B-cell-targeted therapies in systemic lupus erythematosus

Abstract

Autoreactive B cells are one of the key immune cells that have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). In addition to the production of harmful auto-antibodies (auto-Abs), B cells prime autoreactive T cells as antigen-presenting cells and secrete a wide range of pro-inflammatory cytokines that have both autocrine and paracrine effects. Agents that modulate B cells may therefore be of potential therapeutic value. Current strategies include targeting B-cell surface antigens, cytokines that promote B-cell growth and functions, and B- and T-cell interactions. In this article, we review the role of B cells in SLE in animal and human studies, and we examine previous reports that support B-cell modulation as a promising strategy for the treatment of this condition. In addition, we present an update on the clinical trials that have evaluated the therapeutic efficacy and safety of agents that antagonize CD20, CD22 and B-lymphocyte stimulator (BLyS) in human SLE. While the results of many of these studies remain inconclusive, belimumab, a human monoclonal antibody against BLyS, has shown promise and has recently been approved by the US Food and Drug Administration as an indicated therapy for patients with mild to moderate SLE. Undoubtedly, advances in B-cell immunology will continue to lead us to a better understanding of SLE pathogenesis and the development of novel specific therapies that target B cells.

Figure 1

Role of B cells in SLE: targeting B cells on different fronts. In SLE, auto-reactive B cells produce a panoply of pathogenic auto-antibodies that bind to self-antigens. The survival and differentiation of B cells into antibody-producing plasma cells are potentiated and maintained at various levels by different signals that are received from other immune cells. Recognition of nucleic acids and immune complexes by pDCs through TLR7 and TLR9 induces the production of IFN-α in pDCs, which increases the production of BAFF by mDCs. BAFF, after binding to its three receptors BAFF-R, TACI and BCMA, which are expressed on B cells, induces the survival, proliferation and differentiation of B cells into plasma cells. IL-6 is another cytokine that is essential for plasma-cell differentiation. IL-6 is secreted by mDCs and T cells, with the latter interacting with B cells through CD40:CD40L and cognate MHC-II:TCR engagement. B cells also secrete IL-6 after activation, creating an autocrine positive feedback loop that exacerbates its stimulatory effect. Current B-cell-targeted therapies are based on strategies that interfere with B-cell survival and differentiation. CD19 and CD20 are expressed by most B-cell subsets at various developmental stages and anti-CD19/20 antibodies represent therapeutics that eliminates B cells. Anti-CD22, in addition to triggering B-cell death, has an additional effect on inhibiting BCR signaling. Anti-BAFF limits the survival and proliferation of activated B cells, and anti-IL-6 limits the differentiation of activated B cells into plasma cells. Anti-CD40:CD40L represents another therapeutic target by inhibiting T–B cell interaction, thereby reducing T-cell help. BAFF, B-cell activating factor of the TNF family; BCR, B-cell receptor; BCMA, B-cell maturation antigen; IFN, interferon; IL-6, interleukin-6; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; SLE, systemic lupus erythematosus; TACI, transmembrane activator-1 and CMCL interactor; TCR, T-cell receptor; TLR, toll-like receptor.