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Article ; Online: B Cell Signaling and Activation in Autoimmunity.

Hendriks, Rudi W / Corneth, Odilia B J

2023 Volume 12, Issue 3

Abstract: Autoreactive B cells play a key role in the initiation or aggravation of many systemic and tissue-specific autoimmune disorders [ ... ]. ...

Abstract	Autoreactive B cells play a key role in the initiation or aggravation of many systemic and tissue-specific autoimmune disorders [...].
MeSH term(s)	Humans ; Autoimmunity ; Autoimmune Diseases ; B-Lymphocytes ; Signal Transduction
Language	English
Publishing date	2023-02-03
Publishing country	Switzerland
Document type	Editorial ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12030499
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Article ; Online: Aberrant B Cell Signaling in Autoimmune Diseases.

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

Cells

2022 Volume 11, Issue 21

Abstract: Aberrant B cell signaling plays a critical in role in various systemic and organ-specific autoimmune diseases. This is supported by genetic evidence by many functional studies in B cells from patients or specific animal models and by the observed ... ...

Abstract	Aberrant B cell signaling plays a critical in role in various systemic and organ-specific autoimmune diseases. This is supported by genetic evidence by many functional studies in B cells from patients or specific animal models and by the observed efficacy of small-molecule inhibitors. In this review, we first discuss key signal transduction pathways downstream of the B cell receptor (BCR) that ensure that autoreactive B cells are removed from the repertoire or functionally silenced. We provide an overview of aberrant BCR signaling that is associated with inappropriate B cell repertoire selection and activation or survival of peripheral B cell populations and plasma cells, finally leading to autoantibody formation. Next to BCR signaling, abnormalities in other signal transduction pathways have been implicated in autoimmune disease. These include reduced activity of several phosphates that are downstream of co-inhibitory receptors on B cells and increased levels of BAFF and APRIL, which support survival of B cells and plasma cells. Importantly, pathogenic synergy of the BCR and Toll-like receptors (TLR), which can be activated by endogenous ligands, such as self-nucleic acids, has been shown to enhance autoimmunity. Finally, we will briefly discuss therapeutic strategies for autoimmune disease based on interfering with signal transduction in B cells.
MeSH term(s)	Animals ; Receptors, Antigen, B-Cell/metabolism ; B-Lymphocytes ; Signal Transduction/genetics ; Autoimmune Diseases ; Toll-Like Receptors/metabolism
Chemical Substances	Receptors, Antigen, B-Cell ; Toll-Like Receptors
Language	English
Publishing date	2022-10-27
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11213391
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Article ; Online: A Versatile Protocol to Quantify BCR-mediated Phosphorylation in Human and Murine B Cell Subpopulations.

Rip, Jasper / Hendriks, Rudi W / Corneth, Odilia B J

Bio-protocol

2021 Volume 11, Issue 3, Page(s) e3902

Abstract: Signal transduction is the process by which molecular signals are transmitted from the cell surface to its interior, resulting in functional changes inside the cell. B cell receptor (BCR) signaling is of crucial importance for B cells, as it regulates ... ...

Abstract	Signal transduction is the process by which molecular signals are transmitted from the cell surface to its interior, resulting in functional changes inside the cell. B cell receptor (BCR) signaling is of crucial importance for B cells, as it regulates their differentiation, selection, survival, cellular activation and proliferation. Upon BCR engagement by antigen several protein kinases, lipases and linker molecules become phosphorylated. Phosphoflow cytometry (phosphoflow) is a flow cytometry-based method allowing for analysis of protein phosphorylation in single cells. Due to recent advances in methodology and antibody availability - together with the relatively easy quantification of phosphorylation - phosphoflow is increasingly and more commonly used, compared to classical western blot analysis. It can however be challenging to set-up a method that works for all targets of interest. Here, we present a step-by-step phosphoflow protocol allowing the evaluation of the phosphorylation status of signaling molecules in conjunction with extensive staining to identify various human and murine B cell subpopulations, as was previously published in the original paper by Rip
Language	English
Publishing date	2021-02-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.3902
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Article: Targeting Bruton's Tyrosine Kinase in Inflammatory and Autoimmune Pathologies.

