Figure 3.

Phases of B-cell depletion: a working model. This model assumes that disease is balanced by protective and pathogenic B-cell functions with active disease characterized by a pathogenic B-cell environment with dominance of effector B cells and/or autoantibodies (owing to expansion of pathogenic cells or deficit of regulatory cells). The benefit of early B-cell depletion would depend on: the extent of initial B-cell killing and early re-expansion; the relative impact of depletion on protective versus pathogenic B cells; the relative importance of effector versus regulatory B-cell functions at the time of treatment; and the pathogenic contribution of short-lived autoantibodies. Long-term outcome would depend on: the relative numerical and functional balance between pathogenic and regulatory B cells; and the pathogenic contribution of long-lived autoantibodies, which would continue to be produced by long-lived plasma cells unless they are directly targeted by other agents or eventually decreased by chronic B-cell depletion. Long-term remission could be achieved if immunological tolerance is restored during the reconstitution period owing to the confluence of factors discussed elsewhere.^1,21 This model provides a template for understanding the phases and underpinnings of B-cell depletion, how to design combination therapies either for induction or maintenance, and how to evaluate the success or failure of B-cell targeted therapies. Abbreviation: T_REG cell, regulatory T cell. Permission obtained from Drug Discovery Today: Therapeutic Strategies 6, Sanz, I. Indications of rituximab in autoimmune diseases, 13–19 © (2009) Elsevier Ltd, with permission from Elsevier.