Abstract
Bruton’s tyrosine kinase (BTK) was discovered due to its importance in B cell development, and it has a critical role in signal transduction downstream of the B cell receptor (BCR). Targeting of BTK with small molecule inhibitors has proven to be efficacious in several B cell malignancies. Interestingly, recent studies reveal increased BTK protein expression in circulating resting B cells of patients with systemic autoimmune disease (AID) compared with healthy controls. Moreover, BTK phosphorylation following BCR stimulation in vitro was enhanced. In addition to its role in BCR signaling, BTK is involved in many other pathways, including pattern recognition, Fc, and chemokine receptor signaling in B cells and myeloid cells. This broad involvement in several immunological pathways provides a rationale for the targeting of BTK in the context of inflammatory and systemic AID. Accordingly, numerous in vitro and in vivo preclinical studies support the potential of BTK targeting in these conditions. Efficacy of BTK inhibitors in various inflammatory and AID has been demonstrated or is currently evaluated in clinical trials. In addition, very recent reports suggest that BTK inhibition may be effective as immunosuppressive therapy to diminish pulmonary hyperinflammation in coronavirus disease 2019 (COVID-19). Here, we review BTK’s function in key signaling pathways in B cells and myeloid cells. Further, we discuss recent advances in targeting BTK in inflammatory and autoimmune pathologies.
Highlights
Loss of immunological tolerance associated with the activation of autoreactive B cells and their differentiation into autoantibody-producing cells are important pathogenic features in human systemic autoimmune disease (AID)
Bruton’s tyrosine kinase (BTK) phosphorylates DEAD-box helicase 41 (DDX41) and stimulates its binding to dsDNA and activation of the STING pathway (Lee et al, 2015). All these pathways lead to downstream signaling and activation of transcription factors, such as activator protein 1 (AP-1), nuclear factor (NF)-κB, and/or interferon regulatory factors (IRFs), promoting differentiation, survival, and pro-inflammatory cytokine production (Figure 1; Weber et al, 2017)
Though further research is needed, these results indicate BTK inhibitors (BTKi) may be a therapeutic option in Systemic sclerosis (SSc)
Summary
Loss of immunological tolerance associated with the activation of autoreactive B cells and their differentiation into autoantibody-producing cells are important pathogenic features in human systemic autoimmune disease (AID). This fueled research into the effects of BTKi in the context of inflammatory and AID by solely targeting BCR signaling or by targeting multiple pathways in several cell types simultaneously. Engagement of triggering receptor expressed on myeloid cells-1 (TREM-1) induces BTK activation and leads to inflammatory responses (Ormsby et al, 2011).
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