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

Frontiers in cell and developmental biology

2021 Volume 9, Page(s) 668131

Abstract: Bruton's tyrosine kinase (BTK) was discovered due to its importance in B cell development, and it has a critical role in signal transduction downstream of the B cell receptor (BCR). Targeting of BTK with small molecule inhibitors has proven to be ... ...

Abstract	Bruton's tyrosine kinase (BTK) was discovered due to its importance in B cell development, and it has a critical role in signal transduction downstream of the B cell receptor (BCR). Targeting of BTK with small molecule inhibitors has proven to be efficacious in several B cell malignancies. Interestingly, recent studies reveal increased BTK protein expression in circulating resting B cells of patients with systemic autoimmune disease (AID) compared with healthy controls. Moreover, BTK phosphorylation following BCR stimulation
Language	English
Publishing date	2021-06-04
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2021.668131
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Article ; Online: Increased proportions of circulating PD-1

Miedema, Jelle R / de Jong, Lieke J / Kahlmann, Vivienne / Bergen, Ingrid M / Broos, Caroline E / Wijsenbeek, Marlies S / Hendriks, Rudi W / Corneth, Odilia B J

Respiratory research

2024 Volume 25, Issue 1, Page(s) 196

Abstract: Background: The treatment response to corticosteroids in patients with sarcoidosis is highly variable. CD4: Methods: We used multi-color flow cytometry to quantify activation marker expression on PB T cell populations in 22 treatment-naïve patients ... ...

Abstract	Background: The treatment response to corticosteroids in patients with sarcoidosis is highly variable. CD4 Methods: We used multi-color flow cytometry to quantify activation marker expression on PB T cell populations in 22 treatment-naïve patients and 21 healthy controls (HCs). Pulmonary function tests at baseline, 3 and 12 months were used to measure treatment effect. Results: Patients with sarcoidosis showed an absolute forced vital capacity (FVC) increase of 14.2% predicted (± 10.6, p < 0.0001) between baseline and 3 months. Good response to prednisone (defined as absolute FVC increase of ≥ 10% predicted) was observed in 12 patients. CD4 Conclusions: Increased proportions of circulating PD-1 Trial registration: NL44805.078.13.
MeSH term(s)	Humans ; Male ; Sarcoidosis, Pulmonary/drug therapy ; Sarcoidosis, Pulmonary/blood ; Sarcoidosis, Pulmonary/immunology ; Sarcoidosis, Pulmonary/diagnosis ; Female ; Middle Aged ; Programmed Cell Death 1 Receptor ; Prednisone/therapeutic use ; T-Lymphocytes, Regulatory/drug effects ; T-Lymphocytes, Regulatory/immunology ; Adult ; Treatment Outcome ; Memory T Cells/drug effects ; Memory T Cells/immunology ; Memory T Cells/metabolism ; CD4-Positive T-Lymphocytes/drug effects ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Glucocorticoids/therapeutic use ; Vital Capacity/drug effects ; Aged
Chemical Substances	Programmed Cell Death 1 Receptor ; Prednisone (VB0R961HZT) ; PDCD1 protein, human ; Glucocorticoids
Language	English
Publishing date	2024-05-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2041675-1
ISSN	1465-993X ; 1465-993X
ISSN (online)	1465-993X
ISSN	1465-993X
DOI	10.1186/s12931-024-02833-y
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Article ; Online: Aberrant B cell receptor signaling in circulating naïve and IgA

Neys, Stefan F H / Heutz, Judith W / van Hulst, Jennifer A C / Vink, Madelief / Bergen, Ingrid M / de Jong, Pascal H P / Lubberts, Erik / Hendriks, Rudi W / Corneth, Odilia B J

Journal of autoimmunity

2024 Volume 143, Page(s) 103168

Abstract: Objective: Altered B cell receptor (BCR) signaling has been implicated in the pathogenesis of rheumatoid arthritis (RA). Here we aimed to identify signaling aberrations in autoantibody-positive and autoantibody-negative RA patients by performing a ... ...

