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Molecular mechanism of immune response requlated by HLA

HLA调节免疫反应的分子机制

基本信息

批准号：
05044177
负责人：
SASAZUKI Takehiko
金额：
$ 8.32万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1995
项目状态：
已结题

项目摘要

To investigate the molecular mechanism of immune response regulated by HLA,we investigated the T cell epitopes on HBs Ag, Cryptomeria Ag and HLA bound peptides eluted from HLA-A2, subtypes and HLA-B27 subtypes. Two antigenic T cell epitopes of Hepatitis B surface antigen (HBsAg), designated as HBs16-31 and HBs81-99, were identified.HBs16-31 was recognized by five HBsAg specific T cell lines from vaccinees with both high and low antibody titers, whereas HBs81-99 was recognized by two T cell lines derived from vaccinees with high antibody titers, suggesting taht HBs81-99 plays a critical role in anti-HBs antibody production in humans vaccinated with HBsAg. Japanese cedar pollinosis is a type I allergic disease caused by Japanese cedar (Cryptomeria japonica) pollen. The frequency of HLA-DP5 (DPA1^<**>02022 and DPB1^<**>0501) was significantly increased in the patients with Japanese cedar pollinosis. Using CPAg-specific T cell lines, we found that disease-associated HLA-DP5 restricted T ce … More lls specific for CPAg existed in the patients. Furthermore, an immunodominant peptide which induced HLA-DP5 restricted Th2 was identified. These observations suggest that the HLA-DP5 may be at least in part involved in the pathogenesis, by helping the IgE antibody production against CPAg. To investigate how single amino acid substitutions in MHC class I molecules affect differences in peptide repertoires, we cluted and sequenced the naturally processed peptides from three HLA-A2 subtypes (HLA-A^<**>0204, -A^<**>0206 and -A^<**>0207) which differ by a single amino acid residue substitution each with -A^<**>0201 at the floor of the binding groove. Allele-specific peptide-motifs for each HLA-A2 subtype substantially differed from that of -A^<**>0201 in the dominant anchor residues. The relative signal intensities for eighteen self peptides determined by mass spectrometry precisely reflected these peptide-motifs. According to the models, the differences in peptide-motifs could be explained by substituted-residue-driven conformational changes for each MHC-peptide complex. These results demonstrate the fine differences among HLA-A2 subtype self peptide repertoires and contribute to the prediction of antigenic peptides. Less

为了研究HLA调控免疫应答的分子机制，我们研究了从HLA- a2、亚型和HLA- b27亚型中洗脱的HBs Ag、Cryptomeria Ag和HLA结合肽上的T细胞表位。鉴定出乙型肝炎表面抗原（HBsAg）的两个抗原T细胞表位，分别为HBs16-31和HBs81-99。HBs16-31被来自高抗体滴度和低抗体滴度疫苗的5种HBsAg特异性T细胞系识别，而HBs81-99则被来自高抗体滴度疫苗的2种T细胞系识别，这表明HBs81-99在HBsAg疫苗接种人的抗hbs抗体产生中起关键作用。杉木花粉病是由杉木（Cryptomeria japonica）花粉引起的I型过敏性疾病。杉木花粉症患者HLA-DP5 （DPA1^<**>02022和DPB1^<**>0501）的频率显著升高。使用CPAg特异性T细胞系，我们发现疾病相关的HLA-DP5限制了T细胞的表达，患者体内存在更多CPAg特异性细胞。此外，还鉴定了一种诱导HLA-DP5限制性Th2的免疫优势肽。这些观察结果表明，HLA-DP5可能通过帮助产生针对CPAg的IgE抗体，至少部分参与了发病机制。为了研究MHC I类分子中单个氨基酸替换如何影响肽库的差异，我们对来自三种HLA-A2亚型（HLA-A^<**>0204, -A^<**>0206和-A^<**>0207）的天然加工肽进行了聚类和测序，这三种亚型在结合槽底部分别与-A^<**>0201进行了单个氨基酸残基替换。每个HLA-A2亚型的等位基因特异性肽基序在显性锚定残基上与-A^<**>0201有很大差异。质谱法测定的18种自肽的相对信号强度准确地反映了这些肽基序。根据这些模型，肽基的差异可以用取代残基驱动的构象变化来解释每个mhc肽复合物。这些结果证明了HLA-A2亚型自身肽库之间的细微差异，并有助于预测抗原肽。少