| Research Abstract |
Mixed connective tissue disease, MCTD,is one of prototypic systemic autoimmune diseases, and has a characteristic of specific autoimmune responses to snRNP,especially to 70 kD polypeptide. Human immune responses, including autoimmunity, are ignited by the presentation of epitopic peptides bound on HLA antigen binding groove to T cells. The peptides, bound to an HLA specificity, share promiscuous sequences. To establish a strategy to develop specific and harmless weapons to fight against the disease, we first analyzed the association between patients with MCTD and HLA phenotypes, and found HLA-DR2/DR4 shared epitope association with Caucasian patients with MCTD,and HLA-DR9 association with Japanese patients. Secondly, we searched sequences of HLA binding motifs within the 70kD polypeptide, found four sequences within RNA binding region of the polypeptide, and synthesized the 20mer peptides. Thirdly, those peptides were utilized for the proliferative response assay of 70kD palypeptide stimulated T cell lines from a Caucasian patient with MCTD.We demonstrate here that those peptides could modulate the autoimmune response of the patients, and show feasibility of those peptides as candidates for epitope therapy which should be disease-specific and of less adverse effects because those peptides are basically autoantigens. Lastly, we introduced peripheral blood mononucleated cells into SCID mice to establish animal models for autoimmunity to the 70kD polypeptide and for MCTD,and we successfully established the mice producing human immunoglobulins, which could also serve as tools to screen those peptides for therapeutic modulators of autoimmunity to snRNP.
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