Pathogenic Inflammation and Its Therapeutic Targeting in Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE, lupus) is a highly complex and heterogeneous autoimmune disease that most often afflicts women in their child-bearing years. It is characterized by circulating self-reactive antibodies that deposit in tissues, including skin, kidneys, and brain, and the ensuing inflammatory response can lead to irreparable tissue damage. Over many years, clinical trials in SLE have focused on agents that control B- and T-lymphocyte activation, and, with the single exception of an agent known as belimumab which targets the B-cell survival factor BAFF, they have been disappointing. At present, standard therapy for SLE with mild disease is the agent hydroxychloroquine. During disease flares, steroids are often used, while the more severe manifestations with major organ involvement warrant potent, broad-spectrum immunosuppression with cyclophosphamide or mycophenolate. Current treatments have severe and dose-limiting toxicities and thus a more specific therapy targeting a causative factor or signaling pathway would be greatly beneficial in SLE treatment. Moreover, the ability to control inflammation alongside B-cell activation may be a superior approach for disease control. There has been a recent focus on the innate immune system and associated inflammation, which has uncovered key players in driving the pathogenesis of SLE. Delineating some of these intricate inflammatory mechanisms has been possible with studies using spontaneous mouse mutants and genetically engineered mice. These strains, to varying degrees, exhibit hallmarks of the human disease and therefore have been utilized to model human SLE and to test new drugs. Developing a better understanding of the initiation and perpetuation of disease in SLE may uncover suitable novel targets for therapeutic intervention. Here, we discuss the involvement of inflammation in SLE disease pathogenesis, with a focus on several key proinflammatory cytokines and myeloid growth factors, and review the known outcomes or the potential for targeting these factors in SLE.

Keywords: SLE/lupus; immunopathology; inflammation; interleukin-6; lupus models; nephritis; proinflammatory cytokines; therapeutics.

Figure 1

Inflammation is a key factor in the pathogenesis of lupus. A hallmark of lupus is the presence of hyperactive B cells and loss of B-cell tolerance. Immune complexes containing nucleic acid autoantigens can engage and activate endosomal TLRs and promote inflammation in SLE. Plasma cell expansion and the production of autoantibodies are also features, although the autoantibodies are benign unless generated in an inflammatory milieu, wherein class-switching to pathogenic isotypes occurs. Proinflammatory cytokines not only drive T-cell activation and dendritic cell maturation, but they can stimulate extramedullary hematopoiesis leading to expansion of innate immune cells, and they can induce the production of acute-phase proteins (APPs). Autoantibodies become deposited in tissues such as the glomeruli of the kidney, leading to the activation of myeloid effector cells via Fcγ and complement receptors, leading to tissue destruction. Numerous factors, including genetic make-up, environment, diet, and stress, can modify disease course and severity.

Figure 2

The roles of B cells in lupus pathogenesis. B cells have multiple roles in autoimmunity through (A) their ability to produce autoantibodies and (B) via their role as antigen-presenting cells and (C) as producers of inflammatory cytokines.

Figure 3

Duplicitous signaling roles of IL-6. (A) Classical IL-6 signaling occurs via direct interaction of IL-6 with the membrane-bound IL-6 receptor, which has a limited cellular distribution, and the ubiquitously expressed gp130. gp130 lacks intrinsic kinase activity; IL-6 signals are transduced intracellularly via the recruitment and activation of the JAK/STAT pathway. (B) Cells lacking the IL-6 receptor are not receptive to IL-6 except (C) in the presence of the IL-6/soluble IL-6 receptor complex which interacts with gp130 expressing cells and this is defined as IL-6 trans-signaling. (D) Inhibition of IL-6 trans-signaling can be achieved via the presence of excess soluble gp130Fc fusion protein.