Affiliation:
1. Schroeder Arthritis Institute Krembil Research Institute, University Health Network Toronto Ontario Canada
2. Schroeder Arthritis Institute, Krembil Research Institute, and Division of Rheumatology, Schroeder Arthritis Institute, University Health Network, and Departments of Medicine and Immunology, University of Toronto Toronto Ontario Canada
Abstract
ObjectiveElevated levels of serum interferon‐α (IFNα) and the disruption of B cell tolerance are central to systemic lupus erythematosus (SLE) immunopathogenesis; however, the relationship between these 2 processes remains unclear. The purpose of this study was to investigate the impact of elevated IFNα levels on B cell tolerance mechanisms in vivo and determine whether any changes observed were due to the direct effect of IFNα on B cells.MethodsTwo classical mouse models of B cell tolerance were used in conjunction with an adenoviral vector encoding IFNα to mimic the sustained elevations of IFNα seen in SLE. The role of B cell IFNα signaling, T cells, and Myd88 signaling was determined using B cell–specific IFNα receptor–knockout, CD4+ T cell–depleted, or Myd88‐knockout mice, respectively. Flow cytometry, enzyme‐linked immunosorbent assay, real‐time quantitative polymerase chain reaction, and cell cultures were used to study the effects of elevated IFNα on the immunologic phenotype.ResultsElevation of serum IFNα disrupts multiple B cell tolerance mechanisms and leads to autoantibody production. This disruption was dependent upon B cell expression of IFNα receptor. Many of the IFNα‐mediated alterations also required the presence of CD4+ T cells as well as Myd88, suggesting that IFNα acts directly on B cells to modify their response to Myd88 signaling and their ability to interact with T cells.ConclusionThe results provide evidence that elevated IFNα levels act directly on B cells to facilitate autoantibody production and further highlight the importance of IFN signaling as a potential therapeutic target in SLE.image
Funder
Canadian Institutes of Health Research
Subject
Immunology,Rheumatology,Immunology and Allergy
Cited by
9 articles.
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