HLA-B提呈抗原肽在三氯乙烯药疹样皮炎发病中的作用
发布时间：2018-08-31 18:52
【摘要】：职业接触三氯乙烯(Trichloroethylene,TCE)引起的药疹样皮炎是我国东南沿海地区严重影响作业工人健康的重要问题。TCE药疹样皮炎病因复杂,它是由环境和基因等多种因素共同引起的一种自身免疫性疾病,与人类白细胞抗原(Human leukocyte antigen,HLA)的多态性存在明显关联,对于其发病机制的研究目前还处于未知状态。本课题组在分子流行病学研究中发现HLA-B*13:01等位基因与TCE药疹样发病存在强关联。提示HLA-B*13:01分子在TCE药疹样皮炎发病过程中可能发挥着重要作用。HLA分子具有明显的多态性,主要功能是抗原的提呈和加工,在免疫反应中,通过形成HLA-抗原肽复合物将抗原特异性地呈递给T细胞受体,进而激活T细胞,启动免疫应答。因此,我们提出如下假说：HLA-B*13:01分子通过提呈特异性抗原肽参与了TCE药疹样皮炎的发生过程。为了验证该假说我们设计的试验方案如下：(1)选择HLA-B*13:02作为对照,分析HLA-B*13:01提呈抗原肽的特异性及其与疾病发生的关系。因为HLA-B*13:01和HLA-B*13:02的一级结构仅存在3个氨基酸的差别,但HLA-B*13:02等位基因与TCE药疹样皮炎无显著关联,因此,我们研究HLA-B*13:01结合抗原肽,可以将HLA-B*13:02抗原肽作为对照研究组。(2)利用已经构建的表达HLA-B*13:01 及 HLA-B*13:02的B淋巴母细胞HMy2.C1R细胞系,通过免疫亲和层析法,分离HLA Ⅰ类分子与抗原肽复合物,然后经酸解离和分子筛过滤,获得纯化后的小分子抗原肽；采用反相高效液相色谱-质谱技术来分离并测定抗原肽的一级结构；比较HLA-B*13:01与HLA-B*13:02提呈抗原肽的一级结构差异,分析特定HLA分子结合抗原肽的共同基序。(3)根据抗原肽与HLA分子结合的关键锚定位点,即抗原肽第二位(Position 2,P2)和羧基末端(PΩ),高频率出现氨基酸的情况,合成HLA-B*13:01/HLA-B*13:02的不同类型抗原肽,验证这些抗原肽与HLA.B分子的结合力,并同时观察TCE以及三氯乙醇(Trichloroethanol,TCOH)对抗原肽与HLA-B分子结合的影响,揭示TCE通过改变HLA分子与抗原肽结合而诱导疾病发生的机制。研究结果如下：(一)HLA分子结合抗原肽结构分析：本研究最终获得57条HLA-B*13:01抗原肽序列和88条HLA-B*13:02抗原肽序列。通过分析抗原肽每个位点氨基酸出现的频率,发现在HLA-B*13:01抗原肽中,P2位锚定氨基酸为亮氨酸(Leucine,L)和谷氨酰胺(Glutamine,Q),频率分别为39%和33%；PΩ位锚定氨基酸为L(35%),苯丙氨酸(Phenylalanine,F).异亮氨酸(Isoleucine,I)(15%)和色氨酸(Tryptophan,W)(11%).HLA-B*13:02抗原肽中,P2位锚定氨基酸为Q(26%)和L(16%)；PΩ位为L(26%)、缬氨酸(Valine,V)(21%)和Ⅰ(14%)。对比HLA-B*13:01和HLA-B*13:02抗原肽P2和PΩ位锚定氨基酸的特点,发现P2位二者锚定氨基酸一致,均为L和Q；PQ位锚定氨基酸存在差异,除L外HLA-B*13:01抗原肽的PΩ位优势氨基酸还包括F,W和Ⅰ,HLA-B*13:02则为V和I.HLA-B*13:01与HLA-B*13:02一级结构仅在第94位(I,HLA-B*13:01; T,HLA-B*13:02).第95位(I,HLA-B*13:01;W,HLA-B*13:02)和第97位(R,HLA-B*13:01;T,HLA-B*13:02)3个氨基酸存在差别,其中95和97位氨基酸构成HLA分子与抗原肽结合的F口袋,F口袋刚好与抗原肽PΩ位氨基酸侧链结合,F口袋的形状及特性决定了与之结合的抗原肽氨基酸侧链类型,提示HLA-B*13:01与HLA-B*13:02抗原肽在PQ位置氨基酸存在的差别与HLA分子中参与构成F口袋的分子结构有关。(二)抗原肽的功能分析：通过HLA-抗原肽结合力试验发现,在HLA-B*13:01抗原肽中,RQDDPSYRST(Q-F,即P2位为Q,PΩ位为F,下同)、AGDGTFQKW(G-W)、ALLNLAERL(L-L)、KLYEEKTGNAW(L-W)、 LFDHAVSKF(F-F)、RMDEEFTKI(M-I)和FLSKIEEKLT(L-T)等与HLA-B*13：01结合力较高,结合力分别为54%、50%、45%、44%、36%、36%和32%；在HLA-B*13:02抗原肽中,KLKGEENTV(L-V)的结合力较高,结合力达到73%。在抗原肽特异性交叉验证中,HLA-B*13:01抗原肽Q-F和G-W与HLA-B*13:01的结合力分别为54%和50%,但与HLA-B*13:02的结合力分别下降到24%和0.09%,提示这两条抗原肽是HLA-B*13:01的特异性抗原肽；在HLA-B*13:02抗原肽中,L-V与HLA-B*13:02的结合力为73%,但与HLA-B*13:01的结合力下降到27%,提示L-V是HLA-B*13:02的特异性抗原肽。(三)TCE/TCOH对HLA-B分子结合抗原肽的影响：研究发现TCE可以明显降低Q-F、L-T和G-W等抗原肽与HLA-B*13:01的结合力,它们与HLA-B*13:01的结合力分别为54%、32%和50%,经TCE处理后,其结合力分别下降为11%、11%和32%,降低值分别为43%、21%和18%。Q-F这条抗原肽与HLA-B*13:01结合受TCE影响最大。TCOH使Q-F和L-W与HLA-B*13:01的结合力分别由54%和44%降低到43%和33%,降低值分别为11%和11%。但是TCE/TCOH对抗原肽与HLA-B*13:02的结合力并不产生影响。以上结果提示TCE确实可以通过HLA-B*13:01提呈的特异性抗原肽介导疾病的发生。综上所述,本研究得出以下结论：(1)研究发现HLA-B*13:01与HLA-B*13:02提呈抗原肽的差别主要在于抗原肽的PΩ位氨基酸,而该位点氨基酸主要结合于HLA-B分子的F口袋,提示TCE药疹样皮炎的发生与HLA-B*13:01分子F口袋的结构特异性有关；(2)TCE和TCOH可以影响某些抗原肽与HLA-B*13:01的结合,使HLA-B*13:01对所结合的抗原肽的偏好发生改变,而不改变抗原肽与HLA-B*13:02的结合,这与HLA-B*13:02基因与TCE药疹样皮炎无关联的结果相吻合。当抗原肽PQ位氨基酸为F(苯丙氨酸)时,其与HLA-B*13:01的结合受TCE和TCOH的影响最大,提示TCE或TCOH可以改变HLA-B*13:01抗原肽的结构特征,通过提呈致病性抗原肽,进一步引起机体免疫应答。本研究从HLA分子功能角度阐述了HLA-B*13:01与疾病关联的分子机制,不仅丰富了国际抗原肽谱的数据库,而且为进一步研究TCE药疹样皮炎的发病机制提供了实验依据。
