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

Figure 1. Simplified schematic of BTK’s position in the signaling cascade

Antigen-BCR binding triggers a signaling pathway in which BTK is recruited to the cell membrane from the cytosol, docks with the linker protein BLNK and phosphorylates PLCγ2, with downstream calcium flux and cellular activation via nuclear translocation of transcription factors NFκB and NFAT. Yellow=kinase, blue=adaptor, pink=transcription factor. Dashed arrows=multiple proteins involved. Inspired by Dal Porto and Cambier (129).

Figure 2. Structural rendering of subunits of BTK

PH/Tec domain, blue and orange (130) (residues 2–170, 1BTK.pdb). SH3 domain, green (131)(residues 212–275, 1AWW.pdb). SH2 domain, purple (132) (residues 270–386, 2GE9.pdb). Kinase domain, red (133) (residues 397–659, 1K2P.pdb). The arrangement of the structures is for context, and is not intended to imply relative position or lack of inter-domain motion. PH=pleckstrin homology; SH=SRC homology. Image made with the PyMOL Molecular Graphics System, Version 1.6.0.0 (Schrödinger, LLC).