Role of PD-1/PD ligand system in the pathogenesis of rheumatoid arthritis

点击翻译按钮获取中文摘要

The aim of the investigation is to clarify whether (1) the abnormalities of the inhibitory co-stimulatory system PD-1/PD-L ligand (PD-L1), which we first described, exist in rheumatoid arthritis (RA) and (2) if so, the abnormalities of PD-1/PD-L system result in the induction of RA. The followings are our achievements ;1. Synovial fluid (SF) from RA patients contained PD-1+CD4+T cells, while such cells were essentially not detected in peripheral blood or SF from osteoarthritis patients. These cells were considered to have the inhibitory function since they also expressed CTLA-4 and were positive for the intracelluar IL-10. Interferon (IFN)-gamma strongly induced the cell-surface expression of PD-L1, but not the other co-stimulatory molecules such as B7.1 and B7.2, on cultivated synovial cells in vitro.2. The expression of PD-1 and PD-L1 in articular tissue of RA patients was examined immunohistochemically using the newly developed monoclonal antibodies. PD-L1 was strongly expressed on the surface layer cells of synovial tissue and the endothelial cells. PD-L1 was also expressed on the majority of infiltrated cells expressed PD-L1. It is currently under examination by the double staining method on frozen samples what kind of cells express PP-I and which cytokines these cells produce.3. On collagen induced arthritis (CIA) mice, synovial cells were positive for PD-L1 while some of the bone marrow cells were PD-L2 positive. Administration of anti PD-L1 antibodies to the CIA mice tended to inhibit the onset of arthritis.4. PD-1 knockout (KO) mice are known to develop arthritis naturally, and it is highly, possible that CIA on these mice is severer than CIA on wild type mice due to the lack of PD-1 system, which again indicate the involvement of PD-1/PD-L1 system on the etiology of RA. The process to make the KO mice specific pathogen free is currently on-going.