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ANALYSIS OF AUTOANTIGENIC PEPTIDE-HLA CLASS II COMPLEXES ASSOCIATED WITH AUTOIMMUNE DISEASES

与自身免疫性疾病相关的自身抗原肽-HLA II 类复合物的分析

基本信息

批准号：
09470097
负责人：
NISHIMURA Yasuharu
金额：
$ 7.17万
依托单位：
KUMAMOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

Polymorphism of HLA class II molecules influences structures of peptides bound to HLA class II molecules and susceptibility to many autoimmune diseases. Several autoimmune diseases including insulin-dependent diabetes mellitus (IDDM), infant-onset myasthenia gravis, optico-spinal (Asian) type multiple sclerosis (MS) and anti-phospholipid syndrome are associated with HLA class II alleles unique to Asians in the Japanese population, and some of them exhibits unique clinical manifestations different from those observed in other ethnic groups. In this study, we identified HLA-DPB1ィイD1*ィエD10501 as a disease-susceptibility gene for optico-spinal (Asian) type MS. We also found that the peptide-binding motifs are different between mouse I-AィイD1g7ィエD1βィイD156ィエD1His ィイD157ィエD1Ser unique to IDDM-susceptible NOD mouse and mutated I-AィイD1g7ィエD1 βィイD156ィエD1ProィイD157ィエD1Asp which is not associated with susceptible to IDDM. To better understand mechanisms for association between particular HLA class I … More I alleles and autoimmune diseases, it is important to identify self peptides presented by disease-susceptible HLA class II molecules and triggering disease-causative autoreactive T cells. For this aim, we generated T cell clones reactive to autoantigens which are suggested to trigger development of these autoimmune diseases. We established several autoreactive T cell clones restricted by disease-susceptible HLA class II molecules, but many other autoreactive T cell clones were restricted by other HLA class II molecules and specific to diverse autoantigenic peptides indicating that the epitope-spreading occurred in these autoimmune diseases. Furthermore, we identified many, analogues of an autoantigenic peptide carrying single residue substitutions which can inhibit proliferative response of the autoreactive T cell clone. We also generated a cDNA expression vector which can efficiently deliver peptides to HLA DR-mediated antigen presentation pathway by utilizing mutated invariant-chain in which CLIP-region is substituted for other peptides. It will be possible to generate a cell library expressing diverse array of peptides in the context of HLA-DR molecules, and this will be useful for identification of ligands for T cell receptor of unknown specificity, their diversity and mimicry non-self peptides triggering autoreactive T cells. Less

人类白细胞抗原II类分子的多态性会影响与人类白细胞抗原II类分子结合的多肽的结构，从而影响许多自身免疫性疾病的易感性。几种自身免疫性疾病，包括胰岛素依赖型糖尿病(IDDM)、婴儿起病的重症肌无力、视髓(亚洲)型多发性硬化症(MS)和抗磷脂综合征，在日本人群中与亚洲人特有的HLAII类等位基因相关，其中一些表现出不同于其他民族的独特临床表现。在本研究中，我们发现HLADPB1ィイD1g7ィエD1g7ィイD1g7ィエD1Pro D156βィイD156ィエD1HisィイD157ィエD1Ser是IDDM易感NOD小鼠所特有的，突变的I-AィイD1g7ィエD1ProβィイD156ィエD1ProィイD157ィエD1Asp与突变的I-A D1g7 D1g7βィイD156ィエD1ProィイD157ィエD1Asp的多肽结合基序也不同。为了更好地了解特定HLAI类…之间的关联机制对于更多的I等位基因和自身免疫性疾病，重要的是识别由疾病易感的HLAII类分子呈递的自体多肽，并触发致病的自身反应性T细胞。为此，我们产生了对自身抗原有反应的T细胞克隆，这被认为是触发这些自身免疫性疾病的发展的原因。我们建立了几个受疾病易感的HLAII类分子限制的自身反应性T细胞克隆，但许多其他自身反应性T细胞克隆受到其他HLAII类分子的限制，并对不同的自身抗原肽具有特异性，表明在这些自身免疫性疾病中存在表位扩散。此外，我们还鉴定了一种自身抗原肽的许多类似物，这种自身抗原肽携带单一残基取代，可以抑制自身反应性T细胞克隆的增殖反应。我们还利用突变的不变链，用片段替换其他多肽，构建了一种能够有效地将多肽运送到人类白细胞抗原DR介导的抗原递呈途径的c DNA表达载体。在人类白细胞抗原-DR分子的背景下建立表达多种多肽的细胞库是可能的，这将有助于识别未知特异性的T细胞受体的配体，它们的多样性和模拟触发自身反应性T细胞的非自身多肽。较少