本文選題：T細胞表位　切入點：抗原加工提呈途徑　出處：《大連理工大學》2009年博士論文　論文類型：學位論文

【摘要】： T細胞表位能夠激活T細胞的免疫應答,在特異性免疫應答中發(fā)揮重要的作用。而T細胞表位的產(chǎn)生依賴于抗原加工提呈過程。細胞毒性T細胞(cytotoxicy T lymphocyte,CTL)表位的產(chǎn)生需要經(jīng)過內(nèi)源性抗原蛋白被蛋白酶體裂解產(chǎn)生內(nèi)源性抗原肽、抗原肽被與抗原提呈相關的轉(zhuǎn)運蛋白(transporter associated with antigen processing,TAP)轉(zhuǎn)運至內(nèi)質(zhì)網(wǎng)(endoplasmic reticulum,ER)中、抗原肽與主要組織相容性復合體(majorhistocompatibility complex,MHC)Ⅰ類分子結(jié)合形成抗原肽-MHCⅠ類分子復合物、復合物被提呈至抗原提呈細胞(antigen presenting cells,APC)表面,與T細胞表面抗原受體(T cell receptor,TCR)結(jié)合激活CTL細胞這些主要過程。而輔助性T細胞(helperT cell,Th)表位的產(chǎn)生需要經(jīng)過外源性抗原蛋白在內(nèi)體/溶酶體(endosome/lysosome)中被裂解產(chǎn)生外源性抗原肽、抗原肽與MHCⅡ類分子結(jié)合形成抗原肽-MHCⅡ類分子復合物、復合物被提呈至APC表面,與TCR結(jié)合激活Th細胞這些主要過程。因此,抗原的加工提呈過程對T細胞表位的產(chǎn)生起到?jīng)Q定性作用。為了深入了解抗原的加工提呈機制,本文應用定量構效關系(quantitative structure activity relationships,QSAR)方法對抗原加工提呈途徑中三個重要的選擇性階段進行了理論預測研究。 1.在內(nèi)源性抗原的加工提呈途徑中,抗原肽-MHCⅠ類分子復合物起到激活CTL細胞免疫應答的關鍵作用。而MHCⅠ類分子只能與特定的抗原肽結(jié)合,那么深入研究哪些抗原肽能夠與MHCⅠ類分子結(jié)合,準確預測抗原肽與MHCⅠ類分子的結(jié)合親和力將有助于深入了解抗原肽與MHCⅠ類分子結(jié)合的生物機理,有助于揭示CTL表位的產(chǎn)生機制。為了研究抗原肽與MHCⅠ類分子的結(jié)合特異性,本文建立了三種MHCⅠ類配體的QSAR模型,并采用偏最小二乘法(partial least squares,PLS)方法求解。通過比較各個模型的預測性能可知,在建立MHCⅠ類配體的QSAR模型時需要考慮氨基酸殘基之間的相互作用。另外,本文通過分析抗原肽中不同位置氨基酸對結(jié)合MHCⅠ類分子形成的權重系數(shù),獲得了抗原肽與MHCⅠ類分子的結(jié)合特異性。 2.在內(nèi)源性抗原的加工提呈途徑中,真核細胞中的泛素—蛋白酶體系統(tǒng)對內(nèi)源性抗原蛋白發(fā)揮著重要的降解功能。本文建立了蛋白酶體裂解內(nèi)源性抗原蛋白的QSAR模型來研究蛋白酶體對抗原蛋白裂解的特異性,并采用PLS方法求解模型。得到模型的預測準確度為82.8%。在相同的檢驗集下與同領域其他模型比較可知,本文模型的預測性能最優(yōu)。本文通過分析預測模型中不同位置上氨基酸對裂解位點形成的權重系數(shù),發(fā)現(xiàn)裂解位點“｜”及其近鄰位置氨基酸具有明顯的特異性。研究結(jié)果表明蛋白酶體對抗原蛋白的酶切處理不是隨機的,而是有一定模式和選擇性的。 3.在外源性抗原的加工提呈途徑中,抗原肽與MHCⅡ類分子復合物起到激活Th細胞免疫應答的關鍵作用。MHCⅡ類分子只能與特定的抗原肽結(jié)合,為了研究抗原肽與MHCⅡ類分子的結(jié)合特異性,本文分別建立了四種基于9-mer核心結(jié)合序列的MHCⅡ類配體QSAR模型和四種基于13-mer擴展核心結(jié)合序列的MHCⅡ類配體QSAR模型,采用CV-ISC-PLS方法進行求解。通過比較各個模型預測性能可知建立模型時需要考慮核心結(jié)合序列兩側(cè)的擴展位置并應采用合適的氨基酸描述符對氨基酸進行描述。另外,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類分子形成的權重系數(shù),獲取了抗原肽與MHCⅡ類分子的結(jié)合特異性。所得結(jié)果表明抗原肽的氨基酸特異性與實驗結(jié)果基本一致。
[Abstract]:T cell epitope can activate T cell immune response, play an important role in specific immune response. The production of T cell epitopes depends on the antigen processing and presentation process. Cytotoxic T cells (cytotoxicy T lymphocyte, CTL) epitopes generated by endogenous antigen protein by the proteasome cleavage to produce endogenous antigen peptide antigen peptide is associated with the transporter protein and antigen (transporter associated with antigen processing, TAP) transport to the endoplasmic reticulum (endoplasmic reticulum, ER), and antigen peptide major histocompatibility complex (majorhistocompatibility complex, MHC) with class I molecules to form antigen peptide -MHC class I molecule complex. The complex is presented to antigen-presenting cells (antigen presenting cells, APC) surface with T cell surface antigen receptor (T cell receptor, TCR) combined with activated CTL cells of the main process. The helper T cells (helperT cell Th) epitopes generated by exogenous antigen protein, body / lysosome (endosome/lysosome) was cracking to produce exogenous antigen peptide, peptide binding MHC class II molecules to form antigen peptide -MHC class II molecule complexes, complexes were presented to the surface of APC the main process of activation of Th cells combined with TCR. Therefore, antigen processing and presenting a decisive role in the production of T cell epitopes. In order to understand the mechanism of antigen processing and presentation, the quantitative structure-activity relationship (quantitative structure activity relationships, QSAR) method of antigen processing and presentation of three important selective phase pathway were studied. Theoretical prediction
