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.
Highlights
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with heterogeneity in clinical manifestations and disease course, characterized by pathogenic autoantibody formation, immune complex deposition, and end-organ damage
We have proposed that a repopulation with transitional B cells, a putative regulatory population, is associated with sustained clinical remission while a quick resurgence of memory cells portends a poor outcome
Multiple immunologic abnormalities can contribute to the emergence and amplification of disease, the predominant abnormalities will probably vary in different patients
Summary
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with heterogeneity in clinical manifestations and disease course, characterized by pathogenic autoantibody formation, immune complex deposition, and end-organ damage. Excessive activity of T-follicular helper cells in mice induces hyperactive germinal center, breakdown of B-cell tolerance, autoantibody production, and a lupus-like phenotype [21] Another interesting example of the importance of coordination of B-cell/T-cell interactions for the prevention of autoimmunity was recently provided by an elegant study demonstrating that deficiency of two regulatory molecules, DEF6 and SWAP70 (homologous intracellular signaling proteins in T cells and B cells regulated by IRF4), leads to the development of lupus in mice with simultaneous dysregulation of CD4+ T cell IL-21 production and increased IL-21 B-cell responsiveness [22]. Identified genetic variants likely to affect end-organ damage in human SLE include FcγRIIa and FcγRIIIa [73], ITGAM (functioning in immune complex clearance and cell adhesion/migration) [62], and kallikrein polymorphisms [74]
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