IDENTIFICATION AND PREDICTION OF T-CELL EPITOPES BY USING HLA CLASS II-BINDING PEPTIDE MOTIFS

MHC II类分子的晶体结构的知识的最新进展已经推进了对肽和HLA II类分子之间相互作用的分子基础的理解。HLA II类分子的多态性影响与HLA II类分子结合的肽的结构。为了阐明特定HLA II类等位基因与自身免疫性疾病易感性之间统计相关性的机制，重要的是识别由疾病易感的HLA II类分子呈现并触发致病自身反应性T细胞的自身肽。在本研究中，我们试图找出触发自身免疫性疾病，包括类风湿性关节炎，胰岛素自身免疫综合征，胰岛素依赖型糖尿病和婴儿型重症肌无力的自身肽。已知日本人群对所有这些疾病的易感性与亚洲人特有的特定HLA-DR-DQ单倍型以及其中一些疾病的临床特征密切相关。 ...更多信息 高加索人和亚洲人包括日本人的情况不同。我们研究了疾病易感和非易感HLA II类分子之间结合肽基序的差异，并预测了携带疾病易感HLA II类分子结合基序的自身免疫自身肽的候选者。事实上，通过这种策略成功地鉴定了胰岛素自身反应性CD 4 ^+T细胞的主要表位。我们还发现西方型和亚洲型多发性硬化症之间的免疫遗传背景的异质性。我们的数据表明，我们的策略是有用的，以确定自身免疫性自身肽，这表明，不仅疾病易感的HLA II类，但也引起疾病的自身肽是不同的高加索人和亚洲人之间。这些差异很可能与两个民族之间疾病的不同临床表现有关。最近发现T细胞对抗原的反应不是一个开/关现象，并且在小鼠中报道了T细胞对改变的肽配体的反应改变。我们研究了对非自身肽特异性的人T细胞克隆对大量类似肽的反应，以发现T细胞反应的频繁改变。这种改变的人T细胞应答的基本知识可能有助于通过改变的人致病性自身反应性T细胞应答的肽配体进行操纵。少

Recent advances in knowledge of crystal structures of MHC class II molecules has advanced understanding of the molecular basis for interactions between peptides and HLA class II molecules. Polymorphism of HLA class II molecules influences structures of peptides bound to HLA class II molecules. To elucidate mechanisms for statistical association between particular HLA class II alleles and susceptibility to autoimmune diseases, it is important to identify self peptides presented by disease-susceptible HLA class II molecules and triggering disease-causative autoreactive T cells. In this study, we tryed to identify self-peptides triggering autoimmune diseases including rheumatoid arthritis, insulin autoimmune syndrome, insulin dependent diabetes mellitus and infant-onset myasthenia gravis. Susceptibility to all of these diseases in the Japanese population are known to be strongly associated with particular HLA-DR-DQ haplotypes unique to Asians, and clinical features of some of these diseas … More es are different between Caucasians and Asians including Japanese. We investigated differences in binding-peptide motifs between disease susceptible and non-susceptible HLA class II molecules and predicted candidates of autoimmune self-peptides carrying binding-motifs to disease-susceptible HLA class II molecules. Indeed the major epitope for insulin-autoreactive CD4^+T cell was successfully identified by this strategy. We also found heterogeneity in immunogenetic background between Western type and Asian type of multiple sclerosis. Our data indicated that our strategy is useful to identify autoimmune self-peptides, and it is suggested that not only disease-susceptible HLA class II but also self-peptides causing diseases are different between Caucasians and Asians. These differences may well correlate to different clinical manifestations of diseases between the two ethnic groups. Recently it was found that T cell respose to antigen was not an on/off phenomenon, and altered T cell responses to altered peptide ligands were reported in mouse. We investigated responses of human T cell clones specific to non-self peptides to large panels of analogue peptides to find frequent alterations of T cell responses. This basic knowledg of altered human T cell responses may be useful for manipulation by altered peptide ligands of human pathogenic autoreactive T cell responses. Less