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Cells
Special Issues
B Cell Signaling and Activation in Autoimmunity
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B Cell Signaling and Activation in Autoimmunity

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (1 April 2021) | Viewed by 44340

Special Issue Editors

Dr. Rudi Hendriks

E-Mail Website1 Website2
Guest Editor
Department of Pulmonary Medicine, Erasmus MC Rotterdam PO Box 2040, NL 3000 CA Rotterdam, The Netherlands
Interests: asthma; autoimmunity; BTK; epigenetics; immune signaling; lymphocytes
Special Issues, Collections and Topics in MDPI journals
Dr. Odilia Corneth

E-Mail Website
Guest Editor
Department of Pulmonary Medicine, Erasmus MC Rotterdam PO Box 2040, NL 3000 CA Rotterdam, The Netherlands
Interests: BCR signaling; BTK; autoimmune disease; pulmonary fibrosis

Special Issue Information

Dear Colleagues,

Although the evidence is overwhelming that B cells have a critical role in the initiation of many autoimmune diseases, the molecular mechanisms underlying dysregulation of B cell activity remain poorly understood. In addition, genetic associations underline the importance of B cells in autoimmunity. Defects in both early B cell tolerance checkpoints and various signaling pathways in B cells lead to the accumulation of autoimmune B cells, which are thought to contribute to aberrant T cell activation. Recently, transitional B cells, as well as age-associated B cells, have been proposed to play a key role in the development of autoimmune diseases. Current concepts for autoimmune pathogenesis focus on enhanced activation of B cells associated with unbalanced signaling in various pathways, particularly downstream of the B-cell receptor, the BAFF receptor and toll-like receptors. In this context, promising results in autoimmune mouse models have recently prompted clinical trials with BCR signaling inhibitors in patients with various autoimmune diseases.

This Special Issue is calling for reviews and original articles covering recent advances in fundamental and translational research on aberrant activation and signaling in B cells, emphasizing their role in various autoimmune disorders or in diseases with a critical autoimmune component.

We look forward to your contributions,

Dr. Rudi Hendriks,
Dr. Odilia Corneth
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • autoimmune disease
  • B lymphocytes
  • BCR
  • TLR
  • BAFF
  • B cell activation
  • mouse models
  • signal transduction

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Published Papers (8 papers)

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Editorial

Jump to: Research, Review

3 pages, 184 KiB  
Editorial
B Cell Signaling and Activation in Autoimmunity
by Rudi W. Hendriks and Odilia B. J. Corneth
Cells 2023, 12(3), 499; https://doi.org/10.3390/cells12030499 - 3 Feb 2023
Cited by 2 | Viewed by 1661
Abstract
Autoreactive B cells play a key role in the initiation or aggravation of many systemic and tissue-specific autoimmune disorders [...] Full article
(This article belongs to the Special Issue B Cell Signaling and Activation in Autoimmunity)

Research

Jump to: Editorial, Review

17 pages, 2256 KiB  
Article
Dysregulated PI3K Signaling in B Cells of CVID Patients
by Ina Harder, Matthias Münchhalfen, Geoffroy Andrieux, Melanie Boerries, Bodo Grimbacher, Hermann Eibel, Maria Elena Maccari, Stephan Ehl, Jürgen Wienands, Julia Jellusova, Klaus Warnatz and Baerbel Keller
Cells 2022, 11(3), 464; https://doi.org/10.3390/cells11030464 - 28 Jan 2022
Cited by 7 | Viewed by 3855
Abstract
The altered wiring of signaling pathways downstream of antigen receptors of T and B cells contributes to the dysregulation of the adaptive immune system, potentially causing immunodeficiency and autoimmunity. In humans, the investigation of such complex systems benefits from nature’s experiments in patients [...] Read more.
The altered wiring of signaling pathways downstream of antigen receptors of T and B cells contributes to the dysregulation of the adaptive immune system, potentially causing immunodeficiency and autoimmunity. In humans, the investigation of such complex systems benefits from nature’s experiments in patients with genetically defined primary immunodeficiencies. Disturbed B-cell receptor (BCR) signaling in a subgroup of common variable immunodeficiency (CVID) patients with immune dysregulation and expanded T-bethighCD21low B cells in peripheral blood has been previously reported. Here, we investigate PI3K signaling and its targets as crucial regulators of survival, proliferation and metabolism by intracellular flow cytometry, imaging flow cytometry and RNAseq. We observed increased basal but disturbed BCR-induced PI3K signaling, especially in T-bethighCD21low B cells from CVID patients, translating into impaired activation of crucial downstream molecules and affecting proliferation, survival and the metabolic profile. In contrast to CVID, increased basal activity of PI3K in patients with a gain-of-function mutation in PIK3CD and activated PI3K delta syndrome (APDS) did not result in impaired BCR-induced AKT-mTOR-S6 phosphorylation, highlighting that signaling defects in B cells in CVID and APDS patients are fundamentally different and that assessing responses to BCR stimulation is an appropriate confirmative diagnostic test for APDS. The active PI3K signaling in vivo may render autoreactive T-bethighCD21low B cells in CVID at the same time to be more sensitive to mTOR or PI3K inhibition. Full article
(This article belongs to the Special Issue B Cell Signaling and Activation in Autoimmunity)
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15 pages, 2454 KiB  
Article
Aberrant B Cell Receptor Signaling in Naïve B Cells from Patients with Idiopathic Pulmonary Fibrosis
by Stefan F. H. Neys, Peter Heukels, Jennifer A. C. van Hulst, Jasper Rip, Marlies S. Wijsenbeek, Rudi W. Hendriks and Odilia B. J. Corneth
Cells 2021, 10(6), 1321; https://doi.org/10.3390/cells10061321 - 26 May 2021
Cited by 14 | Viewed by 3545
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue B Cell Signaling and Activation in Autoimmunity)
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Graphical abstract

