scholarly journals Bruton's Tyrosine Kinase Links the B Cell Receptor to Nuclear Factor κb Activation

2000 ◽  
Vol 191 (10) ◽  
pp. 1735-1744 ◽  
Author(s):  
Urmila D. Bajpai ◽  
Keming Zhang ◽  
Mark Teutsch ◽  
Ranjan Sen ◽  
Henry H. Wortis
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Nuclear Translocation ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Immunoglobulin M ◽  
Bruton’S Tyrosine Kinase ◽  
Nuclear Factor ◽  
Bruton's Tyrosine Kinase

The recognition of antigen by membrane immunoglobulin M (mIgM) results in a complex series of signaling events in the cytoplasm leading to gene activation. Bruton's tyrosine kinase (BTK), a member of the Tec family of tyrosine kinases, is essential for the full repertoire of IgM signals to be transduced. We examined the ability of BTK to regulate the nuclear factor (NF)-κB/Rel family of transcription factors, as the activation of these factors is required for a B cell response to mIgM. We found greatly diminished IgM- but not CD40-mediated NF-κB/Rel nuclear translocation and DNA binding in B cells from X-linked immunodeficient (xid) mice that harbor an R28C mutation in btk, a mutation that produces a functionally inactive kinase. The defect was due, in part, to a failure to fully degrade the inhibitory protein of NF-κB, IκBα. Using a BTK-deficient variant of DT40 chicken B cells, we found that expression of wild-type or gain-of-function mutant BTK, but not the R28C mutant, reconstituted NF-κB activity. Thus, BTK is essential for activation of NF-κB via the B cell receptor.

scholarly journals Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease

2020 ◽  
Vol 140 (4) ◽  
pp. 535-548 ◽  
Author(s):  
Sebastian Torke ◽  
Roxanne Pretzsch ◽  
Darius Häusler ◽  
Philipp Haselmayer ◽  
Roland Grenningloh ◽  
...  
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Demyelinating Disease ◽  
Cell Receptor ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Functionally Impaired ◽  
Anti Cd20 ◽  
Antigen Presenting

Abstract Anti-CD20-mediated B-cell depletion effectively reduces acute multiple sclerosis (MS) flares. Recent data shows that antibody-mediated extinction of B cells as a lasting immune suppression, harbors the risk of developing humoral deficiencies over time. Accordingly, more selective, durable and reversible B-cell-directed MS therapies are needed. We here tested inhibition of Bruton’s tyrosine kinase (BTK), an enzyme centrally involved in B-cell receptor signaling, as the most promising approach in this direction. Using mouse models of MS, we determined that evobrutinib, the first BTK inhibiting molecule being developed, dose-dependently inhibited antigen-triggered activation and maturation of B cells as well as their release of pro-inflammatory cytokines. Most importantly, evobrutinib treatment functionally impaired the capacity of B cells to act as antigen-presenting cells for the development of encephalitogenic T cells, resulting in a significantly reduced disease severity in mice. In contrast to anti-CD20, BTK inhibition silenced this key property of B cells in MS without impairing their frequency or functional integrity. In conjunction with a recent phase II trial reporting that evobrutinib is safe and effective in MS, our mechanistic data highlight therapeutic BTK inhibition as a landmark towards selectively interfering with MS-driving B-cell properties.

scholarly journals Novel Indications for Bruton’s Tyrosine Kinase Inhibitors, beyond Hematological Malignancies

2018 ◽  
Vol 7 (4) ◽  
pp. 62 ◽  
Author(s):  
Robert Campbell ◽  
Geoffrey Chong ◽  
Eliza Hawkes
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Hematological Malignancies ◽  
Kinase Inhibitors ◽  
Cell Receptor ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Malignancies ◽  
Bruton's Tyrosine Kinase ◽  
Novel Target

Bruton’s tyrosine kinase (BTK) is a critical terminal enzyme in the B-cell antigen receptor (BCR) pathway. BTK activation has been implicated in the pathogenesis of certain B-cell malignancies. Targeting this pathway has emerged as a novel target in B-cell malignancies, of which ibrutinib is the first-in-class agent. A few other BTK inhibitors (BTKi) are also under development (e.g., acalabrutinib). While the predominant action of BTKi is the blockade of B-cell receptor pathway within malignant B-cells, increasing the knowledge of off-target effects as well as a potential role for B-cells in proliferation of solid malignancies is expanding the indication of BTKi into non-hematological malignancies. In addition to the expansion of the role of BTKi monotherapy, combination therapy strategies utilizing ibrutinib with established regimens and combination with modern immunotherapy compounds are being explored.

