Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

BTK

  • Jasper Rip
  • Rudi W. Hendriks
  • Odilia B. J. Corneth
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101553

Synonyms

Historical Background

Bruton’s tyrosine kinase (BTK), a member of the Tec family of nonreceptor kinases, is expressed in all hematopoietic cells except T and NK cells and functions in many different signaling pathways (Table 1). It functions as a crucial signaling molecule downstream of many receptors, including the B cell receptor (BCR) on B lymphocytes. Loss-of-function mutations in the Btk gene were shown to drive X-linked agammaglobulinemia (XLA), an inherited immunodeficiency disease marked by near absence of peripheral B cells and circulating immunoglobulins (Ig), first described by Dr. O.C. Bruton in 1952. Since this discovery, many striking findings have contributed to our understanding of the role of Btk in B cell development and function (Fig. 1).
BTK, Table 1

Btk is involved in signaling pathways downstream of various receptors on different immune cell types

Receptor pathway

Cell type(s)

Pre-BCR

Pre-B cells

BCR

B cells

CXCR4

Pre-B, B cells

CD38

Activated B cells

Epo-R

Erythrocytes

TRAIL-R1

Erythrocytes

FcεR

Mast cells, basophils

FCγR

Myeloid cells

GPVI

Platelets

IL-5R

B cells, eosinophils, basophils

IL-6R

Activated B cells, plasma cells

TLR

Myeloid cells, B cells

M-CSFR

Macrophages

CD303 (BDCA-2)

Plasmacytoid dendritic cells

HGF/c-MET

Dendritic cells

fMLFR

Neutrophils

R receptor, Epo erythropoietin, GPVI collagen receptor glycoprotein VI, IL interleukin, TLR toll-like receptor, TRAIL tumor necrosis factor (TNF)-related apoptosis-inducing ligand, HGF hepatocyte growth factor, fMLFR formyl-methionyl-leucyl-phenylalanine receptor

BTK, Fig. 1

Key discoveries in XLA, XID, and BTK research

Similar to humans, mutations in the Btk gene also underlies the milder X-linked immunodeficiency (XID) phenotype in the CBA/N mouse strain. The effects of these mutations are largely limited to the B cell lineage, stressing the importance of Btk in B cell biology. Besides XLA and XID, a role for BTK has also been described in the context of oncogenic signaling and more recently in autoimmune disease. Several inhibitors of BTK have shown great efficacy in treatment of patients with various B cell malignancies, such as chronic lymphocytic leukemia (CLL) and mantle cell leukemia (MCL). In addition, mouse models have shown that a B cell–intrinsic dysregulation of signaling can induce systemic autoimmune disease. These studies indicate that BTK expression levels and activity may be very relevant in B cell malignancies and systemic autoimmune disease.

BTK in B Cell Receptor Signaling

BTK is a cytoplasmic signaling molecule that is evolutionarily highly conserved and has a structure similar to SRC family kinases. The BTK protein consists of five domains (Fig. 2) (Rawlings and Witte 1995). The pleckstrin homology (PH) domain is involved in the recruitment of cytoplasmic BTK to the cell membrane upon receptor activation, and the Tec homology (TH) domain contains a zinc finger motif important for the stability of the protein. The Src homology (SH) 2 and 3 domains are involved in binding of BTK to many other proteins, including the linker molecule SLP65. In addition, the SH3 domain contains the autophosphorylation site Y223. Finally, BTK has a kinase domain that harbors the catalytic capacity of BTK, containing the phosphorylation site Y551 that activates the protein. The kinase domain is also the target site of BTK inhibitors.
BTK, Fig. 2

