B Cells in Systemic Lupus Erythematosus: From Disease Mechanisms to Targeted Therapies

Abstract

B cells exert a prominent contribution to the pathogenesis of systemic lupus erythematosus (SLE). Here, we review the immune mechanisms underlying autoreactive B cell activation in SLE, focusing on how B cell receptor and Toll-like receptor signals integrate to drive breaks in tolerance to nuclear antigens. In addition, we discuss autoantibody-dependent and autoantibody-independent B cell effector functions during lupus pathogenesis. Finally, we address efforts to target B cells therapeutically in human SLE. Despite initial disappointing clinical trials testing B cell depletion in lupus, more recent studies show promise, emphasizing how greater understanding of underlying immune mechanisms can yield clinical benefits.

Keywords: Autoantibodies; B cell depletion; B cells; BAFF; Belimumab; Systemic lupus erythematosus.

Figure 1:. BAFF, APRIL, and their receptors:

Graphical representation of BAFF (trimeric and multimeric forms) and APRIL binding to respective BAFF family receptors to support different B cell functions.

Figure 2:. B cell activation pathways underlying lupus pathogenesis

Schematic representation of the three known activation pathways resulting in the generation of pathogenic effector B cells in SLE. (A) Pathogenic plasmablasts can be generated without T cell help, most notably in the BAFF-Tg model. (B, C) Following initial autoantigen recognition, autoreactive B cells and CD4⁺ T cells interact at the T cell:B cell border. Subsequently, costimulatory signals and cytokine crosstalk promote B cell activation and autoantibody production via either a T cell-dependent EF pathway (B) or within spontaneous, autoimmune GCs (C). Recent studies in human lupus, have uncovered a prominent contribution for EF B cell activation in the generation of autoantibody-producing ASCs via the sequentially defined aNAV and DN2 differentiation stages. Adapted from Jenks SA, Cashman KS, Zumaquero E, et al. Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus. Immunity 2018;49(4):725–739 e726; Hale M, Rawlings DJ, Jackson SW. The long and the short of it: insights into the cellular source of autoantibodies as revealed by B cell depletion therapy. Curr Opin Immunol 2018;55:81–88; Jenks SA, Cashman KS, Woodruff MC, et al. Extrafollicular responses in humans and SLE. Immunol Rev 2019;288(1):136–148.

Figure 3:. B cell-targeted therapies in clinical development

Schematic representation of B cell development showing targets for B cell-directed therapies including: monoclonal antibodies targeting B cell surface antigens (CD19, CAR T cells; CD20, rituximab, ocrelizumab, obinutuzumab; and CD22, epratuzumab); BAFF family directed therapies (belimimab and atacicept); and plasma cell depletion strategies (APRIL, atacicept; CD38, daratumumab; SLAMF7, elotuzumab; BCMA CAR T cells).