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

HLA Class II分子影响肽绑定到HLA Class II分子和susceptibility to多种自动免疫疾病的多态性。一些自动免疫疾病包括胰岛素依赖糖尿病（IDDM）、infant-onset myasthenia gravis、optico-spinal （亚洲）型多表型（MS）和反磷脂综合征与HLA第II类等位基因有关，这些疾病与亚洲人在日本人口中的独特性有关，并在其他族裔中展示了一些独特的临床指示，与那些观察到的独特性差异。在这项研究中，we identified HLA-DPB1-D1*-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-D1g7-D156-D1His D157-D1Ser unique to IDDM-susceptible NOD mouse and mutated I-A型D1 g7型D1型D156型D1 Pro型D157型D1 Asp which is not associated with susceptible to IDDM。在特定HLA类别I之间的关联方面有更好的理解机制 ... More 我的神经过敏和自动免疫疾病，这是很重要的，以识别由疾病可怀疑的HLA类II分子和触发疾病导致的自动T细胞所呈现的自我肽。为了这个目标，我们产生了T细胞克隆人对自动抗原反应，有人建议触发这些自动免疫疾病的发展。我们已确定了一些由疾病可推定HLA第II类分子限制的自动活性T细胞克隆，但许多其他的自动活性T细胞克隆被其他HLA第II类分子限制，并被特定的多样性自动抗原肽指示在这些自动免疫疾病中传播的异常。Furthermore，我们已经确定了许多，关于携带自动抗肽的单一安置替代品的模拟，这些替代品可以抑制自动T细胞克隆体的积极反应。我们还生成了一个cDNA表达载体，其中可以有效地传递肽到HLA DR介导的抗原表达途径，通过利用突变变异链在CLIP区域中被替代为其他肽。这将有可能在HLA-DR分子的上下文中生成细胞库表达肽的多样性阵列，并将用于标识T细胞受体的未知特性、其多样性和微自肽触发自动T细胞的自动T细胞。Less（低）

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