Abstract	Objective: Altered B cell receptor (BCR) signaling has been implicated in the pathogenesis of rheumatoid arthritis (RA). Here we aimed to identify signaling aberrations in autoantibody-positive and autoantibody-negative RA patients by performing a comprehensive analysis of the BCR signaling cascade in different B cell subsets. Methods: We first optimized phosphoflow cytometry for an in-depth analysis of BCR signaling across immunoglobulin isotypes in healthy donors. Subsequently, we compared BCR signaling in circulating B cell subsets from treatment-naïve, newly-diagnosed autoantibody-positive RA and autoantibody-negative RA patients and healthy controls (HCs). Results: We observed subset-specific phosphorylation patterns of the BCR signalosome in circulating B cells from healthy donors. Compared with HCs, autoantibody-positive RA patients displayed enhanced responses to BCR stimulation for multiple signaling proteins, specifically in naïve and IgA Conclusion: Collectively, the isotype-specific analysis of multiple key components of the BCR signalosome identified aberrant BCR signaling responses in treatment-naïve autoantibody-positive RA patients, particularly in naïve B cells and IgA
MeSH term(s)	Humans ; Autoantibodies ; Memory B Cells ; Arthritis, Rheumatoid ; Immunoglobulin Isotypes ; Receptors, Antigen, B-Cell ; Immunoglobulin A
Chemical Substances	Autoantibodies ; Immunoglobulin Isotypes ; Receptors, Antigen, B-Cell ; Immunoglobulin A
Language	English
Publishing date	2024-02-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639452-8
ISSN	1095-9157 ; 0896-8411
ISSN (online)	1095-9157
ISSN	0896-8411
DOI	10.1016/j.jaut.2024.103168
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Article ; Online: Bruton's Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease.

Neys, Stefan F H / Rip, Jasper / Hendriks, Rudi W / Corneth, Odilia B J

Drugs

2021 Volume 81, Issue 14, Page(s) 1605–1626

Abstract: Systemic autoimmune disorders are complex heterogeneous chronic diseases involving many different immune cells. A significant proportion of patients respond poorly to therapy. In addition, the high burden of adverse effects caused by "classical" anti- ... ...

Abstract	Systemic autoimmune disorders are complex heterogeneous chronic diseases involving many different immune cells. A significant proportion of patients respond poorly to therapy. In addition, the high burden of adverse effects caused by "classical" anti-rheumatic or immune modulatory drugs provides a need to develop more specific therapies that are better tolerated. Bruton's tyrosine kinase (BTK) is a crucial signaling protein that directly links B-cell receptor (BCR) signals to B-cell activation, proliferation, and survival. BTK is not only expressed in B cells but also in myeloid cells, and is involved in many different signaling pathways that drive autoimmunity. This makes BTK an interesting therapeutic target in the treatment of autoimmune diseases. The past decade has seen the emergence of first-line BTK small-molecule inhibitors with great efficacy in the treatment of B-cell malignancies, but with unfavorable safety profiles for use in autoimmunity due to off-target effects. The development of second-generation BTK inhibitors with superior BTK specificity has facilitated the investigation of their efficacy in clinical trials with autoimmune patients. In this review, we discuss the role of BTK in key signaling pathways involved in autoimmunity and provide an overview of the different inhibitors that are currently being investigated in clinical trials of systemic autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, as well as available results from completed trials.
MeSH term(s)	Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors ; Autoimmune Diseases/drug therapy ; Autoimmunity/drug effects ; B-Lymphocytes/drug effects ; Clinical Trials as Topic ; Humans ; Lymphocyte Activation/drug effects ; Receptors, Antigen, B-Cell/metabolism ; Signal Transduction/drug effects
Chemical Substances	Receptors, Antigen, B-Cell ; Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2)
Language	English
Publishing date	2021-10-05
Publishing country	New Zealand
Document type	Journal Article ; Review
ZDB-ID	120316-2
ISSN	1179-1950 ; 0012-6667
ISSN (online)	1179-1950
ISSN	0012-6667
DOI	10.1007/s40265-021-01592-0
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Zs.A 762: Show issues

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Article ; Online: Decreased BAFF Receptor Expression and Unaltered B Cell Receptor Signaling in Circulating B Cells from Primary Sjögren's Syndrome Patients at Diagnosis.

