2020-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/709252Systemic 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 174 study objects including patients with SLE, patients with other systemic autoimmune diseases and healthy controls. The specificity of the anti-17kDa for diagnosis of SLE was 92.6%. For those rituximab naïve SLE patients, 85.7% patients had 64.3±21.7% decreased anti17KDa after rituximab. And the decrease corresponded to no disease flare according to SELENA-SLEDAI flare index(SFI.) Both high titer anti17KDa or follow-up value lower than 0.25 O.D. value could be good candidate biomarkers for regimen selection in SLE. The 17KDa protein 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 DNA or 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 mitochondrial dysfunction 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. Evaluation of the clinical application of the commensal-associated antibodies as biomarkers for regimen selection in SLE. 2. Evaluation of the role of the ribosomal protein in the pathogenesis of lupus nephritis in two lupus-prone murine models 3. and to elucidate the probable mechanisms including mitochondrial dysfunction and T cell apoptosis as well as NETs induction.systemic lupus erythematosuscommensal bacteriaribosomal proteinautoantibodylupus nephritisrituximabbiologics