CD4 and rheumatoid arthritis: Similar to other autologous components,19,20 sCOL II can directly activate CD4+ T cells in humans with rheumatic disease and to a lesser extend in healthy control.30 In C57BL/6 mice, combined application of heterologous sCOL II and Freund’s adjuvant activated T cells and caused rheumatoid arthritis.31 In our study, CD4+ T cells exhibited tolerance to normal level of autologous sCOL II, while they were activated when the sCOL II produced by cartilage degeneration was released into peripheral blood.