title: 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.
authors.affiliation: Department of Medicine, Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Valentin
authors.initials: V
authors.lastname: Marian
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Anolik
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology*