Immunology

Elucidation of bone destruction in rheumatoid arthritis and development of novel therapies, 2020.07 - 2022.03

Summary： In rheumatoid arthritis, not only joint erosion but also periarticular bone loss and systemic osteoporosis are observed, while the mechanism of periarticular bone loss and systemic osteoporosis remains largely unknown. In this study, we found that the number of bone marrow plasma cells increases under arthritic conditions and they induce periarticular bone loss by expressing the osteoclast differentiation factor, RANKL. In addition, we clarified that synovial fibroblasts are major RANKL expressing cells which induce joint erosion. This study highlights the importance of plasma-cell RANKL in periarticular bone loss in arthritis and provides mechanistic insight into the manifestation of bone lesion induced by autoimmunity.

Establishment of an integrated locomotive science including dynamics of bone-articular cells and regulation by immune system, 2019.06 - 2024.03

Development of novel therapies against bone erosion in rheumatoid arthritis, 2018.06 - 2020.03

Summary： Rheumatoid arthritis is anautoimmune disease which exhibits chronic inflammation and bone destruction.Osteoclasts are responsible for bone destruction in rheumatoid arthritis,however, osteoclast-inducers have not been identified yet. Here we generated newconditional knockout mice in which osteoclast differentiation factor isspecifically deleted in B cells, T cells and synovial fibroblasts. We foundsynovial fibroblasts are the major osteoclast-inducer cells. It will contributeto the development of new therapies against bone destruction.

Establishment of regulation for autoimmune diseases targeting new T cell subsets, 2018.04 - 2022.03

Summary： In autoimmune diseases such as rheumatoid arthritis, it is urgently necessary to establish novel fundamental therapies based on understanding the mechanism. In this study, we aimed to clarify the molecular mechanisms that govern the pathogenic T cells we identified previously as well as synovial fibroblasts which interact with the pathogenic T cells. By genetic analysis, we proved that synovial fibroblasts are primary cells that induce bone erosion in arthritis in vivo, suggesting the importance of the pathogenic T -synovial fibroblast axis in arthritis. We further clarified a part of the molecular mechanisms that explain pathogenic T cells and synovial fibroblasts. This study will contribute to the establishment of novel therapies for autoimmune diseases including rheumatoid arthritis.

Mechanisms underlying the deficiency of oral immunity and its effect on systemic organ network, 2016.04 - 2018.03

Summary： Oral cavity harbors unique oral microbiota and immune system. In periodontitis, infection of pathogenic bacteria disturbs the homeostasis of oral microbiota, which eventually results in the loss of bone that is important for supporting teeth. However, the mechanism of bone loss in periodontitis has not been fully understood. In this study, we found that a novel arthritogenic T cell subset which we identified previously turned out to be the most potent bone-damaging T cells in periodontitis. Interestingly, the bone-damaging T cells contribute to the host defense by regulating the quality and quantity of oral microbiota. We identified several molecules that are specifically expressed in the bone-damaging T cells, which will contribute to establish the methods to regulate immunological association between oral cavity and remote organs by modulating local tissue destruction and the systemic host defense.