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.
Highlights
Systemic lupus erythematosus (SLE, lupus) is a B-cell-mediated autoimmune disease characterized by the generation of autoantibodies against nuclear antigens and a type III hypersensitivity reaction leading to chronic systemic inflammation
Pathogenic antinuclear antibodies (ANAs) production was sustained, as was IgG immune complex (IC) deposition in kidney glomeruli, renal complement deposition was significantly reduced, which suppressed renal leukocyte infiltration, thereby markedly attenuating glomerulonephritis and improving kidney function [163]. These findings suggest that more emphasis should be put on examining the role of IL-6-trans-signaling in lupus nephritis, with the possibility of targeting this inflammatory pathway in disease
Systemic lupus erythematosus is a highly complex autoimmune disease with multiple immunopathological disorders, the most significant being glomerulonephritis mediated by immune complex deposition in the kidney microvessels
Summary
Systemic lupus erythematosus (SLE, lupus) is a B-cell-mediated autoimmune disease characterized by the generation of autoantibodies against nuclear antigens and a type III hypersensitivity reaction leading to chronic systemic inflammation. More recently, genome-wide association studies, have uncovered various human SLE susceptibility genes that are normally responsible for maintaining immune system tolerance and homeostatic processes. These include antigen processing and presentation (HLA, TAP1/2), clearance of apoptotic debris (C1q, Dnase1), leukocyte cell surface receptors (FCGRI/II/III, ITGAM), and cell. One well-studied model of SLE is the Lyn-deficient mouse (Lyn−/−) [9], which exhibits clinical, pathological, and biochemical features seen in human SLE [comprehensively reviewed in Ref. Much of our current understanding of SLE disease pathogenesis and many preliminary therapeutic studies for SLE have come from the identification, analysis, or testing of these mouse models [reviewed in Ref. Much of our current understanding of SLE disease pathogenesis and many preliminary therapeutic studies for SLE have come from the identification, analysis, or testing of these mouse models [reviewed in Ref. [17, 18]]
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