2018-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/699873Systemic lupus erythematosus (SLE) is more prevalent in Chinese Han population and is often life-threatening, yet the pathogenic cause and mechanism remain mostly unclear. It has been demonstrated that recognition of bacterial DNA by Toll-like receptor (TLR)-9 on B cells or dendritic cell could facilitate autoantibody secretion and aggravate renal disease in lupus-prone mice. However, serum DNA autoantibody levels on renal pathology and survival in murine lupus model were controversial, not mentioning that the origin of autoantibodies that contribute directly to the pathogenesis of SLE is largely unknown. Our preliminary results demonstrated that 17 kDa protein derived from commensal streptococci in the oral cavity may induce pathogenic autoantibody. We further test the implication of the antibody. In a cohort of 79 patients with SLE, 70 patients with other systemic autoimmune diseases and healthy controls(N=25). The specificity and sensitivity of the anti-17kDa for diagnosis of SLE was 92.6% and 34.2% respectively. It was later identified to be a ribosomal protein, which may be the target antigens responsible for the generation of pathogenic autoreactive antibodies in SLE patients but not in healthy donors and patients with other autoimmune diseases. Clinical serology was surveyed as several known antoantigens also have RNA binding capacities, but none of these antibody tilters against RNA binding protein or ribosomal P were shown to correlated well with anti-streptoccoal 17kDa levels. By the Basic Local Alignment Search Tool (BLAST) approach, human mitochondrial ribosomal protein was shown to be most closely related to the target ribosomal protein. Previous study revealed mutation in these mitochondrial ribosomal proteins cause hypertrophic cardiomyopathy and mediate lupus T cells apoptosis. We propose to determine the role of ribosomal protein in immunopathogenesis of SLE. In this project, we hypothesize that the autoantibody production in SLE could be induced by commensal bacterial infection due to the cross-reaction with ribosomal protein. Therefore, the specific aims of this project include:1. Characterization of streptococcal bacterial proteins those are responsible for induction of pathogenic autoantibody production.2. Investigation of the underlying mechanisms of pathogenic autoantibody production induced by the streptococcal ribosomal protein in SLE 3. Evaluation of the role of the ribosomal protein in the pathogenesis of lupus nephritis in a lupus-prone murine model 4. Evaluation of the clinical application of the commensal-associated antibodies in diagnosis and prognosis of SLE, and elucidate the probable mechanisms including mitochondrial dysfunction and T cell apoptosis.systemic lupus erythematosuscommensal bacteriaribosomal proteinautoantibodylupus nephritis