BTK protein structure

BTK plays a key role in BCR signaling (Fig. 3) (Aoki et al. 1994; de Weers et al. 1994), which provides crucial survival signals in circulating mature B cells and – upon antigen recognition – induces proliferation and terminal differentiation of B cells (Corneth et al. 2016). Moreover, BTK signals downstream of the pre-BCR, which is an immature form of the BCR that acts as a checkpoint during B cell development in the bone (Corneth et al. 2016). Upon triggering of the BCR, the Src family tyrosine kinase Lyn will phosphorylate the immunoreceptor tyrosine-based activation motifs (ITAMs) of the BCR complex components CD79a/b, resulting in the recruitment of another tyrosine kinase called Syk. Lyn also phosphorylates the cytoplasmic tail of CD19, which is a coreceptor of the BCR. This will lead to the recruitment and activation of phosphoinositide 3-kinase (PI3K). Activated PI3K generates PIP3, which can recruit BTK to the cell membrane by interacting with the PH domain. Subsequently, Lyn and activated Syk together can fully activate BTK by phosphorylation at Y551. In addition, activated Syk will phosphorylate the linker SLP65, which is crucial for the formation of a signaling complex. BTK and its downstream target phospholipase Cγ2 (PLCγ2) will then be able to bind phosphorylated SLP65 with their SH2 domains, and BTK can phosphorylate PLCγ2. This multiprotein complex is involved in the activation of many pathways, such as calcium mobilization, mitogen-activated protein kinases (MAPK) signaling, NF-κB translocation, and actin remodeling. Furthermore, it has been shown that BTK can interact with other signaling molecules such as Akt, which can also be initiated by PI3K-mediated activation upon CD19 stimulation. Akt signaling induces survival and proliferation of B cells (Corneth et al. 2016).
BTK, Fig. 3

BTK in BCR signaling

Upon BCR signaling, BTK protein levels in B cells are increased. It is not fully understood how BTK levels are regulated, but it is clear that BTK can induce its own transcription in an NFκB dependent way and that microRNA-185 is involved in posttranslational regulation (Corneth et al. 2016). Regulation of BTK levels is vital for normal B cell function. Subphysiological expression levels of BTK cannot restore the BTK-deficient phenotype in mice whereas physiological levels can. Furthermore, enhanced expression of BTK leads to enhanced activation of B cells and the development of autoimmunity in mice.

BTK in Other Signaling Pathways

In addition to BCR signaling, BTK plays a major role in many other signaling pathways (Table 1). Toll-like receptor (TLR) function has been described to depend on the expression of BTK (Rawlings et al. 2012). For example, Btk-deficient B cells show decreased activation following TLR4 stimulation with LPS compared to normal controls. Upon triggering, TLRs recruit adaptor molecules such as myeloid differentiation primary response gene 88 (MyD88) or TIR domain-containing adaptor protein inducing interferon-β (TRIF). Signaling via these adaptor proteins leads to the activation of interferon regulatory factor 3 (IRF3) and translocation of NF-κB, providing proliferation and survival signals. BTK is able to interact directly with TIR domains of the TLRs, but also with adaptor molecules MyD88 and TRIF and other downstream signaling molecules, although the domain of BTK that interacts with these molecules is still unknown. Furthermore, BTK has been shown to mediate synergistic signaling between the BCR and TLR9, which is an endosomal TLR that recognizes nuclear material. Synergistic signaling of the BCR with TLRs provides a strong survival signal for B cells and has been linked to development of autoimmune diseases (Rawlings et al. 2012).

BTK is also involved in chemokine-receptor signaling (de Gorter et al. 2007), in particular downstream of CXCR4 and CXCR5. Chemokine receptors belong to the family of G protein-coupled receptors and signal via G protein subunits, which can be bound by the PH and TH domain of BTK (Tsukada et al. 1994). Homing of B cells to lymph nodes was hampered in Btk-deficient mice, a process in which chemokine receptors play a key role. Furthermore, BTK inhibitors induce lymphocytosis in CLL patients by drawing malignant cells out of their (survival) niche in the lymph nodes and into the circulation (Hendriks et al. 2014).

BTK-mediated signaling has been described in Fc receptor signaling, which is not limited to B cells, but also affects monocytes and macrophages. Depending on the nature of the Fc receptor, signaling through BTK may activate a B cell or induce its apoptosis. In addition, BTK may also play a role in CD38 and CD40 signaling; however, the exact role of BTK in these pathways is less well defined (Corneth et al. 2016).

