Synoviolin is a Novel Pathogenic Factor of Arthropathy and Chronic Inflammation

Inflammation is classical pathogenic concept, but still very crucial for understanding many disorders even in twenty-first century. The purpose of inflammation is to eliminate the damaged tissues and to initiate tissue repair. By contrast, chronic inflammation leads to intractable diseases, including rheumatoid arthritis (RA), atherosclerosis, cancer, diabetes mellitus, and obesity. We recently cloned synoviolin, an E3 ubiquitin ligase, as an overexpressing molecule in rheumatoid synovium and has been verifying its critical roles in RA, inflammatory cytokine signaling, and fibrosis. Moreover, synoviolin-deficient mice exhibited severe anemia caused by defective nursing activity of erythrocytes in the fetal liver. This phenomenon resembles of RA that accelerates nursing activity. Our data indicate a close relationship between embryogenesis and RA. We successfully discovered synoviolin inhibitors, LS-101 and LS-102. These drugs have inhibitory effects to synoviolin in vitro and in vivo. We are now proceeding with the optimization of small compounds, and we hope our research will lead to the development of a new therapy for RA and fibrosis and other synoviolin-related diseases

Human T-Lymphotropic Virus Type 1 (HTLV-1) and Regulatory T Cells in HTLV-1-Associated Neuroinflammatory Disease

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that is the causative agent of adult T cell leukemia/lymphoma (ATL) and associated with multiorgan inflammatory disorders, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. HTLV-1-infected T cells have been hypothesized to contribute to the development of these disorders, although the precise mechanisms are not well understood. HTLV-1 primarily infects CD4+ T helper (Th) cells that play a central role in adaptive immune responses. Based on their functions, patterns of cytokine secretion, and expression of specific transcription factors and chemokine receptors, Th cells that are differentiated from naïve CD4+ T cells are classified into four major lineages: Th1, Th2, Th17, and T regulatory (Treg) cells. The CD4+CD25+CCR4+ T cell population, which consists primarily of suppressive T cell subsets, such as the Treg and Th2 subsets in healthy individuals, is the predominant viral reservoir of HTLV-1 in both ATL and HAM/TSP patients. Interestingly, CD4+CD25+CCR4+ T cells become Th1-like cells in HAM/TSP patients, as evidenced by their overproduction of IFN-γ, suggesting that HTLV-1 may intracellularly induce T cell plasticity from Treg to IFN-γ+ T cells. This review examines the recent research into the association between HTLV-1 and Treg cells that has greatly enhanced understanding of the pathogenic mechanisms underlying immune dysregulation in HTLV-1-associated neuroinflammatory disease