[Abstract]:Drug Eruption-like dermatitis caused by occupational exposure to trichloroethylene (TCE) is an important problem that seriously affects the health of workers in southeastern coastal areas of China. TCE drug Eruption-like dermatitis is an autoimmune disease caused by environmental and genetic factors. It is associated with human leukocyte antigen (HLA). HLA-B*13:01 allele was found to be strongly associated with TCE drug Eruption-like pathogenesis. HLA-B*13:01 may play an important role in the pathogenesis of TCE drug Eruption-like dermatitis. Molecules have obvious polymorphism and their main function is to present and process antigens. In the immune response, HLA-antigen peptide complexes are formed to present antigens specifically to T cell receptors, thereby activating T cells and initiating immune responses. Therefore, we propose the following hypothesis: HLA-B*13:01 molecules participate in TC by presenting specific antigen peptides. To validate this hypothesis, we designed the following protocols: (1) HLA-B*13:02 was selected as the control to analyze the specificity of HLA-B*13:01 antigen-presenting peptides and their relationship with the pathogenesis of the disease. There was no significant association between HLA-B*13:01 binding antigen peptide and TCE Eruption-like dermatitis, so HLA-B*13:02 antigen peptide could be used as a control group. (2) HLA-B*13:01 and HLA-B*13:02 B mother cells HMy2.C1R cell lines were constructed to express HLA-B*13:01 and HLA-B*13:02. The purified peptide was obtained by acid dissociation and molecular sieve filtration. The primary structure of the peptide was separated and determined by RP-HPLC-MS. The primary structure of the peptide was compared between HLA-B*13:01 and HLA-B*13:02, and the common motif of the peptide was analyzed. The key anchoring sites for binding of antigenic peptides to HLA molecules, i.e. the second position 2 (P2) and the carboxyl terminal (P_) of antigenic peptides, occur at high frequencies. Different types of antigenic peptides of HLA-B*13:01/HLA-B*13:02 were synthesized to verify the binding ability of these antigenic peptides to HLA.B molecules. TCE and trichloroethanol (TCO) were also observed. The results are as follows: (1) Structural analysis of HLA-binding antigen peptides: 57 HLA-B*13:01 antigen peptides and 88 HLA-B*13:02 antigen peptides were obtained in this study. The frequencies of amino acids were 39% and 33% for leucine (L) and glutamine (Q), 35% for P_, 15% for phenylalanine (F), and 11% for tryptophan (W), respectively. Among 02 antigen peptides, P2 anchored amino acids were Q (26%) and L (16%); P_anchored amino acids were L (26%), Valine (21%) and I (14%). Compared with HLA-B*13:01 and HLA-B*13:02 antigen peptides P2 and P_anchored amino acids, the anchored amino acids at P2 were both L and Q, and there were differences between them except L, HLA-B*13:01 antigen peptides. The preponderant amino acids at position P_include F, W and I, while HLA-B * 13:02 is V and I. HLA-B * 13:01 and HLA-B * 13:02 are only at position 94 (I, HLA-B * 13:01; T, HLA-B * 13:02). The preponderant amino acids at position 95 (I, HLA-B * 13:01; W, HLA-B * 13:02) and 97 (R, HLA-B * 13:01; T, HLA-B * 13:02) are different from those at position 97 (R, HLA-B * 13:01; T, HLA-B * 13:02). The shape and characteristics of F pocket determine the type of amino acid side chain of antigenic peptides bound to P_site. It is suggested that the difference between HLA-B * 13:01 and HLA-B * 13:02 antigenic peptides in PQ site is related to the molecular structure of HLA molecules involved in forming F pocket. Functional analysis of peptides: HLA-B*13:01 antipeptide binding assay showed that in HLA-B*13:01 antipeptide, RQDDDPSYRST (Q-F, P2 Q Q, P2 Q, P96position F, the same below), AGDGTFQKW (G-W), ALLNLAERL (L-L), KLYEEKTGNAW (L-W), LFDHAVSKF (DEF-F), RMEFTKI (M-I) and FLSKIEKLT (L-L T) and HLA-B*13:15:15:45% of the binding power of RQA-B*15:45%, respectively, the binding power of LFDDDDDDDDDDDDDDDDDDDDDPSSYSYRSSY44% Among the HLA-B*13:02 antigenic peptides, the binding power of KLKGEENTV (L-V) was higher and reached 73%. In the cross-validation of antigenic peptide specificity, the binding power of HLA-B*13:01 antigenic peptide Q-F and G-W to HLA-B*13:01 were 54%, 36% and 32%, respectively, but the binding power to HLA-B*13:02 decreased to 24% and 0.09% respectively, suggesting that the two antigenic peptides were HLA-B*13:01 antigenic peptides. In HLA-B*13:02 antigen peptide, the binding force of L-V to HLA-B*13:02 antigen peptide was 73%, but that of L-V to HLA-B*13:01 decreased to 27%, suggesting that L-V is a specific antigen peptide of HLA-B*13:02. (3) The effect of TCE/TCOH on HLA-B binding antigen peptide: TCE can significantly reduce the binding ability of Q-F, L-T, G-W and other antigen peptides to HLA-B*13:02. The binding power of Q-F to HLA-B*13:01 decreased from 54%, 32% and 50% respectively. After TCE treatment, the binding power of Q-F to HLA-B*13:01 decreased from 54% and 44% to 43% and 33% respectively. The low values were 11% and 11%, respectively. However, TCE / TCOH had no effect on the binding ability of antigen peptides to HLA-B*13:02. These results suggest that TCE can indeed mediate the occurrence of diseases through HLA-B*13:01 specific antigen peptides. In conclusion, the following conclusions were drawn: (1) The difference between HLA-B*13:01 and HLA-B*13:02 antigen peptides was found. It is suggested that the occurrence of TCE eruption dermatitis is related to the structural specificity of HLA-B*13:01 molecular F pocket; (2) TCE and TCOH can influence the binding of some antigenic peptides to HLA-B*13:01, which makes HLA-B*13:01 preferred to binding antigenic peptides. The binding of HLA-B*13:02 antigen peptide to HLA-B*13:02 was not altered, which was consistent with the result that HLA-B*13:02 gene was not associated with TCE Eruption-like dermatitis. In this study, the molecular mechanism of HLA-B*13:01 associated with disease was elucidated from the molecular function of HLA, which not only enriched the database of international antigen peptide spectrum, but also provided experimental basis for further study on the pathogenesis of TCE drug Eruption-like dermatitis.
【学位授予单位】：中国疾病预防控制中心
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R135.7
本文编号：2215862