BTK in Immunodeficiency

Mutations in the BTK gene in humans are the underlying cause of the severe primary immunodeficiency disease, X-linked agamaglobulinemia (XLA) (Tsukada et al. 1993; Vetrie et al. 1993). XLA, which was first described in 1952 by Dr. O. C. Bruton (1952), is the most common primary immunodeficiency with a reported incidence of 1/380,000 live births in the USA. BTK has a crucial function in pre-BCR signaling and therefore in the associated checkpoint during B cell development (Corneth et al. 2016). Early in B cell development (Fig. 4), functional gene recombination events within the Ig heavy chain gene locus result in surface expression of the heavy chain, which marks a crucial checkpoint. In the pre-BCR complex, the Ig heavy chain protein is associated with the invariant surrogate light chain proteins that have homology to Ig light chains. Expression of the pre-BCR induces clonal proliferation of large pre-B cells and subsequently their developmental progression to the stage of resting, small pre-B cells. In human pre-B cells, the pre-BCR-mediated expansion and differentiation is crucially dependent on BTK (Corneth et al. 2016). In the bone marrow of boys with XLA, the number of pre-B cells expressing intracellular Ig heavy chain is rather variable but generally reduced. These pre-B cells are significantly smaller in XLA patients than in healthy controls, which is in agreement with a crucial function of BTK in the induction of proliferative expansion of pre-B cells that Ig heavy chain in their cytoplasm. But even those pre-B cells present in XLA patients appear to have a developmental block, since very few pre-B cells undergo Ig light chain recombination. In healthy individuals, the transition from large cycling to small resting pre-B cells is marked by the initiation of Ig κ and λ light chain rearrangement. Following successful Ig light chain rearrangement, the pre-B cells progress to the immature B cell compartment, in which the BCR is checked for autoreactivity. If these immature B cells do not recognize antigen, they leave the bone marrow (Fig. 4). Taken together, BTK deficiency leads to a severe block in early B cell development in the bone marrow at the pro- to pre-B cell stage, resulting in an almost complete absence (<1%) of mature B cells in the circulation (Pearl et al. 1978) (Fig. 4). As a consequence, there are no plasma cells and very low levels of immunoglobulins in the periphery. Those few B cells that do remain have an immature IgMhi phenotype and harbor BCRs that are auto- or poly-reactive; however, autoimmune diseases in these patients are relatively rare.
BTK, Fig. 4

B cell development. Defects in XLA and XID are indicated

The gene encoding BTK is located on the X-chromosome. Therefore, heterozygous female carriers of a BTK mutation are healthy, whereas affected males present with recurrent infections of the airways, the gastrointestinal tract, and the skin caused by parasites and encapsulated bacteria. B cells of female carriers all express the unaffected X-chromosome and have inactivated the affected chromosome. This is explained by the phenomenon of random X-chromosome inactivation that takes place in every female somatic cell early in embryogenesis, whereby in female XLA carriers developing B cells that harbor the defective BTK gene on their active X chromosome have a selective disadvantage. This is not the case for other cell types that express BTK, indicating that the defect in XLA is B cell-intrinsic. Furthermore, because T cells and NK cells do not express BTK and are therefore unaffected, viral infections do not cause severe problems in patients (Corneth et al. 2016).

XLA is a very heterogeneous disease. Many mutations that cause loss of function of BTK have been described in all domains, except the SH3 domain containing the autophosphorylation Y223 tyrosine residue. In addition, no correlations have so far been made between specific mutations and clinical or immunological symptoms. XLA patients require life-long treatment with intravenous Ig and antibiotics, but when on sufficient treatment they are relatively healthy, indicating that the effects of loss of BTK are mostly restricted to humoral immunity (Corneth et al. 2016). It has been proposed that – based on promising findings in animal models – XLA forms a good candidate for gene therapy replacing current noncurative treatment.

In contrast to human XLA patients, xid CBA/N mice, which harbor a mutation in the Btk gene, present with the milder X-linked immunodeficiency (XID) phenotype (Amsbaugh et al. 1972). Homozygous Btk-deficient mice show normal B cell development in the bone marrow. However, heterozygous females show loss of Btk-deficient B cells beyond the pre-B cell stage, indicating a selective advantage of Btk-sufficient B cells similar to human B cells (Hendriks et al. 1996). Transition through the pre-B cell stage is delayed in Btk-deficient compared to wild-type B cells, consistent with the role for Btk at the pre-BCR checkpoint. Furthermore, Btk is actively involved in light chain rearrangement and λ immunoglobulin light chain usage is reduced in Btk-deficient B cells (Corneth et al. 2016).

