Treatment targets in systemic lupus erythematosus: biology and clinical perspective

Abstract

Systemic lupus erythematosus (SLE) is a complex disease characterized by numerous autoantibodies and clinical involvement in multiple organ systems. The immunological events triggering the onset and progression of clinical manifestations are also complex and multi-step, including breach of tolerance in the adaptive immune system, amplification of autoimmunity through innate and adaptive immune system dysregulation, and end-organ damage. Studies of murine genetic manipulations and human risk variants have provided important clues to the cellular and molecular pathogenesis of SLE, operating at multiple of these steps. The breakdown of B-cell tolerance is probably a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B-cell activation thresholds, B-cell longevity, and apoptotic cell processing. Examples of amplification of autoimmunity on the adaptive immune system side include disturbances in B-cell/T-cell collaboration. B cells can also amplify innate immune cell activation via antibody-dependent and antibody-independent mechanisms. Indeed, one of the key amplification loops in SLE is the activation of plasmacytoid dendritic cells via autoantibodies and RNA-containing and DNA-containing immune complexes, which act as Toll-like receptor ligands, stimulating the secretion of large quantities of IFNα. A more recent link between the innate and adaptive immune system in SLE includes the neutrophil, which can be primed by interferon and autoantibodies to release neutrophil extracellular traps as an additional source of immunogenic DNA, histones, and neutrophil proteins. The innate immune system activation then feeds back, driving autoreactive B-cell and T-cell survival and maturation. This self-perpetuating disease cycle creates the opportunity for targeted treatment inventions at multiple steps.

Figure 1

Pathogenesis-driven biologic targets in systemic lupus erythematosus. The three stages in disease development include breach of tolerance in the adaptive immune system (loss of tolerance in B cells and T cells), amplification of autoimmunity through innate and adaptive immune system dysregulation, and end-organ damage. Examples of genetic predispositions (exclusively mouse; blue) at each stage are shown. Disturbances in innate and adaptive immunity in the middle panel contribute to both emergence and progression of disease. NETosis of neutrophils and production of autoantibodies by plasma cells (PC) leads to interferon (IFN) production by plasmacytoid dendritic cells (pDCs). Potential treatment targets are shown. Antibodies against B-cell surface antigens such as CD20 and CD19 can cause death of B cells. Antibodies against other B-cell surface molecules, such as the inhibitory receptor CD22, are alternative targets for both inhibition of B cells and induction of cell death. Inhibition of co-stimulation is another approach; for example, monoclonal antibodies against CD40 ligand or CTLA4-Ig block co-stimulatory signals, thus inhibiting B-cell activation, but also T-cell activation. B-cell survival can be inhibited via monoclonal antibodies against the cytokine B-cell activating factor (BAFF; belimumab) or other approaches to disrupting the BAFF receptor family. The possibility of interfering with other pathways such as Toll-like receptors (TLRs), IFN, and other cytokines with inhibitors and causing direct PC and pDC effects with proteasome inhibitors is also suggested. CD40L, CD40 ligand; mDC, myeloid dendritic cell; NET, neutrophil extracellular trap.