Identification and characterization of T cell epitope in primary biliary cirrhosis
原发性胆汁性肝硬化 T 细胞表位的鉴定和表征
基本信息
- 批准号:11694287
- 负责人:
- 金额:$ 5.12万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:1999
- 资助国家:日本
- 起止时间:1999 至 2001
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
In patients with primary biliary cirrhosis (PBC), the anti-mitochondrial antibody response is primarily directed against E2 components of the pyruvate dehydrogenase complex (PDC-E2), 2-oxoglutarate dehydrogenase complex (OGDC-E2), the branched chain 2 oxo-acid dehydrogenase complex (BCOADC-E2), and the E3 binding protein (E3BP) of PDC. We have previously demonstrated that the PDC-E2 163-176 peptide (GDLLAEIETDKATI) is the immunodominant autoreactive T cell epitope which is restricted by HLA DR53 (DRA1^*0101/DRB4^*0101). To address the issue of molecular mimicry and cross-recognition among mitochondrial antigens, we analyzed the reactivity to a series of single amino acid substituted peptides of ten cloned T cell lines derived from both healthy subjects and patients with PBC which recognize a single T cell receptor (TCR) ligand, PDC-E2 163-176 peptide/HLA DR53. In addition, we performed antagonism and agonism assays using analogue peptides to determine the most critical TCR contact resi … More due(s). Our data demonstrate that the overall fine specificities are unique for every single T cell clone but that these T cell clones are roughly categorized into two distinct groups based on their recognition motifs of TCR ligand ; the ^<170>ExDK^<173> (group A) and the ^<168>EIExD^<172> (group B). ^<170>E is the most critical TCR contact residue for both groups of cloned T cell lines whereas ^<173>K and ^<168>E are critical TCR contact residues for group A and group B cloned T cell lines, respectively. Importantly, both group A and group B T cell clones were established from the peripheral blood of both patients with PBC and healthy subjects. Most importantly, some of the group A cloned T cell lines cross-react to human E3BP 34-47, human OGDC-E2 100-113, and several peptides derived from various microbial proteins carrying an ExDK motif, while group B cloned T cell lines react only to E3BP 34-47 carrying an EIExD motif. Furthermore, an RGxG motif was exclusively found in the complementarity determining region (CDR3) of the TCR Vβ in the group B cloned T cell lines, while G, S, and/or R were frequently found in the CDR3 of the TCR Vβ in the group A cloned T cell lines. These data may provide a molecular basis for understanding molecular mimicry and cross-recognition among mitochondrial antigens in PBC. Less
在原发性胆汁性肝硬化(PBC)患者中,抗线粒体抗体应答主要针对丙酮酸脱氢酶复合物(PDC-E2)、2-酮戊二酸脱氢酶复合物(OGDC-E2)、支链2-氧代酸脱氢酶复合物(BCOADC-E2)和PDC的E3结合蛋白(E3 BP)的E2组分。我们先前已经证明PDC-E2 163-176肽(GDLLAEIETDKATI)是受HLA DR 53(DRA 1 ^*0101/DRB 4 ^*0101)限制的免疫显性自身反应性T细胞表位。为了解决线粒体抗原之间的分子模拟和交叉识别的问题,我们分析了对来自健康受试者和PBC患者的10个克隆T细胞系的一系列单个氨基酸取代肽的反应性,所述T细胞系识别单个T细胞受体(TCR)配体,PDC-E2 163-176肽/HLA DR 53。此外,我们使用类似肽进行了拮抗和激动试验,以确定最关键的TCR接触抗性。 ...更多信息 到期。我们的数据表明,对于每个单个T细胞克隆,总体精细特异性是独特的,但是这些T细胞克隆基于它们的TCR配体的识别基序大致分为两个不同的组;^<170>ExDK^<173>(组A)和^<168>EIExD^<172>(组B)。对于<170>两组克隆的T细胞系,β E是最关键的TCR接触残基,而<173><168>对于A组和B组克隆的T细胞系,β K和β E分别是关键的TCR接触残基。重要的是,A组和B组T细胞克隆都是从PBC患者和健康受试者的外周血中建立的。最重要的是,一些A组克隆的T细胞系与人E3 BP 34-47、人OGDC-E2 100-113和衍生自携带ExDK基序的各种微生物蛋白的几种肽交叉反应,而B组克隆的T细胞系仅与携带EIExD基序的E3 BP 34-47反应。此外,在B组克隆的T细胞系中,仅在TCR Vβ的互补决定区(CDR 3)中发现RGxG基序,而在A组克隆的T细胞系中,在TCR Vβ的CDR 3中经常发现G、S和/或R。这些数据可能为理解PBC中线粒体抗原之间的分子模拟和交叉识别提供了分子基础。少
项目成果