Neys, Stefan F H / Verstappen, Gwenny M / Bootsma, Hendrika / Kroese, Frans G M / Hendriks, Rudi W / Corneth, Odilia B J

International journal of molecular sciences

2022 Volume 23, Issue 9

Abstract: Animal models of autoimmunity and human genetic association studies indicate that the dysregulation of B-cell receptor (BCR) signaling is an important driver of autoimmunity. We previously showed that in circulating B cells from primary Sjögren's ... ...

Abstract	Animal models of autoimmunity and human genetic association studies indicate that the dysregulation of B-cell receptor (BCR) signaling is an important driver of autoimmunity. We previously showed that in circulating B cells from primary Sjögren's syndrome (pSS) patients with high systemic disease activity, protein expression of the BCR signaling molecule Bruton's tyrosine kinase (BTK) was increased and correlated with T-cell infiltration in the target organ. We hypothesized that these alterations could be driven by increased B-cell activating factor (BAFF) levels in pSS. Here, we investigated whether altered BCR signaling was already present at diagnosis and distinguished pSS from non-SS sicca patients. Using (phospho-)flow cytometry, we quantified the phosphorylation of BCR signaling molecules, and investigated BTK and BAFF receptor (BAFFR) expression in circulating B cell subsets in an inception cohort of non-SS sicca and pSS patients, as well as healthy controls (HCs). We found that both BTK protein levels and BCR signaling activity were comparable among groups. Interestingly, BAFFR expression was significantly downregulated in pSS, but not in non-SS sicca patients, compared with HCs, and correlated with pSS-associated alterations in B cell subsets. These data indicate reduced BAFFR expression as a possible sign of early B cell involvement and a diagnostic marker for pSS.
MeSH term(s)	Agammaglobulinaemia Tyrosine Kinase/metabolism ; B-Cell Activation Factor Receptor/genetics ; B-Cell Activation Factor Receptor/metabolism ; B-Lymphocyte Subsets/metabolism ; B-Lymphocytes/metabolism ; Humans ; Receptors, Antigen, B-Cell/metabolism ; Sjogren's Syndrome/diagnosis ; Sjogren's Syndrome/metabolism
Chemical Substances	B-Cell Activation Factor Receptor ; Receptors, Antigen, B-Cell ; Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2)
Language	English
Publishing date	2022-05-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23095101
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Article ; Online: Phosphoflow Protocol for Signaling Studies in Human and Murine B Cell Subpopulations.

Rip, Jasper / de Bruijn, Marjolein J W / Kaptein, Allard / Hendriks, Rudi W / Corneth, Odilia B J

Journal of immunology (Baltimore, Md. : 1950)

2020 Volume 204, Issue 10, Page(s) 2852–2863

Abstract: BCR signaling, involving phosphorylation of various downstream molecules, including kinases, lipases, and linkers, is crucial for B cell selection, survival, proliferation, and differentiation. Phosphoflow cytometry (phosphoflow) is a single-cell-based ... ...

