Targeting Bruton’s Tyrosine Kinase in Inflammatory and Autoimmune Pathologies

Neys, Stefan F. H.; Hendriks, Rudi W.; Corneth, Odilia B. J.

doi:10.3389/fcell.2021.668131

Cited by 27 publications

(30 citation statements)

References 150 publications

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“…129,130 However, a double-blind study of canakinumab, a monoclonal antibody to IL-1β&0x44; failed to show a improved survival. 131 Whereas Janus kinase inhibition which targets multiple inflammatory cytokines 132 seemed to improve survival, 133 antibodies to either IL-6 or its receptor did not show a clear benefit. 128 Since its discovery in the serum of patients with severe inflammation and in rheumatoid arthritic fluids, sPLA2 as a proinflammatory enzyme has invoked intense interest in selective inhibitors of sPLA2-IIA in the hope of developing new and efficient therapies for inflammatory diseases.…”

Section: Treatmentmentioning

confidence: 99%

Hyperinflammation, apoptosis, and organ damage

Kuypers

2022

Exp Biol Med (Maywood)

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The cytokine storm (CS) in hyperinflammation is characterized by high levels of cytokines, extreme activation of innate as well as adaptive immune cells and initiation of apoptosis. High levels of apoptotic cells overwhelm the proper recognition and removal system of these cells. Phosphatidylserine on the apoptotic cell surface, which normally provides a recognition signal for removal, becomes a target for hemostatic proteins and secretory phospholipase A2. The dysregulation of these normal pathways in hemostasis and the inflammasome result in a prothrombotic state, cellular death, and end-organ damage. In this review, we provide the argument that this imbalance in recognition and removal is a common denominator regardless of the inflammatory trigger. The complex reaction of the immune defense system in hyperinflammation leads to self-inflicted damage. This common endpoint may provide additional options to monitor the progression of the inflammatory syndrome, predict severity, and may add to possible treatment strategies.

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Section: Treatmentmentioning

confidence: 99%

Hyperinflammation, apoptosis, and organ damage

Kuypers

2022

Exp Biol Med (Maywood)

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“…Therefore, our results contribute to the evidence for a role for B cells in IPF pathogenesis and, most interestingly, point to abnormalities in naïve B cells. Further studies building on these findings and involving larger patient cohorts should clarify whether targeting BCR signaling, for example with currently available specific small molecule inhibitors [66], has potential value as a treatment option for IPF patients.…”

Section: Discussionmentioning

confidence: 98%

Aberrant B Cell Receptor Signaling in Naïve B Cells from Patients with Idiopathic Pulmonary Fibrosis

Neys

Heukels

Hulst

et al. 2021

Cells

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Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease in which an impaired healing response to recurrent micro-injuries is thought to lead to fibrosis. Recent findings hint at a role for B cells and autoimmunity in IPF pathogenesis. We previously reported that circulating B cells from a fraction of patients, compared with healthy controls, express increased levels of the signaling molecule Bruton’s tyrosine kinase (BTK). However, it remains unclear whether B cell receptor (BCR) signaling is altered in IPF. Here, we show that the response to BCR stimulation is enhanced in peripheral blood B cells from treatment-naïve IPF patients. We observed increased anti-immunoglobulin-induced phosphorylation of BTK and its substrate phospholipase Cγ2 (PLCγ2) in naïve but not in memory B cells of patients with IPF. In naïve B cells of IPF patients enhanced BCR signaling correlated with surface expression of transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) but not B cell activating factor receptor (BAFFR), both of which provide pro-survival signals. Interestingly, treatment of IPF patients with nintedanib, a tyrosine kinase inhibitor with anti-fibrotic and anti-inflammatory activity, induced substantial changes in BCR signaling. These findings support the involvement of B cells in IPF pathogenesis and suggest that targeting BCR signaling has potential value as a treatment option.

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“…This points to a tendency of such B cells to further mature into antibody-secreting cells after entering the CNS, a process associated with less favorable outcomes in MS (15). Bruton's tyrosine kinase (BTK) inhibitors, which are currently first-line treatments for chronic lymphocytic leukemia (16), represent an emerging class of compounds for the treatment of autoimmune diseases (17,18). BTK is known for its role as a key signaling molecule downstream of the B cell receptor (BCR) to regulate cell proliferation and survival.…”

Section: Cxcr3 Expression On B Cells Is Triggered By T-box Transcript...mentioning

confidence: 99%

Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib

Rijvers¹,

Langelaar²,

Bogers³

et al. 2022

JCI Insight

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Recent clinical trials have shown promising results for the next-generation Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib in the treatment of multiple sclerosis (MS). BTK has a central role in signaling pathways that govern the development of B cells. Whether and how BTK activity shapes B cells as key drivers of MS is currently unclear. Compared with levels of BTK protein, we found higher levels of phospho-BTK in ex vivo blood memory B cells from patients with relapsing-remitting MS and secondary progressive MS compared with controls. In these MS groups, BTK activity was induced to a lesser extent after anti-IgM stimulation. BTK positively correlated with CXCR3 expression, both of which were increased in blood B cells from clinical responders to natalizumab (anti–VLA-4 antibody) treatment. Under in vitro T follicular helper–like conditions , BTK phosphorylation was enhanced by T-bet–inducing stimuli, IFN-γ and CpG-ODN, while the expression of T-bet and T-bet–associated molecules CXCR3, CD21, and CD11c was affected by evobrutinib. Furthermore, evobrutinib interfered with in vitro class switching, as well as memory recall responses, and disturbed CXCL10-mediated migration of CXCR3 + switched B cells through human brain endothelial monolayers. These findings demonstrate a functional link between BTK activity and disease-relevant B cells and offer valuable insights into how next-generation BTK inhibitors could modulate the clinical course of patients with MS.

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Targeting Bruton’s Tyrosine Kinase in Inflammatory and Autoimmune Pathologies

Cited by 27 publications

References 150 publications

Hyperinflammation, apoptosis, and organ damage

Hyperinflammation, apoptosis, and organ damage

Aberrant B Cell Receptor Signaling in Naïve B Cells from Patients with Idiopathic Pulmonary Fibrosis

Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib

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