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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470097/
• 关键词: Autoimmune diseases; HLA class II genes; Disease susceptibility; Autoreactive T cell; Autoantigenic peptides; HLA-binding motif; エピトープライブラリー; 抗リン脂質抗体症候群; SLE; β2-glycoproteinI; CD4^+T細胞; サイトカイン; クリプティックエピトープ; 多発性硬化症; 全身性エリテマトーデス; 自己抗原; インス

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

HLA II类分子的多态性影响与HLA II类分子结合的肽的结构和对许多自身免疫性疾病的易感性。包括胰岛素依赖型糖尿病（IDDM）、婴儿型重症肌无力、视脊髓（亚洲）型多发性硬化症（MS）和抗磷脂综合征在内的几种自身免疫性疾病与日本人群中亚洲人特有的HLA II类等位基因相关，其中一些疾病表现出与其他种族人群不同的独特临床表现。在本研究中，我们鉴定了HLA-DPB 1等位基因D10501是视脊髓型MS的一个易感基因。我们还发现小鼠I-A等位基因D1 g7等位基因D1 β等位基因D156等位基因D1 His等位基因D157等位基因D1 Ser与IDDM易感NOD小鼠特有的突变型I-A等位基因D1 g7等位基因D1β等位基因D156等位基因D1 His等位基因D157等位基因D1 Ser之间的肽结合基序不同。A β D1 g7 β D1 β D156 β D1 Pro β D157 β D1 Asp与IDDM易感性无关。为了更好地理解特定HLA I类之间的关联机制， ...更多信息 I等位基因和自身免疫性疾病，重要的是鉴定由疾病易感的HLA-II类分子呈递并触发致病性自身反应性T细胞的自身肽。为了这个目的，我们产生了对自身抗原有反应的T细胞克隆，这些自身抗原被认为是引发这些自身免疫性疾病的发展的原因。我们建立了几个自身反应性T细胞克隆的疾病易感的HLA II类分子的限制，但许多其他自身反应性T细胞克隆的其他HLA II类分子的限制和特定的不同的自身抗原肽，表明表位扩散发生在这些自身免疫性疾病。此外，我们确定了许多，类似物的自身抗原肽携带单残基取代，可以抑制自身反应性T细胞克隆的增殖反应。我们还产生了一个cDNA表达载体，它可以有效地提供肽的HLA DR介导的抗原呈递途径，通过利用突变的恒定链，其中CLIP区取代其他肽。在HLA-DR分子的背景下，将有可能产生表达多种肽阵列的细胞文库，并且这将用于鉴定未知特异性的T细胞受体的配体、其多样性和模拟触发自身反应性T细胞的非自身肽。少

项目成果

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西村 泰治: "分子予防医学「MHCとペプチド」"医学書院(東京). 12(324-335) (1999)

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Wakitani, S. et al.: "The relationship between HLA-DRB1 alleles and disease subsets of rheumatoid arthritis in Japanese." Brit. J. Rheumatol.36. 630-636 (1997)

Wakitani, S. 等人：“HLA-DRB1 等位基因与日本人类风湿性关节炎疾病亚型之间的关系。”

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