Abstract	BCR signaling, involving phosphorylation of various downstream molecules, including kinases, lipases, and linkers, is crucial for B cell selection, survival, proliferation, and differentiation. Phosphoflow cytometry (phosphoflow) is a single-cell-based technique to measure phosphorylated intracellular proteins, providing a more quantitative read-out than Western blotting. Recent advances in phosphoflow basically allow simultaneous analysis of protein phosphorylation in B cell (sub)populations, without prior cell sorting. However, fixation and permeabilization procedures required for phosphoflow often affect cell surface epitopes or mAb conjugates, precluding the evaluation of the phosphorylation status of signaling proteins across different B cell subpopulations present in a single sample. In this study, we report a versatile phosphoflow protocol allowing extensive staining of B cell subpopulations in human peripheral blood or various anatomical compartments in the mouse, starting from freshly isolated or frozen cell suspensions. Both human and mouse B cell subpopulations showed different basal and BCR stimulation-induced phosphorylation levels of downstream signaling proteins. For example, peritoneal B-1 cells and splenic marginal zone B cells exhibited significantly increased basal (ex vivo) signaling and increased responsiveness to in vitro BCR stimulation compared with peritoneal B-2 cells and splenic follicular B cells, respectively. In addition, whereas stimulation with anti-IgM or anti-Igκ L chain Abs resulted in strong pCD79a and pPLCγ2 signals, IgD stimulation only induced CD79a but not pPLCγ2 phosphorylation. In summary, the protocol is user friendly and quantifies BCR-mediated phosphorylation with high sensitivity at the single-cell level, in combination with extensive staining to identify individual B cell development and differentiation stages.
MeSH term(s)	Animals ; B-Lymphocyte Subsets/physiology ; B-Lymphocytes/physiology ; CD79 Antigens/metabolism ; Cell Differentiation ; Cells, Cultured ; Flow Cytometry/methods ; Humans ; Immunoglobulin D/metabolism ; Immunoglobulin M/metabolism ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Phospholipase C gamma/metabolism ; Phosphorylation ; Receptors, Antigen, B-Cell/metabolism ; Signal Transduction ; Single-Cell Analysis
Chemical Substances	CD79 Antigens ; Immunoglobulin D ; Immunoglobulin M ; Receptors, Antigen, B-Cell ; PLCG2 protein, human (EC 3.1.4.3) ; Phospholipase C gamma (EC 3.1.4.3)
Language	English
Publishing date	2020-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1901117
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Ud II Zs.37: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Circulating T cells in sarcoidosis have an aberrantly activated phenotype that correlates with disease outcome.

Miedema, Jelle R / de Jong, Lieke J / van Uden, Denise / Bergen, Ingrid M / Kool, Mirjam / Broos, Caroline E / Kahlmann, Vivienne / Wijsenbeek, Marlies S / Hendriks, Rudi W / Corneth, Odilia B J

Journal of autoimmunity

2023 , Page(s) 103120

Abstract: Rationale: Disease course in sarcoidosis is highly variable. Bronchoalveolar lavage fluid and mediastinal lymph nodes show accumulation of activated T cells with a T-helper (Th)17.1 signature, which correlates with non-resolving sarcoidosis. We ... ...

Abstract	Rationale: Disease course in sarcoidosis is highly variable. Bronchoalveolar lavage fluid and mediastinal lymph nodes show accumulation of activated T cells with a T-helper (Th)17.1 signature, which correlates with non-resolving sarcoidosis. We hypothesize that the peripheral blood (PB) T cell phenotype may correlate with outcome. Objectives: To compare frequencies, phenotypes and function of circulating T cell populations in sarcoidosis patients with healthy controls (HCs) and correlate these parameters with outcome. Methods: We used multi-color flow cytometry to quantify activation marker expression on PB T cell subsets in treatment-naïve patients and HCs. The disease course was determined after 2-year follow-up. Cytokine production was measured after T cell stimulation in vitro. Measurements and main results: We observed significant differences between patients and HCs in several T cell populations, including CD8 Conclusions: Circulating T cell subpopulations of sarcoidosis patients display phenotypic abnormalities that correlate with disease outcome, supporting a critical role of aberrant T cell activation in sarcoidosis pathogenesis.
Language	English
Publishing date	2023-10-18
Publishing country	England
Document type	Journal Article
ZDB-ID	639452-8
ISSN	1095-9157 ; 0896-8411
ISSN (online)	1095-9157
ISSN	0896-8411
DOI	10.1016/j.jaut.2023.103120
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