期刊论文数量(53)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Shigematsu, H., Shimoda, S., Nakamura, M., et al.: "Fine specificity of T cells reactive to human PDC-E2 163-176 peptide. the immunodominant autoantigen in primary biliary cirrhosis : Implications for molecular mimicry and cross-recognition among mitochon
Shigematsu, H.、Shimoda, S.、Nakamura, M. 等人:“T 细胞对人 PDC-E2 163-176 肽反应的精细特异性。原发性胆汁性肝硬化中的免疫显性自身抗原:对分子拟态和交叉的影响
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Fukushima, N., Ikematsu, H., Nakamura, M., Matsui, M., Shimoda, S., Hayashida, K., Niho, Y., Koike, K., Gershwin, M.E., Ishibashi, H.: "Nucleotide variations amongst VH genes of AMA-producing B cell clones in primary biliary cirrhosis"J Autoimmunity. 14(3
福岛 N.、池松 H.、中村 M.、松井 M.、下田 S.、林田 K.、二穗 Y.、小池 K.、格什温 M.E、石桥 H.:“
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Ishibashi,H.,et al: "自己抗体と自己免疫Autoantibodies and Autoimmunity'99"山本一彦,高崎芳成,三森経世,Jack D Keene. 55 (1999)
Ishibashi, H. 等人:“自身抗体和自身免疫99”Kazuhiko Yamamoto、Yoshinari Takasaki、Keiyo Mimori、Jack D Keene 55 (1999)。
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Shimoda, S., Nakamura, M., Shigematsu, H., Tanimoto, H., Gushima, T., Gershwin, M.E., Ishibashi, H.: "Mimicry peptides of human PDC-E2 163-176 peptide, the immunodominant T-cell epitope of primary biliary cirrhosis"Hepatology. 31(6). 1212-1216 (2000)
Shimoda, S.、Nakamura, M.、Shigematsu, H.、Tanimoto, H.、Gushima, T.、Gershwin, M.E.、Ishibashi, H.:“人 PDC-E2 163-176 肽的模拟肽,免疫显性 T
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Van de Water J, Ishibashi H, Coppel RL, Gershwin ME: "Molecular mimicry and primary biliary cirrhosis : Premises not promises"Hepatology. 33(4). 771-775 (2001)
Van de Water J、Ishibashi H、Coppel RL、Gershwin ME:“分子拟态和原发性胆汁性肝硬化:前提不承诺”肝病学。
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NAKAMURA Minoru其他文献
Identification of the casual variants in human primary biliary cirrhosis (PBC) by the combination of a genome-wide association study, Whole-genome sequencing, and in silico/ in vitro functional analyses.
通过结合全基因组关联研究、全基因组测序和计算机/体外功能分析,鉴定人类原发性胆汁性肝硬化 (PBC) 的偶然变异。
- DOI:
- 发表时间:
2016 - 期刊:
- 影响因子:0
- 作者:
HITOMI Yuki;AIBA Yoshihiro;YASUNAMI Michio;NAKAMURA Minoru;TOKUNAGA Katsushi. - 通讯作者:
TOKUNAGA Katsushi.
NAKAMURA Minoru的其他文献
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{{ truncateString('NAKAMURA Minoru', 18)}}的其他基金
Genome-wide associationstudy to detect disease-associated genes in Japanese patients with primary biliary cirrhosis
全基因组关联研究检测日本原发性胆汁性肝硬化患者的疾病相关基因
- 批准号:
23591006 - 财政年份:2011
- 资助金额:
$ 5.12万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
New clinical classification and the criteria for predicting long-term outcome in primary biliary cirrhosis
原发性胆汁性肝硬化的新临床分类和长期结局预测标准
- 批准号:
20590800 - 财政年份:2008
- 资助金额:
$ 5.12万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new molecular targets and the study for the mechanism of bile ducts-and hepatocyte-destruction in primary biliary cirrhosis
原发性胆汁性肝硬化新分子靶点的鉴定及胆管和肝细胞破坏的机制研究
- 批准号:
17590696 - 财政年份:2005
- 资助金额:
$ 5.12万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Construction of antibody-library to identify etiology-associated-antigen
构建抗体库来鉴定病因相关抗原
- 批准号:
15591075 - 财政年份:2003
- 资助金额:
$ 5.12万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
FUNCTIONAL AND DNA ALALYSIS OF THE NOVEL PROTEIN (R21 PROTEIN) INVOLVED IN MEMBRANE FUSION
参与膜融合的新型蛋白质(R21 蛋白质)的功能和 DNA 分析
- 批准号:
10670416 - 财政年份:1998
- 资助金额:
$ 5.12万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of HTLV-1 neutralizing epitopes and the development of an HTLV-1 peptide based vaccine
HTLV-1 中和表位的鉴定以及基于 HTLV-1 肽的疫苗的开发
- 批准号:
04670391 - 财政年份:1992
- 资助金额:
$ 5.12万 - 项目类别:
Grant-in-Aid for General Scientific Research (C)
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