The role of Bruton’s tyrosine kinase in autoimmunity and implications for therapy

ABSTRACT

Bruton’s tyrosine kinase (BTK) mediates B cell signaling and is also present in innate immune cells but not T cells. BTK propagates B cell receptor (BCR) responses to antigen-engagement as well as to stimulation via CD40, toll-like receptors (TLRs), Fc receptors (FCRs) and chemokine receptors. Importantly, BTK can modulate signaling, acting as a “rheostat” rather than an “on-off” switch; thus, overexpression leads to autoimmunity while decreased levels improve autoimmune disease outcomes. Autoreactive B cells depend upon BTK for survival to a greater degree than normal B cells, reflected as loss of autoantibodies with maintenance of total antibody levels when BTK is absent. This review describes contributions of BTK to immune tolerance, including studies testing BTK-inhibitors for treatment of autoimmune diseases.

KEYWORDS:

• Bruton’s tyrosine kinase
• autoimmunity
• B lymphocyte signaling
• autoimmune inflammatory arthritis
• type 1 diabetes
• systemic lupus erythematosus
• BTK inhibitors

Financial and competing interests disclosure

P Kendall is the inventor of a patent for the use of BTK inhibitors for type-1 diabetes. This work was supported by National Institutes of Health Grants: National Institute of Arthritis and Musculoskeletal and Skin Diseases R01 AR049010 (LC), National Institute of Diabetes and Digestive and Kidney Diseases R01 DK084246 (PLK), and National Institute of Heart, Lung and Blood T32 HL069765 (LEN). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.