Contributions of B cells to lupus pathogenesis

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies. This review summarizes first the results obtained in the mouse that have revealed how B cell tolerance is breached in SLE. We then review the B cell subsets, in addition to the autoAb producing cells, which contribute to SLE pathogenesis, focusing on marginal zone B cells, B-1 cells and regulatory B cells. Finally, we review the interactions between B cells and other immune cells that have been implicated in SLE, such as dendritic cells, macrophages, neutrophils and T cells.

Keywords: Autoimmunity; B cells; Lupus.

Figure 1

Activated neutrophils produce neutrophil extracellular traps (NETs). This mechanism of immune protection exposes large amounts of autoantigens that form immune complexes (IC) with autoAbs. The IC can induce plasmacytoid dendritic cells (pDCs) to secrete IFNα, which in turn stimulates neutrophils to generate more NETs. Furthermore, pDC-derived IFNα and IL6 induce B cell differentiation into plasma cells. In the spleen, TLR activation triggers neutrophils to differentiate into B cell helper neutrophils (N_BH), which are located in the perifollicular region and secrete APRIL, IL–21, and BAFF to induce MZB cells to secrete antibodies. In addition, N_BH can induce MZB cells to express Activation Induced Cytidine Deaminase (AID) and undergo class-switch.

Figure 2

Marginal zone macrophages (MZMϕ) retain MZB cells in the marginal zone and clear apoptotic cell debris. In their absence, such as in the BXD2 mouse, exposes autoreactive MZB cells to autoantigens from apoptotic cells. Such antigen-activated autoreactive MZB cells can either migrate to the red pulp and become short-lived plasmablasts or migrate into the follicle where they engage cognate CD4⁺ T cells from the T cell zone. Those activated CD4⁺ T cells can activate cognate follicular B cell, which proliferate in the follicle to form a germinal center (GC). Proliferating GC B cells undergo affinity maturation in the dark zone, then enter the light zone where it encounters follicular helper T (T_FH) cells. T_FH help induce the engaged B cell to undergo class switch and become either long lived antibody secreting plasma cells or memory B cells. Mountz’s group have shown in the BXD2 model that IL – 17 signaling arrests both T_FH cells and GC B cells in the GC, and thereby prolongs GC reaction and promote antibody production.