本文選題：T細(xì)胞表位 + 抗原加工提呈途徑��； 參考：《大連理工大學(xué)》2009年博士論文

【摘要】： 在T細(xì)胞介導(dǎo)的特異性免疫應(yīng)答中,T細(xì)胞表面抗原受體(T-cell receptor,TCR)僅能識別抗原肽與主要組織相容性復(fù)合體(major histocompatibility complex,MHC)分子結(jié)合形成的復(fù)合物。此復(fù)合物的形成是依賴于抗原的加工提呈途徑。內(nèi)源性抗原(病毒、腫瘤抗原等)需要經(jīng)過蛋白酶體(proteaome)的降解、與抗原提呈相關(guān)的轉(zhuǎn)運(yùn)蛋白(transporter associated with antigen processing,TAP)的轉(zhuǎn)運(yùn)、MHCⅠ類分子的結(jié)合后才能被細(xì)胞毒性T細(xì)胞(cytotoxic T lymphocyte,CTL)識別,相應(yīng)的抗原肽稱為CTL表位;外源性抗原(細(xì)菌產(chǎn)生的毒素)也需要經(jīng)過溶酶體酶的降解和MHCⅡ類分子的結(jié)合后才能被輔助性T細(xì)胞(helper T cell,Th)識別,相應(yīng)的抗原肽稱為Th表位。一般來講,抗原的加工提呈途徑?jīng)Q定了T細(xì)胞對表位的選擇性。為了進(jìn)一步弄清抗原的加工提呈機(jī)制,提高T細(xì)胞表位預(yù)測的準(zhǔn)確性和合理性,本文應(yīng)用支持向量機(jī)方法對抗原加工提呈途徑中三個(gè)重要的選擇性階段進(jìn)行了理論預(yù)測研究。 1.在內(nèi)源性抗原的加工提呈途徑中,真核細(xì)胞中的泛素-蛋白酶體系統(tǒng)對抗原蛋白發(fā)揮著重要的酶切降解功能。為了進(jìn)一步理解蛋白酶體的酶切機(jī)制,本文對蛋白酶體的裂解位點(diǎn)特異性進(jìn)行了研究。文中采用支持向量分類器(support vector classifier,SVC)方法建立了蛋白酶體的裂解位點(diǎn)預(yù)測模型,預(yù)測準(zhǔn)確度達(dá)到83.1%。在相同檢驗(yàn)集下,本模型的性能表現(xiàn)要優(yōu)于其他預(yù)測模型。通過分析預(yù)測模型中不同位置上氨基酸對裂解位點(diǎn)形成的權(quán)重系數(shù),本文獲取了蛋白酶體裂解位點(diǎn)及其兩側(cè)區(qū)域氨基酸的裂解特異性。這些裂解特異性反映了蛋白酶體與抗原蛋白相互作用信息,同時(shí)表明蛋白酶體對抗原蛋白的酶切處理不是隨機(jī)的,而是有一定模式和選擇性的。研究結(jié)果為進(jìn)一步揭示蛋白酶體裂解抗原蛋白的機(jī)理提供了重要的信息。 2.在內(nèi)源性抗原的加工提呈途徑中,MHCⅠ類分子發(fā)揮著啟動(dòng)和調(diào)節(jié)免疫應(yīng)答的重要作用�？乖闹挥薪Y(jié)合MHCⅠ類分子后,才能被細(xì)胞毒性T細(xì)胞(CTL)識別,然而,對于一個(gè)給定的MHCⅠ類分子,只有一組特定的抗原肽才能與之結(jié)合。因此,準(zhǔn)確判斷哪些抗原肽能與指定MHCⅠ類分子結(jié)合,不僅有助于理解免疫機(jī)制,而且有助于開發(fā)高效的抗腫瘤疫苗。為了進(jìn)一步了解MHCⅠ類分子與抗原肽結(jié)合的特異性,本文利用支持向量回歸機(jī)(support vector regression,SVR)方法以及四種氨基酸編碼方式建立了四個(gè)抗原肽與MHCⅠ類分子結(jié)合親和力的預(yù)測模型。四個(gè)模型的性能比較顯示,基于氨基酸物理化學(xué)性質(zhì)建立的模型具有更好的預(yù)測能力。此外,本文通過分析抗原肽中不同位置氨基酸對結(jié)合MHCⅠ類分子形成的權(quán)重系數(shù),獲取了抗原肽與MHCⅠ類分子的結(jié)合特異性。 3.在外源性抗原的加工提呈途徑中,抗原肽與MHCⅡ類分子的結(jié)合是激活輔助性T細(xì)胞特異性免疫應(yīng)答的先決條件。對于給定的一種MHCⅡ類分子,準(zhǔn)確預(yù)測與之結(jié)合的抗原肽,不僅有助于人們進(jìn)一步理解免疫的基本原理,還對表位疫苗的開發(fā)、自身免疫性疾病(如類風(fēng)濕關(guān)節(jié)炎、胰島素依賴性糖尿病等)的治療等有著重要的意義。本文應(yīng)用迭代自洽(iterative self-consistent,ISC)策略與支持向量回歸機(jī)(SVR)的組合方法和四種氨基酸編碼方式,對17種MHCⅡ分子(包括14種人類的HLA DR分子和3種鼠類的H2 IA分子)的配體數(shù)據(jù)進(jìn)行了回歸分析,分別建立了預(yù)測模型。與其他預(yù)測模型的比較結(jié)果顯示,本文模型具有更優(yōu)的性能表現(xiàn)。此外,本文以HLA DRB1*0101為例,通過分析抗原肽中不同位置氨基酸對結(jié)合MHCⅡ類分子形成的權(quán)重系數(shù),獲取了抗原肽與MHCⅡ類分子的結(jié)合特異性。研究結(jié)果為進(jìn)一步揭示Th細(xì)胞表位的產(chǎn)生機(jī)制提供了重要的信息。
[Abstract]:In the specific immune response mediated by T cells, the T cell surface antigen receptor (T-cell receptor, TCR) only recognizes the combination of the antigen peptide and the major histocompatibility complex (major histocompatibility complex, MHC) molecules. The formation of this complex is based on the process of antigen processing. Tumor antigen, etc., need to be degraded by proteasome (proteaome), the transport of transporter associated with antigen processing (TAP) associated with antigen, and the binding of MHC class I molecules can be identified by the cytotoxic T cells (cytotoxic T lymphocyte), and the corresponding antigen peptide is called the epitope; Bacteria produced toxins also need to be identified by the degradation of lysosomal enzymes and the binding of MHC class II molecules to be identified by helper T cell (Th), and the corresponding antigen peptides are called Th epitopes. Generally speaking, the process of antigen processing determines the selectivity of the epitopes of T cells. In order to further clarify the mechanism of antigen processing, In order to improve the accuracy and rationality of the prediction of T cell epitopes, this paper uses the support vector machine method to predict the three important selective stages of the original processing approach.
