The role of Bruton’s tyrosine kinase in autoimmunity and implications for therapy

Crofford, Leslie J.; Nyhoff, Lindsay E.; Sheehan, Jonathan H.; Kendall, Peggy L.

doi:10.1586/1744666x.2016.1152888

Cited by 152T-cell and B-cell ImmunologyImmunodeficiency and Autoimmune DisordersSystemic Lupus Erythematosus Research

The role of Bruton’s tyrosine kinase in autoimmunity and implications for therapy

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Crofford, Leslie J., Nyhoff, Lindsay E., Sheehan, Jonathan H., Kendall, Peggy L.·2016·Expert Review of Clinical Immunology

DOI 10.1586/1744666x.2016.1152888PMC PMC5070917

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Abstract

Bruton's tyrosine kinase (BTK) mediates B cell signaling and is also present in innate immune cells but not T cells. BTK propagates B cell receptor (BCR) responses to antigen-engagement as well as to stimulation via CD40, toll-like receptors (TLRs), Fc receptors (FCRs) and chemokine receptors. Importantly, BTK can modulate signaling, acting as a "rheostat" rather than an "on-off" switch; thus, overexpression leads to autoimmunity while decreased levels improve autoimmune disease outcomes. Autoreactive B cells depend upon BTK for survival to a greater degree than normal B cells, reflected as loss of autoantibodies with maintenance of total antibody levels when BTK is absent. This review describes contributions of BTK to immune tolerance, including studies testing BTK-inhibitors for treatment of autoimmune diseases.

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BTK transduces constitutive signaling downstream of the BCR in many B-cell malignancies.
“Importantly, BTK transduces constitutive signaling downstream of the BCR in many B-cell malignancies, so BTK has long been considered an attractive target for treating these diseases.”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [1]

