| Co-Investigator(Kenkyū-buntansha) |
SENJU Satoru DIV. IMMUNOGENET., DEPT. NEUROSCI. & IMMUNOL., KUMAMOTO UNIV. SCHL. MED., RES. ASSOCIATE, 大学院・医学研究科, 助手 (50274709)
MATSUSHITA Sho DIV. IMMUNOGENET., DEPT. NEUROSCI. & IMMUNOL., KUMAMOTO UNIV. SCHL. MED., ASSOCIATE PROFESSOR, 大学院・医学研究科, 助教授 (50167649)
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| Research Abstract |
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
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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
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