B cells are present in Btk-deficient mice in the circulation, although they are ~50% reduced in number compared to normal control mice (Fig. 4). They retain an immature IgMhiIgDlo phenotype and show impaired activation and differentiation in vitro. They fail to proliferate upon IgM or IgD stimulation and cannot obtain an activated phenotype upon IgM stimulation. BCR-mediated survival signals are decreased in Btk-deficient B cells, and they are more sensitive to apoptosis due to lower expression of the survival proteins BCL2 and BCL-XL. However, they do respond normally to Phorbol myristate acetate/ionomycin stimulation, which bypasses the BCR (Corneth et al. 2016).

Follicular and marginal zone B cell numbers in the spleen are reduced in Btk-deficient mice, although the proportions of these populations are relatively normal. In contrast, B1 B cells, which are a specific subset of self-renewing B cells of mainly fetal origin with a specific BCR repertoire, are completely absent in the spleen and peritoneal and pleural cavities. As a consequence, IgM and IgG3 isotype antibody levels are decreased in Btk-deficient mice, which can be explained by the lack of natural antibodies produced by B1 cells, but other isotypes are normally present. Btk-deficient mice fail to show a B cell response to thymus independent TI antigens, which is thought to be dependent on B1 cells. In addition, Btk-deficient mice have reduced antigen-specific antibody levels upon primary immunization with thymus dependent TII antigens. However, secondary immunization mounts a normal memory response, suggesting that Btk is not crucial for germinal center, memory B cells, or plasma cell formation. In contrast with the observed normal T cell-dependent responses to model antigens in adjuvants, Btk-deficient mice have reduced numbers of GC B cells in their draining lymph nodes following pulmonary infection with influenza virus (Corneth et al. 2016).

As in humans, the defect in Btk-deficient mice is restricted to humoral immunity. Infections with pathogens which require the presence of natural antibodies will lead to more severe disease. However, Btk-deficient mice will develop less severe disease upon infections with pathogens that induce the production of harmful antibodies or primarily infect B1 cells (Corneth et al. 2016).

BTK in Cancer

Btk has been implicated in both murine and human leukemia and lymphoma (Hendriks et al. 2014). Murine Btk-deficient pre-B cells show increased proliferation in vitro. Although Btk deficiency alone does not lead to tumor formation in vivo, combined deficiency with SLP65 enhances pre-B cell leukemia in mice compared to SLP65 single mutants, showing tumor suppressive capacity of Btk in pre-B cells which was independent of its kinase function. Mutations in BTK have been found in human childhood pre-B cell acute lymphoblastic leukemia (pre-B ALL), but these were all mutations affecting kinase functions of BTK; a single XLA patient with pre-B ALL has been described. On the other hand, overexpression of Btk in murine B cells leads to decreased susceptibility to apoptosis. Again overexpression of Btk alone did not lead to tumor development but did increase the incidence and mortality rate of mice in a chronic lymphatic leukemia (CLL) mouse model. Interestingly, in this model, deficiency of Btk prevented tumor development, clearly illustrating the differential roles for Btk in pre-B cells and mature B cells. Although it is still unclear whether mutations in BTK can cause B cell tumors in humans, these data show the importance of correct regulation of expression levels of BTK.

