scholarly journals The Expression of BTK/p-BTK Is Different between CD5+ and CD5- B Lymphocyte from Autoimmune Hemolytic Anemia/Evans Syndromes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4886-4886
Author(s):  
Limin Xing ◽  
Yingying Qu ◽  
Ningning Duan ◽  
Zonghong Shao
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
B Lymphocytes ◽  
Autoimmune Hemolytic Anemia ◽  
Bruton’S Tyrosine Kinase ◽  
Healthy Controls ◽  
Bruton's Tyrosine Kinase ◽  
Significant Difference ◽  
B Cell Subsets

Abstract Objective To investigate the expression level of Bruton's tyrosine kinase (Btk) on CD19+B lymphocytes in peripheral blood (PB) of autoimmune hemolytic anemia (AIHA)/Evans patients. Methods The expression of Btk and Phosphorylated Btk(p-Btk) on CD5+CD19+B and CD5-CD19+B lymphocytes were detected using flow cytometry in AIHA/ Evans patients with different disease states, healthy controls (HC) and chronic lymphocytic leukemia (CLL) patients and analyzed its correlation with clinical parameters. Results 36 AIHA/ES patients (16 hemolytic, 20 remission), 11 CLL patients and 15 healthy controls (HC) were enrolled in this study. The expression of Btk and p-Btk on CD5+B lymphocytes in AIHA/Evans patients were higher than those in HCs and CLL patients, the latter two groups had no significant difference, and were positively correlated with the quantity of IgE. The ratio of p-Btk to Btk on CD5+B lymphocytes of hemolytic group and remission group was obviously higher than that on CD5-B lymphocytes [(74.62±6.42)%, (29.63±10.19)%, P=0.001], [(77.95±9.57)%, (26.29±6.86)%, P=0.006]. The ratio of p-BTK to BTK on CD5+B lymphocytes [(54.89±9.56)%] and CD5-B lymphocytes [(30.86±12.47)%, P=0.109)] showed no significant difference in HCs. There was no significant difference of Btk on CD5+B and CD5- B lymphocytes in AIHA/Evans patients, but the expression of p-Btk on CD5+B lymphocytes significantly higher than that on CD5-B lymphocytes in AIHA/Evans patients. Conclusion The expression levels of p-BTK in different B cell subsets of AIHA/Evans patients were significantly different, the expression levels of p-BTK in CD5+B cells were obviously higher than that in CD5-B cells, and higher than that in CD5+ B cells in CLL patients, and positively correlated with the number of serum IgE. Key words: anemia hemolytic autoimmune; Bruton's tyrosine kinase, Phosphorylated Bruton's tyrosine kinase; B cell subsets Disclosures No relevant conflicts of interest to declare.

Bruton's tyrosine kinase inhibition in the treatment of preclinical models and multiple sclerosis

2021 ◽  
Vol 27 ◽  
Author(s):  
Anja Steinmaurer ◽  
Isabella Wimmer ◽  
Thomas Berger ◽  
Paulus Stefan Rommer ◽  
Johann Sellner
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Bruton’S Tyrosine Kinase ◽  
Cumulative Number ◽  
Phase 2 ◽  
Bruton's Tyrosine Kinase ◽  
Relapsing Remitting

