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BTK Signaling in B Cell Differentiation and Autoimmunity

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B Cell Receptor Signaling

Part of the book series: Current Topics in Microbiology and Immunology ((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.

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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

PLCÎł:

Phospholipase C Îł

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

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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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  1. Department of Pulmonary Medicine, Erasmus MC Rotterdam, Room Ee2251a, PO Box 2040, NL 3000, CA, Rotterdam, The Netherlands

    Odilia B. J. Corneth, Roel G. J. Klein Wolterink & Rudi W. Hendriks

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Correspondence to Rudi W. Hendriks .

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  1. WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan

    Tomohiro Kurosaki

  2. Cellular and Molecular Immunology, Georg August University Goettingen, Göttingen, Germany

    JĂĽrgen Wienands

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Corneth, O.B.J., Klein Wolterink, R.G.J., Hendriks, R.W. (2015). BTK Signaling in B Cell Differentiation and Autoimmunity. In: Kurosaki, T., Wienands, J. (eds) B Cell Receptor Signaling. Current Topics in Microbiology and Immunology, vol 393. Springer, Cham. https://doi.org/10.1007/82_2015_478

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