scholarly journals Fatal Disseminated Mouse Adenovirus Type 1 Infection in Mice Lacking B Cells or Bruton's Tyrosine Kinase

2004 ◽  
Vol 78 (11) ◽  
pp. 5584-5590 ◽  
Author(s):  
Martin L. Moore ◽  
Erin L. McKissic ◽  
Corrie C. Brown ◽  
John E. Wilkinson ◽  
Katherine R. Spindler
Keyword(s):  
T Cell ◽  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Critical Role ◽  
Adenovirus Type ◽  
Immunoglobulin M ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase

ABSTRACT Mouse adenovirus type 1 (MAV-1) infection of B-cell-deficient and Bruton's tyrosine kinase (Btk)-deficient mice resulted in fatal disseminated disease resembling human adenovirus infections in immunocompromised patients. Mice lacking B cells or Btk were highly susceptible to acute MAV-1 infection, in contrast to controls and mice lacking T cells. To our knowledge, this is the first demonstration that mice with an X-linked immunodeficiency phenotype (Btk deficient) are susceptible to virus-induced disease. Mice lacking B cells or Btk on a C57BL/6 background succumbed with encephalomyelitis, hepatitis, and lymphoid necrosis. Mice lacking B cells on a BALB/c background succumbed with enteritis and hepatitis. Survival of acute MAV-1 infection correlated with early T-cell-independent neutralizing antibody and T-cell-independent antiviral immunoglobulin M. Treatment of MAV-1-infected Btk−/− mice 4 to 9 days postinfection with antiserum harvested 6 to 9 days postinfection from MAV-1-infected Btk+/+ mice was therapeutic. Our findings implicate a critical role for B-cell function in preventing disseminated MAV-1 infection, particularly production of early T-cell-independent antiviral immunoglobulin M.

Activation of NF-κB in B cell receptor signaling through Bruton’s tyrosine kinase-dependent phosphorylation of IκB-α

2019 ◽  
Vol 97 (5) ◽  
pp. 675-690 ◽  
Author(s):  
Marilena Pontoriero ◽  
Giuseppe Fiume ◽  
Eleonora Vecchio ◽  
Annamaria de Laurentiis ◽  
Francesco Albano ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Bruton’S Tyrosine Kinase ◽  
Receptor Signaling ◽  
Bruton's Tyrosine Kinase ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling

scholarly journals The protein product of the c-cbl protooncogene is phosphorylated after B cell receptor stimulation and binds the SH3 domain of Bruton's tyrosine kinase.

1995 ◽  
Vol 182 (2) ◽  
pp. 611-615 ◽  
Author(s):  
G O Cory ◽  
R C Lovering ◽  
S Hinshelwood ◽  
L MacCarthy-Morrogh ◽  
R J Levinsky ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Receptor ◽  
Sh3 Domain ◽  
Protein Product ◽  
B Cell Receptor ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Differentiation ◽  
Receptor Stimulation ◽  
Bruton's Tyrosine Kinase

X-linked agammaglobulinemia, a B cell immunodeficiency, is caused by mutations in the Bruton's tyrosine kinase (Btk) gene. The absence of a functional Btk protein leads to a failure of B cell differentiation and antibody production. B cell receptor stimulation leads to the phosphorylation of the Btk protein and it is, therefore, likely that Btk is involved in B cell receptor signaling. As a nonreceptor tyrosine kinase, Btk is likely to interact with several proteins within the context of a signal transduction pathway. To understand such interactions, we have generated glutathione S-transferase fusion proteins corresponding to different domains of the human Btk protein. We have identified a 120-kD protein present in human B cells as being bound by the SH3 domain of Btk and which, after B cell receptor stimulation, is one of the major substrates of tyrosine phosphorylation. We have shown that this 120-kD protein is the protein product of c-cbl, a protooncogene, which is known to be phosphorylated in response to T cell receptor stimulation and to interact with several other tyrosine kinases. Association of the SH3 domain of Btk with p120cbl provides evidence for an analogous role for p120cbl in B cell signaling pathways. The p120cbl protein is the first identified ligand of the Btk SH3 domain.

scholarly journals Bruton’s Tyrosine Kinase Mediates the Synergistic Signalling between TLR9 and the B Cell Receptor by Regulating Calcium and Calmodulin

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e74103 ◽  
Author(s):  
Elaine F. Kenny ◽  
Susan R. Quinn ◽  
Sarah L. Doyle ◽  
Paul M. Vink ◽  
Hans van Eenennaam ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase
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