Figure 1

From: B-cell-targeted therapies in systemic lupus erythematosus

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.