Systemic lupus erythematosus, a prototypical systemic autoimmune disease, is the result of a series of interactions within the immune system that ultimately lead to the loss of self-tolerance to nuclear autoantigens. Here, we present an integrated model that explains how self-tolerance is initially lost and how the loss of tolerance is then amplified and maintained as a chronic autoimmune state. Key to this model are the self-reinforcing interactions of T and B cells, which we suggest lead to perpetuation of autoimmunity as well as its spread to multiple autoantigen targets.