Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

Robak, Ewa; Robak, Tadeusz

doi:10.3390/jcm11102807

Cited by 30 publications

(24 citation statements)

References 147 publications

(208 reference statements)

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“…ITP is an autoimmune disease, in which auto-reactive CD4 + T cells are thought to play pivotal roles in helping B cells to produce auto-reactive antibodies. More recently, BTKis have been under development for immune-mediated diseases, such as ITP [ 30 ]. Besides, auto-reactive CD8 + T cells contribute to disease pathogenesis by attacking platelet and megakaryocyte directly.…”

Section: Discussionmentioning

confidence: 99%

TCR CDR3 Sequencing as a Clue to Elucidate the Landscape of Dysimmunity in Patients with Primary Immune Thrombocytopenia

Zhan

et al. 2022

JCM

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Background: Primary immune thrombocytopenia (ITP) is an autoimmune disorder. The existence of autoreactive T cells has long been proposed in ITP. Yet the identification of autoreactive T cells has not been achieved, which is an important step to elucidate the pathogenesis of ITP. Methods: ITP patients’ peripheral blood was collected prior to the treatment and one month after initiating dexamethasone treatment per related therapeutic guideline. Serum cytokines were profiled to examine T cell subtypes imbalance using a protein chip. TCR Vβ analysis in CD8+T cells of ITP patients, and TCR CDR3 DNA sequencing of CD4+T and CD8+T cells were performed to determine the autoreactive T cells’ clones. Results: Cytokine profiling revealed imbalanced distribution of T cells subtypes, which was confirmed by CD4+T and CD8+T cells’ oligoclonal expansion of TCR Vβ analysis and TCR CDR3 DNA sequencing. VDJ segments were found to be more frequently presented in ITP patients, when compared with health controls. There was an individualized CD4+T cell or CD8+T cell CDR3 sequence in each ITP patient. Conclusions: The present study revealed that T cell clones expanded in ITP patients’ peripheral blood, and each clone had an individualized TCR CDR3 sequence. The expanded T cell clones preferred to use some specific VDJ segment. Further studies are warranted to get access to individualized treatment such as Car-T in patients with ITP.

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Section: Discussionmentioning

confidence: 99%

TCR CDR3 Sequencing as a Clue to Elucidate the Landscape of Dysimmunity in Patients with Primary Immune Thrombocytopenia

Zhan

et al. 2022

JCM

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“…The majority of BTKi target ATP binding sites and can be divided into irreversible or reversible types, depending on their binding site and mode [ 53 , 54 ]. Small molecule covalent irreversible BTK inhibitors cause enzyme inactivation and BCR signal transduction blockage by binding with nucleophilic cysteine 481 residue (Cys-481) thiol group within the ATP-binding site of the kinase domain of BTK [ 55 ].…”

Section: Development and Current Use Of Btk Inhibitors As Cancer Therapymentioning

confidence: 99%

Bruton’s Tyrosine Kinase Inhibitors: The Next Frontier of B-Cell-Targeted Therapies for Cancer, Autoimmune Disorders, and Multiple Sclerosis

Garg

Padron

Rammohan

et al. 2022

JCM

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Bruton’s tyrosine kinase (BTK) is an important protein belonging to the tyrosine kinase family that plays a key role in the intracellular signaling and proliferation, migration, and survival of normal and malignant B-lymphocytes and myeloid cells. Understanding the role of BTK in the B-cell signaling pathway has led to the development of BTK inhibitors (BTKi) as effective therapies for malignancies of myeloid origin and exploration as a promising therapeutic option for other cancers. Given its central function in B-cell receptor signaling, inhibition of BTK is an attractive approach for the treatment of a wide variety of autoimmune diseases that involve aberrant B-cell function including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). Here, we review the role of BTK in different cell signaling pathways, the development of BTKi in B-cell malignancies, and their emerging role in the treatment of MS and other autoimmune disorders.

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“…As many as 20 new BTK inhibitors are under development. 90 Nonetheless, bleeding remains a significant side effect that is associated with the use of these therapies. 91 Platelet activation requires intra-platelet signalling, triggered by platelet receptor-ligand interactions, leading to enhanced platelet aggregation.…”

Section: Btk Inhibitorsmentioning

confidence: 99%

“…As many as 20 new BTK inhibitors are under development. 90 Nonetheless, bleeding remains a significant side effect that is associated with the use of these therapies. 91 …”

Section: Standard Wm Therapies May Accentuate the Bleeding Phenotypementioning

confidence: 99%

Bleeding Propensity in Waldenström Macroglobulinemia: Potential Causes and Evaluation

et al. 2022

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Waldenström Macroglobulinaemia (WM) is a rare, incurable, low-grade, B cell lymphoma. Symptomatic disease commonly results from marrow or organ infiltration and hyperviscosity secondary to IgM paraprotein, manifesting as anaemia, bleeding and neurological symptoms among others. The causes of the bleeding phenotype in WM remain obscure but are likely to involve several intersecting mechanisms. Evidence of defects in platelet function is lacking in the literature, but factors impacting platelet function and coagulation pathways such as hyperviscosity, vascular bed disturbances, abnormal haematopoiesis, acquired von Willebrand Factor (VWF) syndrome and cryoglobulinaemia may contribute to bleeding. Understanding the pathophysiological mechanisms behind bleeding are important, as common WM therapies including chemo-immunotherapy and Bruton’s tyrosine kinase inhibitors, carry attendant bleeding risks. Furthermore, due to the relatively indolent nature of this lymphoma, most patients diagnosed with WM are often older and have one or more comorbidities requiring treatment with anticoagulant or antiplatelet drugs. It is thus important to understand the origin of the WM bleeding phenotype to better stratify patients according to their bleeding risk and thus enhance confidence in clinical decisions regarding treatment management. In this review, we detail the evidence for various contributing factors to the bleeding phenotype in WM and focus on current and emerging diagnostic tools that will aid evaluation and management of bleeding in these patients.

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Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

Cited by 30 publications

References 147 publications

TCR CDR3 Sequencing as a Clue to Elucidate the Landscape of Dysimmunity in Patients with Primary Immune Thrombocytopenia

TCR CDR3 Sequencing as a Clue to Elucidate the Landscape of Dysimmunity in Patients with Primary Immune Thrombocytopenia

Bruton’s Tyrosine Kinase Inhibitors: The Next Frontier of B-Cell-Targeted Therapies for Cancer, Autoimmune Disorders, and Multiple Sclerosis

Bleeding Propensity in Waldenström Macroglobulinemia: Potential Causes and Evaluation

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