19 pages, 4612 KiB  
Article
Flow Cytometric Methods for the Detection of Intracellular Signaling Proteins and Transcription Factors Reveal Heterogeneity in Differentiating Human B Cell Subsets
by Casper Marsman, Tineke Jorritsma, Anja ten Brinke and S. Marieke van Ham
Cells 2020, 9(12), 2633; https://doi.org/10.3390/cells9122633 - 8 Dec 2020
Cited by 20 | Viewed by 5535
Abstract
The flow cytometric detection of intracellular (IC) signaling proteins and transcription factors (TFs) will help to elucidate the regulation of B cell survival, proliferation and differentiation. However, the simultaneous detection of signaling proteins or TFs with membrane markers (MMs) can be challenging, as [...] Read more.
The flow cytometric detection of intracellular (IC) signaling proteins and transcription factors (TFs) will help to elucidate the regulation of B cell survival, proliferation and differentiation. However, the simultaneous detection of signaling proteins or TFs with membrane markers (MMs) can be challenging, as the required fixation and permeabilization procedures can affect the functionality of conjugated antibodies. Here, a phosphoflow method is presented for the detection of activated NF-κB p65 and phosphorylated STAT1, STAT3, STAT5 and STAT6, together with the B cell differentiation MMs CD19, CD27 and CD38. Additionally, a TF-flow method is presented that allows the detection of the B cell TFs PAX5, c-MYC, BCL6 and AID and antibody-secreting cell (ASC) TFs BLIMP1 and XBP-1s, together with MMs. Applying these methods on in vitro-induced human B cell differentiation cultures showed significantly different steady-state levels, and responses to stimulation, of phosphorylated signaling proteins in CD27-expressing B cell and ASC populations. The TF-flow protocol and Uniform Manifold Approximation and Projection (UMAP) analysis revealed heterogeneity in TF expression within stimulated CD27- or CD38-expressing B cell subsets. The methods presented here allow for the sensitive analysis of STAT, NF-κB p65 signaling and TFs, together with B cell differentiation MMs, at single-cell resolution. This will aid the further investigation of B cell responses in both health and disease. Full article
(This article belongs to the Special Issue B Cell Signaling and Activation in Autoimmunity)
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Review