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Bruton tyrosine kinase mediates TLR9-dependent human dendritic cell activation
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Tolerant Anti-Insulin B Cells Are Effective APCs
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Pre-B Cell Receptor Signaling Induces Immunoglobulin κ Locus Accessibility by Functional Redistribution of Enhancer-Mediated Chromatin Interactions
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Tumor suppressor function of Bruton tyrosine kinase is independent of its catalytic activity
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Novel small molecule therapeutics in rheumatoid arthritis
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Btk regulates localization, in vivo activation, and class switching of anti-DNA B cells
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Bruton's tyrosine kinase regulates TLR9 but not TLR7 signaling in human plasmacytoid dendritic cells
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Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells
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Bruton's Tyrosine Kinase Deficiency Inhibits Autoimmune Arthritis in Mice but Fails to Block Immune Complex–Mediated Inflammatory Arthritis
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Increased Pro-inflammatory Cytokine Production After Lipopolysaccharide Stimulation in Patients with X-linked Agammaglobulinemia
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Kinase inhibitors: the road ahead
Ferguson, F. M., & Gray, N. S. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.21 · Cited by 1,009 · see citing works
Pemphigus: Current and Future Therapeutic Strategies
Didona, D., Maglie, R., Eming, R., & Hertl, M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01418 · Cited by 261 · see citing works
Bruton tyrosine kinase degradation as a therapeutic strategy for cancer
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Mechanism-based criteria to improve therapeutic outcomes in progressive multiple sclerosis
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Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia
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The Role of B Cells and Antibodies in Multiple Sclerosis, Neuromyelitis Optica, and Related Disorders
Häusser‐Kinzel, S., & Weber, M. S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00201 · Cited by 149 · see citing works
Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models
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Langrish, C. L., Bradshaw, J. M., Francesco, M. R., Owens, T. D., Xing, Y., Shu, J., LaStant, J., Bisconte, A. R., Outerbridge, C. A., White, S. D., et al. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2001130 · Cited by 132 · see citing works
The role of Bruton's tyrosine kinase in the immune system and disease
McDonald, C., Xanthopoulos, C., & Kostareli, E. (2021) · Immunology · doi:10.1111/imm.13416 · Cited by 125 · see citing works
Nitriles: an attractive approach to the development of covalent inhibitors
Bonatto, V., Lameiro, R. F., Rocho, F. D. R., Lameira, J., Leitão, A., & Montanari, C. A. (2022) · RSC Medicinal Chemistry · doi:10.1039/d2md00204c · Cited by 119 · see citing works
Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease
Barnes, P. J. (2016) · Pharmacological Reviews · doi:10.1124/pr.116.012518 · Cited by 114 · see citing works
A phase I trial of PRN1008, a novel reversible covalent inhibitor of Bruton's tyrosine kinase, in healthy volunteers
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Bruton's tyrosine kinase inhibition—An emerging therapeutic strategy in immune‐mediated dermatological conditions
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Inhibition of Bruton Tyrosine Kinase Reduces Neuroimmune Cascade and Promotes Recovery after Spinal Cord Injury
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CPVL promotes glioma progression via STAT1 pathway inhibition through interactions with the BTK/p300 axis
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2025 update on clinical trials in immune thrombocytopenia
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Novel Molecular Leads for the Prevention of Damage and the Promotion of Repair in Neuroimmunological Disease
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Development of New Drugs for Autoimmune Hemolytic Anemia
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The TKI Era in Chronic Leukemias
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Inhibition of Bruton’s Tyrosine Kinase Alleviates Monocrotaline‐Induced Pulmonary Arterial Hypertension by Modulating Macrophage Polarization
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Inhibition of Serum- and Glucocorticoid-Regulated Protein Kinase-1 Aggravates Imiquimod-Induced Psoriatic Dermatitis and Enhances Proinflammatory Cytokine Expression through the NF-kB Pathway
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Preclinical Mechanisms of Topical PRN473, a Bruton Tyrosine Kinase Inhibitor, in Immune-Mediated Skin Disease Models
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The Immunomodulatory Mechanisms of BTK Inhibition in CLL and Beyond
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Rituximab resistance in ITP and beyond
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Effective, safe, and sustained correction of murine XLA using a UCOE-BTK promoter-based lentiviral vector
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Rilzabrutinib for the Treatment of Immune Thrombocytopenia
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General Features of Autoimmune Disease
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Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for rheumatoid arthritis
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Beyond relapses: How BTK inhibitors are shaping the future of progressive MS treatment
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Bruton’s Tyrosine Kinase Supports Gut Mucosal Immunity and Commensal Microbiome Recognition in Autoimmune Arthritis
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New Trials in Lupus and where Are we Going
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Recent Advances in the Design and Development of Anticancer Molecules based on PROTAC Technology
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BTK Inhibitors in Haematology: Beyond B Cell Malignancies
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Pretreatment with ibrutinib facilitates rapid drug desensitization in a difficult case of brentuximab vedotin–induced anaphylaxis
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Driving Potency with Rotationally Stable Atropisomers: Discovery of Pyridopyrimidinedione-Carbazole Inhibitors of BTK
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Role of Lysyl Oxidase-Like Protein 3 in the Pathogenesis of Graves’ Orbitopathy in Orbital Fibroblasts
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Complementary Chinese Herbal Medicine Therapy Improves Survival in Patients With Pemphigus: A Retrospective Study From a Taiwan-Based Registry
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Ibrutinib as a treatment of hematologic autoimmune disorders in patients with indolent B‐cell lymphoma
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Discovery of BGB-8035, a Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase for B-Cell Malignancies and Autoimmune Diseases
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Design and Synthesis of Novel 3‐(2‐Aminopyridin‐3‐yl)‐1,2,4‐Triazolo[4,3‐b]Pyridazine Derivatives as a Reversible Bruton's Tyrosine Kinase Inhibitors
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Evans syndrome revisited
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A thorough QTc study to evaluate the effects of oral rilzabrutinib administered alone and with ritonavir in healthy subjects
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Mechanisms of Resistance to Rituximab Used for the Treatment of Autoimmune Blistering Diseases
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B cell targeting therapies in MS patients during the SARS-CoV-2 pandemic — when immunosuppression meets infection?
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Refractory/relapse thrombocytopenia in a patient with Evans' syndrome successfully treated with zanubrutinib
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Authors: Crofford, L. J., Nyhoff, L. E., Sheehan, J. H., & Kendall, P. L.
Affiliations: Vanderbilt University (US)
Corresponding author: Crofford, Leslie J.
ORCID: Crofford, Leslie J.
Nyhoff, Lindsay E.
Sheehan, Jonathan H.
Kendall, Peggy L.
Venue: Expert Review of Clinical Immunology
Publisher: Informa UK Limited
Published: 2016-03-04
Volume: 12
Issue: 7
Pages: 763-773
ISSN: 1744-666X (ISSN-L)
1744-8409
DOI: 10.1586/1744666x.2016.1152888
PMC: PMC5070917
OpenAlex: W2258682798
Cited by: 142
References: 136
Citations by year: 2026: 9 · 2025: 15 · 2024: 13 · 2023: 18 · 2022: 29 · 2021: 21 · 2020: 9 · 2019: 13 · 2018: 8 · 2017: 5 · 2016: 2
FWCI: 0.90
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Expert Review of Clinical Immunology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (NIAMS R01 AR049010, NIDDK R01 DK84246)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
Keywords: Bruton's tyrosine kinase, autoimmunity, B cell signaling, B cell receptor signaling, CD40 signaling, Toll-like receptors, Fc receptors, chemokine receptors, autoreactive B cells, autoantibodies, immune tolerance, BTK inhibitors, autoimmune disease therapy
MeSH terms: Agammaglobulinaemia Tyrosine Kinase, Animals, Anti-Inflammatory Agents, Autoantibodies, Autoimmune Diseases, B-Lymphocytes, Humans, Immune Tolerance, Lymphocyte Activation, Protein-Tyrosine Kinases, Receptors, Antigen, B-Cell, Signal Transduction, Autoimmunity

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The role of Bruton’s tyrosine kinase in autoimmunity and implications for therapy

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