Abstract
The pathogenesis of autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is driven by genetic predisposition and environmental triggers that lead to dysregulated immune responses. These include the generation of pathogenic autoantibodies and aberrant production of inflammatory cytokines. Current therapies for RA and other autoimmune diseases reduce inflammation by targeting inflammatory mediators, most of which are innate response cytokines, resulting in generalized immunosuppression. Overall, this strategy has been very successful, but not all patients respond, responses can diminish over time and numerous side effects can occur. Therapies that target the germinal center (GC) reaction and/or antibody-secreting plasma cells (PC) potentially provide a novel approach. TANK-binding kinase 1 (TBK1) is an IKK-related serine/threonine kinase best characterized for its involvement in innate antiviral responses through the induction of type I interferons. TBK1 is also gaining attention for its roles in humoral immune responses. In this review, we discuss the role of TBK1 in immunological pathways involved in the development and maintenance of antibody responses, with particular emphasis on its potential relevance in the pathogenesis of humoral autoimmunity. First, we review the role of TBK1 in the induction of type I IFNs. Second, we highlight how TBK1 mediates inducible T cell co-stimulator signaling to the GC T follicular B helper population. Third, we discuss emerging evidence on the contribution of TBK1 to autophagic pathways and the potential implications for immune cell function. Finally, we discuss the therapeutic potential of TBK1 inhibition in autoimmunity.
Highlights
TANK-binding kinase 1 (TBK1) is an IKK-related serine/threonine kinase best known for the induction of antiviral type I interferons (IFN-Is) in innate immunity
An increased T follicular B helper (TFH) population in the germinal center (GC) as well as GC numbers may contribute to aberrant positive selection and autoantibody formation in systemic lupus erythematosus (SLE) [90]. This is exemplified in Sanroque mice, in which exaggerated TFH generation occurs in a cell-intrinsic manner and leads to spontaneous GC formation, and lupus-like pathology [91, 92]
TBK1 is required for IFN-Is production in the context of sensing viral or aberrant cytoplasmic nucleic acids
Summary
TANK-binding kinase 1 (TBK1) is an IKK-related serine/threonine kinase best known for the induction of antiviral type I interferons (IFN-Is) in innate immunity. Targeted intratumoral delivery of IFN-I-inducing (i.e., interferogenic) cyclic dinucleotide GMP-adenosine monophosphate (AMP), which activates the STING-TBK1 pathway and IFN-Is production in endothelial cells, has been shown to control tumor growth by boosting antitumor CD8+ T responses in murine models of melanoma and colon cancer [40]. Using viable TBK1−/− TNF−/− mice, Ishii and colleagues demonstrated functional distinctions between TBK1 signaling in hematopoietic and non-hematopoietic cells for the induction of Ag-specific responses in a plasmid-DNA immunization model [64]. TREX1-deficient mice develop aberrant interferogenic responses and features of lupus owing to the cytoplasmic accumulation of endogenous nucleic acids and chronic activation of the TBK1-dependent DNA-sensing pathway [68,69,70]. TBK1-driven responses other than IFN-Is induction may contribute to humoral autoimmunity and are discussed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: 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.
