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Review
. 2016 Jul;12(7):763-73.
doi: 10.1586/1744666X.2016.1152888. Epub 2016 Mar 4.

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

Leslie J Crofford  1   2 , Lindsay E Nyhoff  2 , Jonathan H Sheehan  3 , Peggy L Kendall  2   4
Affiliations
Review

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

Leslie J Crofford et al. Expert Rev Clin Immunol. 2016 Jul.

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.

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Figures

Figure 1
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
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).
See this image and copyright information in PMC

References

    1. Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9:722–8. First report describing humoral immunodeficiency in a male child with a disease later termed x-linked agammablobulinemia (XLA) and attributed to Bruton’s tyrosine kinase difficiency. - PubMed
    1. Winkelstein JA, Marino MC, Lederman HM, Jones SM, Sullivan K, Burks AW, Conley ME, Cunningham-Rundles C, Ochs HD. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore) 2006;85:193–202. - PubMed
    1. Howard V, Greene JM, Pahwa S, Winkelstein JA, Boyle JM, Kocak M, Conley ME. The health status and quality of life of adults with X-linked agammaglobulinemia. Clinical immunology. 2006;118:201–8. - PubMed
    1. Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, Hammarstrom L, Kinnon C, Levinsky R, Bobrow M, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993;361:226–33. The first of two seminal papers identifying the B cell tyrosine kinase deficient in XLA, later named Bruton’s tyrosine kinase. - PubMed
    1. Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, Sparkes RS, Kubagawa H, Mohandas T, Quan S, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993;72:279–90. One of two seminal papers identifying B cell tyrosine kinase deficient in XLA, later named Bruton’s tyrosine kinase. - PubMed

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