1. presenting pathway in the endogenous antigen processing and antigen peptide -MHC class I molecule complexes play a key role in the activation of CTL cell immune response. MHC class I molecules bind only to specific antigenic peptide, then further study which peptides could bind to MHC molecules, accurately predict peptide binding the affinity of MHC class I molecules will help to deeply understand the mechanism of biological antigen peptide and MHC class I molecules, helps to reveal the mechanism of the CTL table. In order to study binding antigen peptide and the specificity of MHC class I molecule, this paper establishes a QSAR model for three MHC class I ligands, and the use of partial least squares (partial least, squares, PLS) method. Through compare the predictive performance of each model that takes into account the interaction between amino acid residues are required in the QSAR model of MHC class I ligands. In addition, this article through the analysis The binding specificity of antigenic peptides and MHC class I molecules is obtained by the weight coefficients of different amino acids in the antigen peptide binding to the MHC class I molecules.
2. presenting pathway in the endogenous antigen processing in eukaryotic cells in the ubiquitin proteasome system of endogenous antigen proteins play important function degradation. This paper establishes a model of QSAR proteasome cleaving antigen protein to study the proteasome cleavage specificity of antigen protein solutions, and PLS method is used to solve the model. The predictive accuracy of the model is 82.8%. in the same test set with the same domain model comparison, the optimal performance prediction model in this paper. Through the analysis of forecast weight coefficient of amino acids in different positions in the model on the cleavage site formation, found that the cleavage site of "1" and its neighboring amino acid position has obvious specificity. The results show that the proteasome protein enzyme treatment is not random, but selectively.
3. presentation pathway in the exogenous antigen processing and antigen peptide and MHC class II molecules complexes play a key role in.MHC class II molecules can activate Th cell immune response with specific antigenic peptide, in order to study binding antigen peptide and MHC class II molecules specific, this paper establishes four kinds of combination the sequence of MHC class II ligand QSAR model and four kinds of extended core binding MHC class II ligand QSAR model based on the sequence of 13-mer based on 9-mer core is solved by using the CV-ISC-PLS method. Through the comparison of various models to predict the performance that models need to consider the core position with the extended sequence on both sides and should adopt appropriate amino acid descriptors to describe amino acid. In addition, this paper takes HLA DRB1*0101 as an example, through the analysis of the weight coefficient in combination with MHC class II molecules formed in different positions in the amino acid peptide, peptide and The binding specificity of MHC class II molecules shows that the amino acid specificity of the antigen peptide is basically consistent with the experimental results.

【學位授予單位】：大連理工大學
【學位級別】：博士
【學位授予年份】：2009
【分類號】：R392

【引證文獻】

相關碩士學位論文 前1條

1 張磊;基于Fast ICA方法預測Th細胞表位[D];大連理工大學;2012年

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本文編號：1637822