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BTK Signaling in B Cell Differentiation and Autoimmunity

  • Odilia B. J. Corneth
  • Roel G. J. Klein Wolterink
  • Rudi W. Hendriks
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 393)

Abstract

Since the original identification of Bruton’s tyrosine kinase (BTK) as the gene defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) in 1993, our knowledge on the physiological function of BTK has expanded impressively. In this review, we focus on the role of BTK during B cell differentiation in vivo, both in the regulation of expansion and in the developmental progression of pre-B cells in the bone marrow and as a crucial signal transducer of signals downstream of the IgM or IgG B cell antigen receptor (BCR) in mature B cells governing proliferation, survival, and differentiation. In particular, we highlight BTK function in B cells in the context of host defense and autoimmunity. Small-molecule inhibitors of BTK have very recently shown impressive anti-tumor activity in clinical studies in patients with various B cell malignancies. Since promising effects of BTK inhibition were also seen in experimental animal models for lupus and rheumatoid arthritis, BTK may be a good target for controlling autoreactive B cells in patients with systemic autoimmune disease.

Abbreviations

APC

Antibody-producing cell

BAFF

B cell activating factor

BCAP

B cell adapter for PI3K

BCR

B cell receptor

BMX

Bone marrow-expressed kinase

BTK

Bruton’s tyrosine kinase

CIA

Collagen-induced arthritis

CLL

Chronic lymphocytic leukemia

DAG

Diacylglycerol

ER

Endoplasmic reticulum

ERK

Extracellular signal-regulated kinase

GC

Germinal center

GLT

Germline transcripts

GRB2

Growth factor receptor-bound 2

H chain

Heavy chain

Ig

Immunoglobulin

IL-7

Interleukin-7

IP3

Inositol 1,4,5-trisphosphate

ITAM

Immunoreceptor tyrosine-based activation motif

ITK

Inducible T cell kinase

L chain

Light chain

LPS

Lipopolysaccharide

LYN

Lck/Yes novel tyrosine kinase

MAPK

Mitogen-activated protein kinase

MCL

Mantle cell lymphoma

NFAT

Nuclear factor of activated T cells

PI3K

Phosphoinositide 3-kinase

PIP2

Phosphatidylinositol 4,5-bisphosphate

PIP3

Phosphatidylinositol 3,4,5,-triphosphate

PKCβ

Protein kinase C β

PLCγ

Phospholipase C γ

PTEN

Phosphatase and tensin homologue

RA

Rheumatoid arthritis

RLK

Resting lymphocyte kinase

SH2 domain

Src homology 2 domain

SH3 domain

Src homology 3 domain

SHIP1

SH2 domain-containing inositol 5-phosphatase-1

SLC

Surrogate light chain

SLE

Systemic lupus erythematosus

SLP65

SH2 domain leukocyte protein of 65 kD

SYK

Spleen tyrosine kinase

TEC

Tyrosine kinase expressed in hepatocellular carcinoma

TH domain

TEC homology domain

WASP

Wiskott–Aldrich syndrome protein

WT

Wild type

Xid

X-linked immunodeficiency

XLA

X-linked agammaglobulinemia

Notes

Acknowledgements

These studies were partly supported by the Dutch Arthritis Foundation and a VIRGO grant from the Dutch Organization for Scientific Research. We want to acknowledge Menno van Nimwegen, Marjolein de Bruijn, and Guus Rimmelzwaan (Erasmus MC) for their assistance.

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Odilia B. J. Corneth
    • 1
  • Roel G. J. Klein Wolterink
    • 1
  • Rudi W. Hendriks
    • 1
  1. 1.Department of Pulmonary MedicineErasmus MC RotterdamRotterdamThe Netherlands

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