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

Polymorphism of HLA class II molecules influences structures of peptides bound to HLA class IIautoimmune diseases Several autoimmune diseases including . autoimmune diseases molecules and susceptibility to many autoimmune diseasesinsulin-dependent diabetes mellitus (IDDM), infant-onset myasthenia gravisoptico-spinal （Asian）类型multiple sclerosis (MS) and anti-phospholipid syndrome are associatedHLA class II alleles unique to Asians in the Japanese population，and some of他们exhibits unique clinical manifestations different from those observed in otherethnic groups. In this study，we identified HLA-DPB1 * D10501 as a disease-susceptibility gene for optico-spinal (Asian) type我们也曾发现peptide-binding motifs are different between mouseI-A D1g7 I-A D1β D156 I-A D1His I-A 157 I-A D1Ser unique to IDDM-susceptible NOD mouse and mutatedI-A - D1g7 - D1 - β - D156 - D1Pro - D157 - D1Asp which is not associated with susceptible to IDDM. tobetter understand mechanisms for association between particular HLA classMore I alleles and autoimmune diseasesit is important to identify self peptides presented by disease-susceptible HLA class II moleculestriggering disease-causative autoreactive T cells. For this aim，generated T cell clones reactive to autoantigens which are suggested to trigger development of我们established several autoreactive T cell clones restricted bydisease-susceptible HLA class II molecules，but many other autoreactive T cell clones were restricted by other HLA class II molecules andspecific to diverse autoantigenic peptides indicating that the epitopespreading occurred in these自动疾病。Furthermore, we identified many，analogues of an autoantigenic peptide carrying single residue substitutions which can inhibitproliferative response of the autoreactive T cell clone. We also generated a cDNA表达式vectorwhich can ficiently deliver peptides to HLA DR-mediated antigen presentation pathway by utilizingmutated invariant-chain in which CLIP-region is substituted for其他peptides.它将是可能的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

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