The role of B lymphocyte stimulator (BLyS) in systemic lupus erythematosus

Abstract

SLE, a chronic, multisystem autoimmune disorder with a broad range of symptoms, involves defective B cell selection and elimination of self-reactive B cells. B lymphocyte stimulator (BLyS), a soluble ligand of the TNF cytokine family, is a prominent factor in B cell differentiation, homeostasis, and selection. BLyS levels affect survival signals and selective apoptosis of autoantibody-producing B cells. High levels of BLyS may relax B cell selection and contribute to autoantibody production, exacerbating the SLE disease state. This review discusses the mechanism of BLyS action on B cells, its role in SLE, and specific targeting of BLyS in the treatment of SLE.

Figure 1. BLyS and APRIL ligands and receptors.

BLyS is the only ligand for BR3, and both APRIL and BLyS bind to TACI and BCMA. APRIL binds to TACI and BCMA with higher affinity than does BLyS. Intracellular signaling from the ligand binding leads to B cell survival and influences B cell differentiation. These effects involve the activation of transcriptional regulatory factors such as RelA and RelB, which can regulate the expression of antiapoptotic proteins, including Bcl-2, A-1, Bcl-X_L, and Mcl-1.

Figure 2. B cell differentiation and activation and BLyS receptor expression.

(A) B cell development and activation. B cells originate and complete initial phases of differentiation and maturation in the bone marrow. Immature B cells exit the bone marrow and move to the circulation as TR B cells, then complete maturation in the spleen. If activated by antigen and T cell help, these mature preimmune B cells will proliferate and form germinal centers, culminating in the generation of memory and plasma cells that make high-affinity, isotype-switched antibodies. (B) B cell developmental stages and BLyS receptor expression. BLyS dependence ensues at the TR developmental stages, at which BR3 and TACI are first expressed. These receptors remain expressed among all preimmune populations. After antigen-driven activation, BLyS receptor expression shifts to predominantly TACI and/or BCMA expression among memory and long-lived plasma cells (the latter of which permanently reside in bone marrow).