The regulation of autoreactive B cells during innate immune responses

Systemic lupus erythematosus (SLE) highlights the dangers of dysregulated B cells and the importance of initiating and maintaining tolerance. In addition to central deletion, receptor editing, peripheral deletion, receptor revision, anergy, and indifference, we have described a new mechanism of B cell tolerance wherein dendritic cells (DCs) and macrophages (M Phi s) regulate autoreactive B cells during innate immune responses. In part, DCs and M Phi s repress autoreactive B cells by releasing IL-6 and soluble CD40L (sCD40L). This mechanism is selective in that IL-6 and sCD40L do not affect Ig secretion by naive cells during innate immune responses, allowing immunity in the absence of autoimmunity. In lupus-prone mice, DCs and M Phi s are defective in secretion of IL-6 and sCD40L and cannot effectively repress autoantibody secretion suggesting that defects in DC/M Phi-mediated tolerance may contribute to the autoimmune phenotype. Further, these studies suggest that reconstituting DCs and M Phi s in SLE patients might restore regulation of autoreactive B cells and provide an alternative to immunosuppressive therapies.