: Significant progress has been made in understanding the immunopathogenesis of multiple sclerosis (MS) over recent years. Successful clinical trials with CD20-depleting monoclonal antibodies have corroborated the fundamental role of B cells in the pathogenesis of MS and reinforced the notion that cells of the B cell lineage are an attractive treatment target. Therapeutic inhibition of Bruton's tyrosine kinase (BTK), an enzyme involved in B cell and myeloid cell activation and function, is regarded as a next-generation approach that aims to attenuate both errant innate and adaptive immune functions. Moreover, brain-penetrant BTK inhibitors may impact compartmentalized inflammation and neurodegeneration within the central nervous system by targeting brain-resident B cells and microglia, respectively. Preclinical studies in animal models of MS corroborated an impact of BTK inhibition on meningeal inflammation and cortical demyelination. Notably, BTK inhibition attenuated the antigen-presenting capacity of B cells and the generation of encephalitogenic T cells. Evobrutinib, a selective oral BTK inhibitor, has been tested recently in a phase 2 study of patients with relapsing-remitting MS. The study met the primary endpoint of a significantly reduced cumulative number of Gadolinium-enhancing lesions under treatment with evobrutinib compared to placebo treatment. Thus, the results of ongoing phase 2 and 3 studies with evobrutinib, fenobrutinib, and tolebrutinib in relapsing-remitting and progressive MS are eagerly awaited. This review article introduces the physiological role of BTK, summarizes the pre-clinical and trial evidence, and addresses the potential beneficial effects of BTK inhibition in MS.

scholarly journals Bruton’s Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2560
Author(s):  
Antonio García-Merino
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Multiple Sclerosis Therapy ◽  
New Generation

B cells play a central role in the pathogenesis of multiple sclerosis (MS), as demonstrated through the success of various B cell-depleting monoclonal antibodies. Bruton’s tyrosine kinase (BTK) is a critical molecule in intracellular signaling from the receptor of B cells and receptors expressed in the cells of the innate immune system. BTK inhibitors may be a non-cell-depleting alternative to B cell modulation. In this review, the structure, signaling, and roles of BTK are reviewed among the different inhibitors assayed in animal models of MS and clinical trials.

MO008B LYMPHOCYTE SUBSET CHANGES IN PRIMARY MEMBRANEOUS NEPHROPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Nooshin Dalili ◽  
Fatemeh Pour-Reza Gholi ◽  
Katayoun Hasanzadeh ◽  
Sara Assadiasl
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Standard Treatment ◽  
Control Group ◽  
P Value ◽  
Healthy Controls ◽  
Memory B Cell ◽  
Wide Range ◽  
Significant Difference

Abstract Background and Aims Primary membranous nephropathy (PMN) is the most common cause of nephrotic syndrome (NS) in adults. Rituximab a chimeric monoclonal anti-CD20 antibody has been supposed to eliminate autoantibody-producing B cells via direct signaling, complement-mediated cytotoxicity (CMC), and antibody-dependent cellular cytotoxicity (ADCC). According to the fact that a wide range of B lymphocytes may carry this marker, we aimed to identify which subset is more (or less) frequent in PMN patients and which one is more affected by rituximab administration. Method Three groups were enrolled in the present study. They included a healthy control group and two patient groups having the clinical, laboratory, and pathological diagnostic criteria of PMN, comprising either patients on standard treatment or patients on standard treatment plus rituximab. The latter group was studied just before receiving rituximab (pre-rituximab) and two months later (post rituximab). Peripheral blood mononuclear cells (PBMCs) were isolated using Ficoll-hypaque (inno-train, Germany) gradient. Afterward, cells were adjusted to a concentration of 1 _ 106 cells/mL and stained with mouse antihuman CD19-Cy5-conjugated antibody (Cytognos, Spain), mouse antihuman CD24-PE-conjugated antibody (Cytognos, Spain), and mouse antihuman CD38-FITC-conjugated antibody (Cytognos, Spain). Flow cytometry performed by FACS Calibur (BDFacs Calibur Becton Dickinson, USA). Results The total lymphocyte percentage was higher in PMN patients receiving either standard treatment or rituximab than in healthy controls (standard-treatment vs. control: P value = 0.001, pre-rituximab vs. control: P value =0.001). In post-rituximab analysis, CD19+ cell count showed notable reduction (P value = 0.003) B CD19+CD24+CD38- cells, representing the memory B cell population, did not show any significant difference between healthy controls and patients. Furthermore, the count of these cells did not decrease significantly two months after rituximab administration. The subset of CD19+CD24-CD38+ B lymphocytes, a class of naïve/mature lymphocytes with normal function, was significantly higher in the control group than in standard treatment patients (P value = 0.01). However, no statistically significant difference was found in CD19+CD24-CD38+B lymphocytes neither between the rituximab and control groups nor between pre-rituximab and post-rituximab patients. Conclusion The number of regulatory B cells decreased in both standard treatment and rituximab-receiving PMN patients and the proportion of naïve/mature B-lymphocytes was lower in the former group. Moreover, the memory B cells count did not reduce significantly two months after rituximab administration. Hence, it might be the best choice to target the memory B cell subset in immunosuppressive therapy while avoiding the Breg or naïve/mature B lymphocyte depletion to obtain more favorable sustained outcomes.

