Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the loss of adaptive immune tolerance to nucleic acid-containing antigens. The resulting autoantibodies form immune complexes that promote inflammation and tissue damage. Defining the signals that drive pathogenic autoantibody production is an important step in the development of more targeted therapeutic approaches for lupus, which is currently treated primarily with non-specific immunosuppression. Here, we review the contribution of Bruton’s tyrosine kinase (Btk), a component of B and myeloid cell signaling pathways, to disease in murine lupus models. Both gain- and loss-of-function genetic studies have revealed that Btk plays multiple roles in the production of autoantibodies. These include promoting the activation, plasma cell differentiation, and class switching of autoreactive B cells. Small molecule inhibitors of Btk are effective at reducing autoantibody levels, B cell activation, and kidney damage in several lupus models. These studies suggest that Btk may promote end-organ damage both by facilitating the production of autoantibodies and by mediating the inflammatory response of myeloid cells to these immune complexes. While Btk has not been associated with SLE in GWAS studies, SLE B cells display signaling defects in components both upstream and downstream of Btk consistent with enhanced activation of Btk signaling pathways. Taken together, these observations indicate that limiting Btk activity is critical for maintaining B cell tolerance and preventing the development of autoimmune disease. Btk inhibitors, generally well-tolerated and approved to treat B cell malignancy, may thus be a useful therapeutic approach for SLE.
Highlights
The development of a B cell repertoire capable of secreting antibodies against a wide range of foreign antigens is crucial for effective immune responses
Bruton’s tyrosine kinase (Btk) is required for Plasma Cell (PC) accumulation, as the increased PC frequency observed in Lyn−/− mice is normalized in Lyn−/−Btklo mice [51]
While polymorphisms in Btk have not been identified in GWAS studies of Systemic lupus erythematosus (SLE) or other autoimmune diseases, several lines of evidence suggest that increased Btk activity may be associated with autoantibody production in humans
Summary
The development of a B cell repertoire capable of secreting antibodies against a wide range of foreign antigens is crucial for effective immune responses. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies against nuclear antigens. The Role of Btk in Lupus pathogenesis by forming immune complexes that deposit in and damage tissues and synergize with innate immune defects to sustain pro-inflammatory feed-forward loops [1]. Autoantibodies arise prior to the development of overt clinical symptoms [2], suggesting that loss of B cell tolerance is an important initiating event in lupus. Understanding the signaling pathways that mediate autoantibody production may reveal new therapeutic targets for SLE, currently treated primarily by non-specific immunosuppression. We review the contribution of Bruton’s tyrosine kinase (Btk) to lupus, with a focus on its role in B cells
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.