The role of Bruton's tyrosine kinase in the immune system and disease

Abstract

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.

Keywords: BTK inhibitor; Bruton's tyrosine kinase; autoimmunity; chronic lymphocytic leukaemia; ibrutinib; infections; lymphoproliferative disorders.

FIGURE 1

Timeline for the discovery of BTK highlighting key milestones in BTK‐related research and therapies. Each section represents a decade. Ac, acalabrutinib; CLL, chronic lymphocytic leukaemia; GVHD, graft‐versus‐host disease; Ib, ibrutinib; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; WM, Waldenström's macroglobulinaemia; XID, X‐linked immunodeficiency; XLA, X‐linked agammaglobulinaemia

FIGURE 2

Structural overview of BTK and BTK inhibitors and its position within the B‐cell receptor signalling pathway. (a) The 77 kDa BTK protein consists of 659 amino acids, which make up the five domains for protein interaction. The 2 critical sites within the protein are Y223 and (SH3 domain) and Y551 (kinase domain: orange/yellow domain). (b) BTK inhibitors act through the binding to one of the proteins interacting domains and blocking BTK’s catalytic action. The main site of binding for current covalent inhibitors is the C481 residue within the kinase domain. This includes ibrutinib and second‐generation inhibitors acalabrutinib, zanubrutinib and tirabrutinib as depicted at the 3D models (data obtained from SWISS‐MODEL repository by the Swiss Institute of Bioinformatics [101] for the crystal structures of each BTK domain and then NCBI's PubChem database for the line structures for each inhibitor [102]). (c) A simplified version of B‐cell receptor signalling pathway and BTK position within it [103]

FIGURE 3

Overview of the various roles of Bruton's tyrosine kinase (BTK) in innate immunity. Chemokine receptor (CXCR4) activation upon chemokine binding leads to the dissociation of G proteins made up of Gα, Gβ and Gy subunits and downstream activation of BTK. ITAM‐containing (and also ITIM‐containing) Fc receptor crosslinking leads to activation of SYK and in turn BTK. Toll‐like receptors (TLRs) are activated by pathogen‐associated molecular patterns (PAMPs) and‐damage associated molecular patterns (DAMPs). Activation of TLRs is followed by recruitment of MYD88. BTK in turn interacts with MYD88 leading to activation of transcription factors such as NF‐кB. BTK is a direct regulator in the activation of the NLRP3 inflammasome. Efflux of K⁺ into the cell leads to phosphorylation of BTK, most likely by SYK, followed by activation. This phosphorylation promotes assembly of the inflammasome and leads to the cleavage and secretion of IL‐1β [103]