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34 pages, 2804 KiB  
Review
Aberrant B Cell Signaling in Autoimmune Diseases
by Odilia B. J. Corneth, Stefan F. H. Neys and Rudi W. Hendriks
Cells 2022, 11(21), 3391; https://doi.org/10.3390/cells11213391 - 27 Oct 2022
Cited by 17 | Viewed by 4185
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. [...] Read more.
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. Full article
(This article belongs to the Special Issue B Cell Signaling and Activation in Autoimmunity)
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18 pages, 1500 KiB  
Review
B Cell Activation and Escape of Tolerance Checkpoints: Recent Insights from Studying Autoreactive B Cells
by Carlo G. Bonasia, Wayel H. Abdulahad, Abraham Rutgers, Peter Heeringa and Nicolaas A. Bos
Cells 2021, 10(5), 1190; https://doi.org/10.3390/cells10051190 - 13 May 2021
Cited by 31 | Viewed by 9805
Abstract
Autoreactive B cells are key drivers of pathogenic processes in autoimmune diseases by the production of autoantibodies, secretion of cytokines, and presentation of autoantigens to T cells. However, the mechanisms that underlie the development of autoreactive B cells are not well understood. Here, [...] Read more.
Autoreactive B cells are key drivers of pathogenic processes in autoimmune diseases by the production of autoantibodies, secretion of cytokines, and presentation of autoantigens to T cells. However, the mechanisms that underlie the development of autoreactive B cells are not well understood. Here, we review recent studies leveraging novel techniques to identify and characterize (auto)antigen-specific B cells. The insights gained from such studies pertaining to the mechanisms involved in the escape of tolerance checkpoints and the activation of autoreactive B cells are discussed. In addition, we briefly highlight potential therapeutic strategies to target and eliminate autoreactive B cells in autoimmune diseases. Full article
(This article belongs to the Special Issue B Cell Signaling and Activation in Autoimmunity)
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10 pages, 714 KiB  
Review
The Role of BANK1 in B Cell Signaling and Disease
by Gonzalo Gómez Hernández, María Morell and Marta E. Alarcón-Riquelme
Cells 2021, 10(5), 1184; https://doi.org/10.3390/cells10051184 - 12 May 2021
Cited by 23 | Viewed by 6702
Abstract
The B cell scaffold protein with ankyrin repeats (BANK1) is expressed primarily in B cells and with multiple but discrete roles in B cell signaling, including B cell receptor signaling, CD40-related signaling, and Toll-like receptor (TLR) signaling. The gene for BANK1, located in [...] Read more.
The B cell scaffold protein with ankyrin repeats (BANK1) is expressed primarily in B cells and with multiple but discrete roles in B cell signaling, including B cell receptor signaling, CD40-related signaling, and Toll-like receptor (TLR) signaling. The gene for BANK1, located in chromosome 4, has been found to contain genetic variants that are associated with several autoimmune diseases and also other complex phenotypes, in particular, with systemic lupus erythematosus. Common genetic variants are associated with changes in BANK1 expression in B cells, while rare variants modify their capacity to bind efferent effectors during signaling. A BANK1-deficient model has shown the importance of BANK1 during TLR7 and TLR9 signaling and has confirmed its role in the disease. Still, much needs to be done to fully understand the function of BANK1, but the main conclusion is that it may be the link between different signaling functions within the B cells and they may act to synergize the various pathways within a cell. With this review, we hope to enhance the interest in this molecule. Full article
(This article belongs to the Special Issue B Cell Signaling and Activation in Autoimmunity)
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32 pages, 977 KiB  
Review
Skin-Associated B Cells in the Pathogenesis of Cutaneous Autoimmune Diseases—Implications for Therapeutic Approaches
by Tanja Fetter, Dennis Niebel, Christine Braegelmann and Joerg Wenzel
Cells 2020, 9(12), 2627; https://doi.org/10.3390/cells9122627 - 7 Dec 2020
Cited by 35 | Viewed by 7449
Abstract
B lymphocytes are crucial mediators of systemic immune responses and are known to be substantial in the pathogenesis of autoimmune diseases with cutaneous manifestations. Amongst them are lupus erythematosus, dermatomyositis, systemic sclerosis and psoriasis, and particularly those driven by autoantibodies such as pemphigus [...] Read more.
B lymphocytes are crucial mediators of systemic immune responses and are known to be substantial in the pathogenesis of autoimmune diseases with cutaneous manifestations. Amongst them are lupus erythematosus, dermatomyositis, systemic sclerosis and psoriasis, and particularly those driven by autoantibodies such as pemphigus and pemphigoid. However, the concept of autoreactive skin-associated B cells, which may reside in the skin and locally contribute to chronic inflammation, is gradually evolving. These cells are believed to differ from B cells of primary and secondary lymphoid organs and may provide additional features besides autoantibody production, including cytokine expression and crosstalk to autoreactive T cells in an antigen-presenting manner. In chronically inflamed skin, B cells may appear in tertiary lymphoid structures. Those abnormal lymph node-like structures comprise a network of immune and stromal cells possibly enriched by vascular structures and thus constitute an ideal niche for local autoimmune responses. In this review, we describe current considerations of different B cell subsets and their assumed role in skin autoimmunity. Moreover, we discuss traditional and B cell-associated approaches for the treatment of autoimmune skin diseases, including drugs targeting B cells (e.g., CD19- and CD20-antibodies), plasma cells (e.g., proteasome inhibitors, CXCR4 antagonists), activated pathways (such as BTK- and PI3K-inhibitors) and associated activator molecules (BLyS, APRIL). Full article
(This article belongs to the Special Issue B Cell Signaling and Activation in Autoimmunity)
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