Regulation of autoreactive B cells during innate immune responses Public Deposited

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  • March 21, 2019
  • Rutan, Jennifer Ann
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • A diverse repertoire of B cell specificities is critical to combat pathogenic threats, but this diversity is tinged with the threat of autoimmunity. Autoimmune diseases such as systemic lupus erythematosus (SLE) underscore the need for strict regulation of B cell activation during immune responses. Regulation of the adaptive immune response is dependent on B cell receptor (BCR) ligation, affinity of the BCR-antigen interaction, and the presence of costimulatory molecules. Mechanisms of central tolerance and peripheral tolerance eradicate B cells that inappropriately bind self-antigens. Autoreactive B cells that escape these mechanisms of tolerance and encounter antigen in the absence of costimulatory signals enter an unresponsive state known as anergy. Anergic B cells do not differentiate into plasma cells, activate transcription factors such as Blimp-1 and XBP-1, or secrete immunoglobulin (Ig). B cells can also be activated by toll-like receptor (TLR) ligands and contribute to the innate immune response, the first line of defense against pathogens. Bacterial and viral components are the archetypical TLR ligands, but endogenous DNA and RNA can also bind TLRs and activate the innate immune system. Therefore, it is critical to regulate the innate immune response to prevent autoimmunity, and this regulation requires unique mechanisms that are not necessarily dependent on BCR ligation. Ideally, these mechanisms would also discriminate between naive and chronically antigen-experienced B cells, allowing naive B cells to respond to threats while potentially autoreactive B cells remain quiescent. We have recently described a mechanism where antigen-experienced B cells are regulated by IL-6 and sCD40L released by dendritic cells (DCs) and macrophages (M[phi]s) during innate immune responses. Naive B cells are unaffected by these factors, permitting a robust immune response in the absence of autoimmunity. IL-6/sCD40L-mediated repression is dependent on ERK activation and "repressed" antigen-experienced cells exhibit a decrease in activated ERK in the nucleus. Identifying new targets for SLE therapies could enable specific regulation of antigen-experienced B cells instead of non-specific B cell depletion and immunosuppression.
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  • In Copyright
  • Vilen, Barbara J.
  • Open access

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