[Abstract]:Drug Eruption-like dermatitis caused by occupational exposure to trichloroethylene (TCE) is an important problem that seriously affects the health of workers in southeastern coastal areas of China. TCE drug Eruption-like dermatitis is an autoimmune disease caused by environmental and genetic factors. It is associated with human leukocyte antigen (HLA). HLA-B*13:01 allele was found to be strongly associated with TCE drug Eruption-like pathogenesis. HLA-B*13:01 may play an important role in the pathogenesis of TCE drug Eruption-like dermatitis. Molecules have obvious polymorphism and their main function is to present and process antigens. In the immune response, HLA-antigen peptide complexes are formed to present antigens specifically to T cell receptors, thereby activating T cells and initiating immune responses. Therefore, we propose the following hypothesis: HLA-B*13:01 molecules participate in TC by presenting specific antigen peptides. To validate this hypothesis, we designed the following protocols: (1) HLA-B*13:02 was selected as the control to analyze the specificity of HLA-B*13:01 antigen-presenting peptides and their relationship with the pathogenesis of the disease. There was no significant association between HLA-B*13:01 binding antigen peptide and TCE Eruption-like dermatitis, so HLA-B*13:02 antigen peptide could be used as a control group. (2) HLA-B*13:01 and HLA-B*13:02 B mother cells HMy2.C1R cell lines were constructed to express HLA-B*13:01 and HLA-B*13:02. The purified peptide was obtained by acid dissociation and molecular sieve filtration. The primary structure of the peptide was separated and determined by RP-HPLC-MS. The primary structure of the peptide was compared between HLA-B*13:01 and HLA-B*13:02, and the common motif of the peptide was analyzed. The key anchoring sites for binding of antigenic peptides to HLA molecules, i.e. the second position 2 (P2) and the carboxyl terminal (P_) of antigenic peptides, occur at high frequencies. Different types of antigenic peptides of HLA-B*13:01/HLA-B*13:02 were synthesized to verify the binding ability of these antigenic peptides to HLA.B molecules. TCE and trichloroethanol (TCO) were also observed. The results are as follows: (1) Structural analysis of HLA-binding antigen peptides: 57 HLA-B*13:01 antigen peptides and 88 HLA-B*13:02 antigen peptides were obtained in this study. The frequencies of amino acids were 39% and 33% for leucine (L) and glutamine (Q), 35% for P_, 15% for phenylalanine (F), and 11% for tryptophan (W), respectively. Among 02 antigen peptides, P2 anchored amino acids were Q (26%) and L (16%); P_anchored amino acids were L (26%), Valine (21%) and I (14%). Compared with HLA-B*13:01 and HLA-B*13:02 antigen peptides P2 and P_anchored amino acids, the anchored amino acids at P2 were both L and Q, and there were differences between them except L, HLA-B*13:01 antigen peptides. The preponderant amino acids at position P_include F, W and I, while HLA-B * 13:02 is V and I. HLA-B * 13:01 and HLA-B * 13:02 are only at position 94 (I, HLA-B * 13:01; T, HLA-B * 13:02). The preponderant amino acids at position 95 (I, HLA-B * 13:01; W, HLA-B * 13:02) and 97 (R, HLA-B * 13:01; T, HLA-B * 13:02) are