1. in the processing approach of endogenous antigen, the ubiquitin proteasome system in eukaryotic cells plays an important role in enzymatic degradation of antigen protein. In order to further understand the proteasome mechanism of proteasome, the specificity of proteasome cleavage site is studied in this paper. The support vector classifier (support vector) is used in this paper. Classifier, SVC) method established the prediction model of proteasome cleavage site, and the prediction accuracy reached 83.1%. in the same test set. The performance of the model was better than the other prediction models. By analyzing the weight coefficient of the amino acid on the cracking site in different positions in the prediction model, the proteasome cracking site was obtained. The cleavage specificity of the amino acids on the two sides of the region reflects the interaction information between the proteasome and the antigen protein, and indicates that the protease removal of the antigen protein is not random, but has a certain pattern and selectivity. The result of the study is to reveal the mechanism of proteasome cracking antigen protein in a further step. Important information is provided.
2. in the processing and presenting pathway of endogenous antigen, MHC class I molecules play an important role in starting and regulating the immune response. Only after the binding of MHC I molecules can the antigen peptide be identified by the cytotoxic T cells (CTL). However, only a set of specific antigen peptides can be combined with a given MHC class I molecule. Therefore, the accuracy of the antigen peptide is accurate. Judging which peptides can be combined with designated MHC class I molecules not only helps to understand the immune mechanism, but also helps to develop efficient antitumor vaccines. In order to further understand the specificity of the binding of MHC class I molecules to antigenic peptides, this paper uses the support vector regression (support vector regression, SVR) method and four amino acids coding. The prediction model of the binding affinity of four antigen peptides with MHC I was established. The performance comparison of the four models showed that the model based on the physicochemical properties of amino acids had better prediction ability. In addition, the weight coefficients of different amino acids in the antigen peptides for the formation of MHC I molecules were obtained. The binding specificity of the antigen peptide to the MHC class I molecules.
3. in the processing and presenting approach of exogenous antigen, the binding of antigen peptide to MHC class II molecules is a prerequisite for activating the specific immune response of auxiliary T cells. For a given MHC class II molecule, the accurate prediction and combination of antigenic peptides not only help people to understand the basic principles of immunization further, but also to the opening of epitope vaccines. The treatment of autoimmune diseases such as rheumatoid arthritis (rheumatoid arthritis, insulin dependent diabetes) is of great significance. In this paper, the combination of iterative self-consistent (ISC) strategy and support vector regression machine (SVR) and four amino acid coding methods are applied to the 17 MHC II molecules (including 14 kinds of human HLA DR points). The regression analysis of the ligand data of the H2 IA molecules of the 3 species of rodents and the other prediction models showed that the model had better performance. In addition, this paper took HLA DRB1*0101 as an example to analyze the weight of different positions of amino acids in the antigen peptide to the formation of MHC class II molecules. The binding specificity of antigen peptide with MHC class II molecules has been obtained. The results provide important information for further revealing the mechanism of Th cell epitopes.
【學(xué)位授予單位】：大連理工大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2009
【分類號】：R392

【引證文獻(xiàn)】

相關(guān)博士學(xué)位論文 前1條

1 趙曉威;蛋白質(zhì)翻譯后修飾及其相互作用預(yù)測方法研究[D];東北師范大學(xué);2013年

相關(guān)碩士學(xué)位論文 前1條

1 王星;利用聚類后PCA方法的T細(xì)胞表位預(yù)測研究[D];東北師范大學(xué);2013年

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本文編號：1921398