The BAFF/APRIL System in Autoimmunity

Abstract

BAFF, a TNF-like ligand, has emerged as an essential factor for B-cell survival and maturation, and the discovery of this factor has been a major advance for understanding B-cell biology. Excessive BAFF production is associated with the development of autoimmune disorders such as lupus, a problem attributed to the inappropriate survival of self-reactive B cells. These early findings prompted the development of BAFF inhibitors, which are now in human clinical trials. Excessive BAFF production does not cause a total breakdown of B-cell tolerance, but rather the expansion of low/intermediate affinity self-reactive B cells, in particular marginal zone (MZ) B cells. Studies with BAFF transgenic mice have established a new paradigm for autoimmunity, in that BAFF-driven autoimmune disease is entirely T-cell-independent and not linked to affinity maturation of accumulating low/intermediate affinity self-reactive B cells. Interestingly, the expression of the toll-like receptor (TLR) signalling element MyD88 is required for disease, and a reciprocal stimulatory loop exists between TACI and TLR signalling. As TACI is an essential receptor driving T-cell-independent B-cell responses, it raises the possibility of its role in BAFF-mediated autoimmunity, linked to the innate immune system. The BAFF system appears to be truly unique, in that this one factor activates a separate pathogenic autoimmune mechanism not yet represented in any of the current animal models of lupus, and possibly reflecting a mechanism driving disease in a proportion of human autoimmune patients.