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.

Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

“…BTK is a non-receptor cytoplasmic Tec tyrosine kinase protein that harbors a kinase domain, two SRC homology domains (SH2 and SH3), a N-terminal pleckstrin (PH) domain, and a TEC domain. The BCR stimulation leads to a downstream cascade guided by BTK activation through transphosphorylation at Y551 in the catalytic domain, and autophosphorylation at Y223 in the SH3 domain [ 28 , 29 ]. Upon its activation, BTK starts a phosphorylation positive feedback loop with phospholipase C-γ (PLCγ2), which in turn, regulate downstream mediators such as the MAPK pathway and transcription of nuclear factor of activated T-cells (NFAT) [ 30 ].…”

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

“…BTK plays an important role in immunity, participating in numerous pathways including B cells, T cells, and macrophages. It is therefore a driving factor in both lymphoproliferative disorders and response to infection [130,131]. BTKis are considered less immunosuppressive and safer than other chemotherapeutic drugs and have been proposed as useful agents for reconstituting humoral immunity and protecting against infection in patients with CLL [132].…”

Regulation of B Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

“…BTK is a nonreceptor cytoplasmic Tec tyrosine kinase protein that harbors a kinase domain, two SRC homology domains (SH2 and SH3), a N-terminal pleckstrin (PH) domain and a TEC domain. The BCR stimulation leads to a downstream cascade guided by BTK activation through transphosphorylation at Y551 in the catalytic domain, and autophosphorylation at Y223 in the SH3 domain [28,29]. Upon its activation, BTK starts a phosphorylation positive feedback loop with phospholipase C-γ (PLCγ2), which in turn, regulate downstream mediators such as the MAPK pathway and transcription of nuclear factor of activated T cells (NFAT) [30].…”