Role of Crk-associated substrate lymphocyte type in the pathophysiology of rheumatoid arthritis in tax transgenic mice and in humans

Objective. To investigate the role of Crk-associated substrate lymphocyte type (Cas-L), a downstream signaling molecule of β1 integrins, in the pathophysiology of rheumatoid arthritis (RA). Methods. We analyzed human T lymphotropic virus type I (HTLV-I) tax transgenic mice as well as samples from human RA patients. Splenocytes from tax transgenic mice were cultured on mouse endothelial cell-covered Transwell inserts, and cells migrating through the endothelial monolayer were counted. Biochemical studies were performed to analyze the protein expression and tyrosine phosphorylation of Cas-L. Immunohistochemical analysis was performed to detect Cas-L-positive cells that had infiltrated into the joints. Results. Migratory activity of splenocytes from tax transgenic mice with arthritis (ATg) was much higher than that of tax transgenic mice without arthritis (NTg) and littermate control mice. The expression of Cas-L protein and its tyrosine phosphorylation were increased in ATg mice compared with NTg and control mice, and this was accompanied by enhanced autophosphorylation of Fyn and Lck. Immunohistochemical analysis demonstrated a large number of Cas-L-positive lymphocytes migrating into the affected joints. Furthermore, in human RA, Cas-L-positive lymphocytes were shown to infiltrate to the inflammatory lesions. Conclusion. These results strongly suggest that Cas-L plays an important role in the pathophysiology of RA.