM-3 exon -574A/C in children with PNS and 40 healthy children (healthy control group), to calculate the genotype and allele frequency statistics. The enzyme linked immunosorbent assay (ELISA) test was used. The serum IFN- gamma level was used to analyze its role in the development of primary nephrotic syndrome and the clinical diagnostic significance of IFN- gamma. Results: (1) the frequencies of A/A, A/C, C/C genotype of -574 in exon TIM-3 of the healthy Han control group were 30%, 45%, 25% respectively, and the frequencies of the Mongolian loci were 20%, 55%, 25%, and the Mongolian and Han nationality were positive. There was no statistical significance in the control group (x 2=0.6, P0.05), and the frequency of the PNS group was 9.5%, 28.6%, 61.9%, respectively. The difference between the genotype frequency and the Han healthy control group was significant. (x 2=7.08, P=0.05), the difference between the general control group and the case group was significant, and the statistical difference was statistically significant. Significance (x 2=7.16, P=0.05); the frequency of -574C/C allele in children with PNS increased (OR=4.875, ORL=1.58, ORu=14.1; P=0.05); (2) because TIM-3 had a certain regulatory effect on the transcription of IFN- gamma, we were further investigating the level of cytokines in.21 cases of PNS children and 40 normal controls. There was no significant difference in serum IFN- gamma level between group.PNS and normal control group. There was no significant difference between each group (P0.05). Conclusion: the single nucleotide polymorphisms of TIM-3 gene exon -574A/C may be associated with the pathogenesis of children with nephrotic syndrome, but at the level of cytokines, there is no IFN- gamma. Distinctly different changes.
【學位授予單位】：南方醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R726.9

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