BTK protein expression is enhanced in several B cell malignancies, including CLL and mantle cell lymphoma (MCL), and in some patients, phosphorylated BTK is also highly expressed (Hendriks et al. 2014). Because BTK is crucial for B cell survival and proliferation, great effort has been undertaken to develop specific inhibitors targeting BTK. Several of these inhibitors have already shown impressive efficacy in human B cell malignancies in vitro and in vivo. Treatment with ibrutinib, the first FDA approved small molecule inhibitor of BTK approved in the clinic, significantly reduced survival and proliferation of primary tumor cells and tumor cell lines in vitro. Phosphorylation of PLCγ2, Akt, and ERK, important downstream targets of BTK, was reduced in these cultures. Importantly, not only viability of the cells was affected but also adhesion and migration, through inhibition of BTK dependent chemokine receptor signaling. In CLL and MCL, this is considered the main mode of action of BTK inhibition (Byrd et al. 2013; Wang et al. 2013). Upon BTK treatment, patients exhibit lymphocytosis, caused by an egress of malignant cells from the lymph nodes. Upon leaving the lymph nodes, tumor cells lose important survival signals provided by stromal cells, rendering them susceptible to apoptosis. In addition, tumor cells lose the cell intrinsic proliferation signals mediated through BCR signaling induced phosphorylation of PLCγ2 and Akt, which may also contribute to the successful elimination of cancer cells (Hendriks et al. 2014).

BTK inhibition may also affect TLR signaling or the interaction between BCR and TLR signaling in tumors (Hendriks et al. 2014). In Waldenström’s macroglobulinemia patients, who frequently harbor an activating mutation in MyD88, BTK is often constitutively active. BTK inhibition was shown to limit interaction of BTK and MyD88 in these patients and to induce apoptosis in vitro. However, in vivo, it is unclear whether BTK inhibition works primarily through inhibition of the TLR signaling pathway or whether inhibition of the BCR and chemokine receptors is more important.

Apart from affecting tumor cells, BTK inhibition also limits tumor development by targeting the tumor cell survival niche (Hendriks et al. 2014). In multiple myeloma (MM), a plasma cell-derived tumor, BTK inhibition crucially affects osteoclasts in the bone marrow that provide essential survival signals to MM cells, including CCL3, an important marker for disease progression. Ectopic expression of BTK was found in nonhematological tumors, including prostate cancer and breast cancer cell lines. Inhibition of BTK in these tumors shows promising results, suggesting that the role of BTK in aberrant cell proliferation is not limited to the hematopoietic lineage.

Although BTK inhibition has shown impressive efficacy in lymphoma patients, not all patients respond well to this therapy. In some tumors, mutations in BTK or other genes were shown to promote resistance to BTK inhibitors (Chiron et al. 2014). These mutations may be present before onset of treatment, but mutations have been shown to arise during treatment, although it is unclear whether treatment itself may promote these mutations. To overcome this therapy resistance, new treatment strategies are being developed, including novel more selective inhibitors, including Acalabrutinib (Byrd et al. 2016) for treatment of CLL, that are specifically designed to improve on the safety and efficacy of BTK inhibition. Moreover, inhibitors of multiple pathways are combined and now being tested in the clinic. Indeed, combinations of BTK inhibitors with PI3K inhibitors or inhibitors of the Akt pathway have shown better results than monotreatment (Woyach et al. 2014).

BTK in Autoimmunity

B cells are involved in many autoimmune diseases, and B cell intrinsic defects have been shown to be sufficient to induce autoimmunity in mice (Corneth et al. 2016). The discovery that BTK plays a crucial role in the selection of pre-B cells during development and in activation of mature B cells in the periphery prompted studies into the role of BTK in autoimmune diseases. Early studies in mice showed an important role for Btk in the formation of autoreactive antibodies. When the XID mutation was crossed into the lupus-prone NZWxNZB or MRL.lpr/lpr background, spontaneous autoantibody formation and kidney damage were dramatically reduced. Interestingly, stimulation of B cells from these mice with TLR ligands did induce the production of nonautoreactive antibodies. Similarly, Btk deficiency in the NOD mouse model of diabetes prevented the development of autoantibodies without affecting total antibody levels in serum of mice (Corneth et al. 2016).

Studies with NOD mice harboring an insulin-reactive BCR transgene showed that BTK deficiency affects only mature cells in the periphery as insulin specific pre-B cells in the bone marrow were unaffected. Similarly, expression of low levels of the constitutively active E41K-BTK mutant, which allows for B cells survival past the pre-B cell stage, enhances B cells survival and activation, leading to a rapid enhanced formation of IgM plasma cells producing autoreactive antibodies. These data indicate that BTK expression and activation levels affect mature B cells and may be involved in peripheral B cell selection (Corneth et al. 2016).