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 Bruton's Tyrosine Kinase Regulates Immunoglobulin Promoter Activation in Association with the Transcription Factor Bright

2005 ◽  
Vol 25 (6) ◽  
pp. 2073-2084 ◽  
Author(s):  
Jaya Rajaiya ◽  
Melissa Hatfield ◽  
Jamee C. Nixon ◽  
David J. Rawlings ◽  
Carol F. Webb
Keyword(s):  
B Cells ◽  
Dna Binding ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Heavy Chain ◽  
Immunoglobulin Heavy Chain ◽  
Pleckstrin Homology Domain ◽  
Bruton’S Tyrosine Kinase ◽  
Immunoglobulin Gene ◽  
Bruton's Tyrosine Kinase

ABSTRACT Bright (B-cell regulator of immunoglobulin heavy chain transcription) binding to immunoglobulin heavy chain loci after B-cell activation is associated with increased heavy chain transcription. Our earlier reports demonstrated that Bright coimmunoprecipitates with Bruton's tyrosine kinase (Btk) and that these proteins associate in a DNA-binding complex in primary B cells. B cells from immunodeficient mice with a mutation in Btk failed to produce stable Bright DNA-binding complexes. In order to determine if Btk is important for Bright function, a transcription activation assay was established and analyzed using real-time PCR technology. Cells lacking both Bright and Btk were transfected with Bright and/or Btk along with an immunoglobulin heavy chain reporter construct. Immunoglobulin gene transcription was enhanced when Bright and Btk were coexpressed. In contrast, neither Bright nor Btk alone led to activation of heavy chain transcription. Furthermore, Bright function required both Btk kinase activity and sequences within the pleckstrin homology domain of Btk. Bright was not appreciably phosphorylated by Btk; however, a third tyrosine-phosphorylated protein coprecipitated with Bright. Thus, the ability of Bright to enhance immunoglobulin transcription critically requires functional Btk.

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 Transcriptional Regulatory Elements Within the First Intron of Bruton's Tyrosine Kinase

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 214-221
Author(s):  
Jurg Rohrer ◽  
Mary Ellen Conley
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Regulatory Elements ◽  
Negative Regulator ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Differentiation ◽  
Bruton's Tyrosine Kinase ◽  
First Intron ◽  
Transcriptional Regulatory

Defects in the gene for Bruton's tyrosine kinase (Btk) result in the disorder X-linked agammaglobulinemia (XLA). Whereas XLA is characterized by a profound defect in B-cell development, Btk is expressed in both the B lymphocyte and myeloid cell lineages. We evaluated a patient with XLA who had reduced amounts of Btk transcript but no abnormalities in his coding sequence. A single base-pair substitution in the first intron of Btk was identified in this patient, suggesting that this region may contain regulatory elements. Using reporter constructs we identified two transcriptional control elements in the first 500 bp of intron 1. A strong positive regulator, active in both pre-B cells and B cells, was identified within the first 43 bp of the intron. Gel-shift assays identified two Sp1 binding sites within this element. The patient's mutation results in an altered binding specificity of the proximal Sp1 binding site. A negative regulator, active in pre-B cells only, was located between base pairs 281 and 491 of the intron. These findings indicate that regulation of Btk transcription is complex and may involve several transcriptional regulatory factors at the different stages of B-cell differentiation.

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