Analysis of TCR/HLA/ peptide interaction and investigation of etiology of autoimmune diseases

TCR/HLA/肽相互作用分析及自身免疫性疾病病因学研究

基本信息

批准号：
11694294
负责人：
NISHIMURA Yasuharu
金额：
$ 6.25万
依托单位：
KUMAMOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
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：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11694294/
关键词：
Autoimmune diseases Molecular mimicry Type I diabetes Vogt-Koyanagi-Harada disease Autoreactive CD4^+ T cells Expression cloning of T cell epitopes HLA class II T cell response 感染性微生物グルタミン酸脱炭酸酵素65 MHCクラスII分子発現クローニング Vogt-小柳-原田病 /

项目摘要

In the previous studies, we discovered assedations between specific HLA class II alleles and susceptibility to autoimmune diseases, and examined binding peptide motifs of disease-associated HLA class II molecules. In this study, to clarify the mechanisms of the disease-association of specific HLA alleles, we carried out the following researches. Identification of self peptides recognized by disease-related autoreactive T cell clones. We established many auto-antigen specific CD4^+ T cell clones from Asian type multiple sclerosis (MS) and anti-phosopholipid antibody syndrome (APS) patients. We identified many epitopes derived from self antigens and restricting HLA class II molecules, and examined the cytokines produced by the T cell clones. In addition, we searched for the target autoantigen of Vogt -Koyanagi-Harada disease (VKH), an autoimmune diseas e in which inflammatory disorders occur in multiple organs containing melanocytes. By SEREX method, we identified LEDGF (Lens Epithelial … More Cel l Derived Growth Factor) and UACA (Uveal Autoantigen with Coiled coil domains and Ankyrin repeats) as candidates for the target antigen. 2) Establishment of a method to identify cross-reactive epitopes recognized by disease-related autoreactive T cells.We established an expression cloning system to identify epitopes for CD4^+ T cell clones. Using this system, we examined the pattern of epitopes cross-recognized by two CD4^+ T cell clones established from Type I diabetes patients and specific to glutamate decarboxylase 65 (GAD65). Based on this information, we identified several mimicry epitopes of microbial antigen origin. 3) Analysis of T cell response induced by analogues of agonistic epilopes.We generated series of L cell transfectants expressing complexes of HLA-DR4 (DRB1^*0406) and agonist or partial agonist peptides in various densities. Using the transfectants, we discovered that a certain partial agonist peptide, when presented in a very high density, can induce T cell response in a similar magnitude as a full agonist peptide, andthat the T cell response is not accompanied by phosphorylation of ZAP-70 and LAT. We identified unique profiles of produced cytokines, down-modulation of TCR, and intracellular signaling events associated with this unique T cell response. Less

在先前的研究中，我们发现了特定的HLA II类动物和自身免疫性的敏感性，并在本研究中分离的HLA II类分子的肽基序。 - 自动反应性T克隆表位DERF抗原和限制性HLA II分子E t -cell克隆质量…更多的cel l衍生生长因子）和UACA（带盘绕的螺旋域和脚踝重复的紫抗体自动抗原）作为靶抗原的候选物。融合了一个表达克隆系统，以鉴定由CD4^+ T细胞克隆的表达式。将微生物抗原起源的几个模拟表位分析。当认证的肽中，在类似的幅度中，通过phoss phoss phoss phoss phoss phoss。用唯一的t响应进行腹置。