Overexpression of human BTK specifically in B cells in mice leads to a spontaneous autoimmune phenotype resembling systemic lupus erythematosus (SLE) and Sjögren’s syndrome. Mice first develop spontaneous germinal centers and plasma cells in the spleen, followed by an increase in memory B cells and plasma cells in the bone marrow. Plasma cells produce autoreactive antibodies leading to antibody deposition in the kidneys and immune infiltrates of the kidneys, salivary glands, and lungs. This phenotype depends strongly on T cells, as crosses with CD40 ligand-deficient mice, inhibiting B-T cell interaction, abrogated the disease. However, these mice did still develop IgM-autoreactive antibodies, suggesting that BTK may be involved in a two-step induction of autoreactivity, by enhancing survival of autoreactive B cells and subsequent induction of the germinal center response. Importantly, the phenotype depended on BTK kinase activity, as a kinase inactive BTK mutant did not develop autoimmunity, and inhibition of BTK kinase activity by ibrutinib prevented the formation of spontaneous germinal centers (Corneth et al. 2016).

Because these studies show the involvement of Btk in B cell mediated autoimmunity, Btk inhibition has been studied extensively in mouse autoimmune models. In collagen-induced arthritis, a mouse model for rheumatoid arthritis (RA), Btk inhibition before onset of disease completely prevented arthritis development, and treatment after onset greatly decreased disease severity. Similar to Btk-deficient mice in autoimmune models, inhibition of Btk affected the formation of autoantibodies, but nonautoimmune antibodies in serum remained present. Of note, the efficacy of Btk inhibition in this model may be partly due to the important role for Fc-mediated signaling in monocytes and macrophages, which is also dependent on Btk. In addition, in several models of murine lupus, Btk inhibition limits the formations of autoantibodies and prevents or decreases levels of kidney damage, significantly improving survival of mice (Honigberg et al. 2010; Corneth et al. 2016).

BTK expression in human autoimmune patients has not yet been extensively studied, although some studies indicate a pathogenic role for BTK. In RA patients, phosphorylated BTK levels correlate with rheumatoid factor (RF) titers and are increased in anti-citrullinated-protein-antibody (ACPA) positive patients, indicating a link between activation of BTK and autoantibody production. In addition, BTK signaling was required for IL-21 expression by B cells, which is important for the maintenance of tertiary lymphoid follicles involved in autoantibody production. Furthermore, upstream signaling molecule SYK was more highly expressed in blood of RA patients. In SLE patients, expression of downstream target ARID3A was shown to be correlated with disease severity. The promising results of BTK inhibition in mouse autoimmunity studies and the finding that BTK inhibitors are very well tolerated by leukemia patients with limited side effects have prompted several clinical trials of BTK inhibitors in human autoimmune diseases that are currently underway (www.clinicaltrials.gov).

Summary

BTK is a signaling molecule expressed in many hematopoietic cells but most crucially involved in B cell development in the bone marrow and activation and terminal differentiation of peripheral B cells. As it is involved in many signaling pathways, deregulated BTK expression can lead to a number of clinical diseases. BTK deficiency in humans leads to XLA, a severe X-linked immunodeficiency affecting humoral immunity. Male with this defect suffer from severe recurrent infection due to loss of peripheral B cells. In mice, Btk deficiency leads to a milder phenotype with decreased numbers of B cells and impaired humoral immunity. BTK signaling is crucially involved in the proliferation, migration, and adhesion of leukemic cells in several B cell-derived malignancies. Inhibition of BTK in these patients leads to expulsion of cells from their survival niche and discontinuation of intrinsic survival signals and is now a very successful new therapeutic approach in the clinic. In addition, increased expression of Btk in mice can induce an autoimmune phenotype, and BTK has been implicated in human autoimmune diseases. Ongoing clinical trials will reveal the potential of BTK inhibitors in autoimmune patients.

See Also

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Jasper Rip
    • 1
  • Rudi W. Hendriks
    • 1
  • Odilia B. J. Corneth
    • 1
  1. 1.Department of Pulmonary MedicineErasmus Medical Center RotterdamRotterdamThe Netherlands