different from those at position 97 (R, HLA-B * 13:01; T, HLA-B * 13:02). The shape and characteristics of F pocket determine the type of amino acid side chain of antigenic peptides bound to P_site. It is suggested that the difference between HLA-B * 13:01 and HLA-B * 13:02 antigenic peptides in PQ site is related to the molecular structure of HLA molecules involved in forming F pocket. Functional analysis of peptides: HLA-B*13:01 antipeptide binding assay showed that in HLA-B*13:01 antipeptide, RQDDDPSYRST (Q-F, P2 Q Q, P2 Q, P96position F, the same below), AGDGTFQKW (G-W), ALLNLAERL (L-L), KLYEEKTGNAW (L-W), LFDHAVSKF (DEF-F), RMEFTKI (M-I) and FLSKIEKLT (L-L T) and HLA-B*13:15:15:45% of the binding power of RQA-B*15:45%, respectively, the binding power of LFDDDDDDDDDDDDDDDDDDDDDPSSYSYRSSY44% Among the HLA-B*13:02 antigenic peptides, the binding power of KLKGEENTV (L-V) was higher and reached 73%. In the cross-validation of antigenic peptide specificity, the binding power of HLA-B*13:01 antigenic peptide Q-F and G-W to HLA-B*13:01 were 54%, 36% and 32%, respectively, but the binding power to HLA-B*13:02 decreased to 24% and 0.09% respectively, suggesting that the two antigenic peptides were HLA-B*13:01 antigenic peptides. In HLA-B*13:02 antigen peptide, the binding force of L-V to HLA-B*13:02 antigen peptide was 73%, but that of L-V to HLA-B*13:01 decreased to 27%, suggesting that L-V is a specific antigen peptide of HLA-B*13:02. (3) The effect of TCE/TCOH on HLA-B binding antigen peptide: TCE can significantly reduce the binding ability of Q-F, L-T, G-W and other antigen peptides to HLA-B*13:02. The binding power of Q-F to HLA-B*13:01 decreased from 54%, 32% and 50% respectively. After TCE treatment, the binding power of Q-F to HLA-B*13:01 decreased from 54% and 44% to 43% and 33% respectively. The low values were 11% and 11%, respectively. However, TCE / TCOH had no effect on the binding ability of antigen peptides to HLA-B*13:02. These results suggest that TCE can indeed mediate the occurrence of diseases through HLA-B*13:01 specific antigen peptides. In conclusion, the following conclusions were drawn: (1) The difference between HLA-B*13:01 and HLA-B*13:02 antigen peptides was found. It is suggested that the occurrence of TCE eruption dermatitis is related to the structural specificity of HLA-B*13:01 molecular F pocket; (2) TCE and TCOH can influence the binding of some antigenic peptides to HLA-B*13:01, which makes HLA-B*13:01 preferred to binding antigenic peptides. The binding of HLA-B*13:02 antigen peptide to HLA-B*13:02 was not altered, which was consistent with the result that HLA-B*13:02 gene was not associated with TCE Eruption-like dermatitis. In this study, the molecular mechanism of HLA-B*13:01 associated with disease was elucidated from the molecular function of HLA, which not only enriched the database of international antigen peptide spectrum, but also provided experimental basis for further study on the pathogenesis of TCE drug Eruption-like dermatitis.
【学位授予单位】：中国疾病预防控制中心
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R135.7
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