Toll-like receptors: lessons to learn from normal and malignant human B cells

Abstract The humoral immune system senses microbes via recognition of specific microbial molecular motifs by Toll-like receptors (TLRs). These encounters promote plasma cell differentiation and antibody production. Recent studies have demonstrated the importance of the TLR system in enhancing antibody-mediated defense against infections and maintaining memory B cells. These results have led the way to the design of vaccines that target B cells by engaging TLRs. In hematologic malignancies, cells often retain B cell–specific receptors and associated functions. Among these, TLRs are currently exploited to target different subclasses of B-cell leukemia, and TLR agonists are currently being evaluated in clinical trials. However, accumulating evidence suggests that endogenous TLR ligands or chronic infections promote tumor growth, thus providing a need for further investigations to decipher the exact function of TLRs in the B-cell lineage and in neoplastic B cells. The aim of this review is to present and discuss the latest advances with regard to the expression and function of TLRs in both healthy and malignant B cells. Special attention will be focused on the growth-promoting effects of TLR ligands on leukemic B cells and their potential clinical impact.

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Hide and seek: interplay between influenza viruses and B cells

International Immunology ◽

10.1093/intimm/dxaa028 ◽

2020 ◽

Vol 32 (9) ◽

pp. 605-611 ◽

Cited By ~ 2

Author(s):

Masayuki Kuraoka ◽

Yu Adachi ◽

Yoshimasa Takahashi

Keyword(s):

B Cells ◽

B Cell ◽

Surface Protein ◽

Influenza Viruses ◽

Influenza Vaccines ◽

Native Structure ◽

Humoral Immune ◽

Protective Antibodies ◽

Major Surface ◽

And Function

Abstract Influenza virus constantly acquires genetic mutations/reassortment in the major surface protein, hemagglutinin (HA), resulting in the generation of strains with antigenic variations. There are, however, HA epitopes that are conserved across influenza viruses and are targeted by broadly protective antibodies. A goal for the next-generation influenza vaccines is to stimulate B-cell responses against such conserved epitopes in order to provide broad protection against divergent influenza viruses. Broadly protective B cells, however, are not easily activated by HA antigens with native structure, because the virus has multiple strategies to escape from the humoral immune responses directed to the conserved epitopes. One such strategy is to hide the conserved epitopes from the B-cell surveillance by steric hindrance. Technical advancement in the analysis of the human B-cell antigen receptor (BCR) repertoire has dissected the BCRs to HA epitopes that are hidden in the native structure but are targeted by broadly protective antibodies. We describe here the characterization and function of broadly protective antibodies and strategies that enable B cells to seek these hidden epitopes, with potential implications for the development of universal influenza vaccines.

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Essential Immunoregulatory Role for BCAP in B Cell Development and Function

Journal of Experimental Medicine ◽

10.1084/jem.20011751 ◽

2002 ◽

Vol 195 (5) ◽

pp. 535-545 ◽

Cited By ~ 89

Author(s):

Tetsuo Yamazaki ◽

Kiyoshi Takeda ◽

Kumiko Gotoh ◽

Hiroshi Takeshima ◽

Shizuo Akira ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Receptor ◽

Cell Development ◽

B Cell Development ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Phosphoinositide 3 Kinase ◽

And Function ◽

B Cell Deficiency

BCAP was recently cloned as a binding molecule to phosphoinositide 3-kinase (PI3K). To investigate the role of BCAP, mutant mice deficient in BCAP were generated. While BCAP-deficient mice are viable, they have decreased numbers of mature B cells and B1 B cell deficiency. The mice produce lower titers of serum immunoglobulin (Ig)M and IgG3, and mount attenuated responses to T cell–independent type II antigen. Upon B cell receptor cross-linking, BCAP-deficient B cells exhibit reduced Ca2+ mobilization and poor proliferative responses. These findings demonstrate that BCAP plays a pivotal immunoregulatory role in B cell development and humoral immune responses.

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bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice.

Journal of Experimental Medicine ◽

10.1084/jem.183.2.381 ◽

1996 ◽

Vol 183 (2) ◽

pp. 381-391 ◽

Cited By ~ 140

Author(s):

D A Grillot ◽

R Merino ◽

J C Pena ◽

W C Fanslow ◽

F D Finkelman ◽

...

Keyword(s):

B Cells ◽

Transgenic Mice ◽

B Cell ◽

Cell Lineage ◽

Cell Development ◽

B Cell Development ◽

Immunoglobulin M ◽

Protective Mechanism ◽

And Function ◽

Peripheral B Cells

We have assessed during B cell development, the regulation and function of bcl-x, a member of the bcl-2 family of apoptosis regulatory genes. Here we show that Bcl-xL, a product of bcl-x, is expressed in pre-B cells but downregulated at the immature and mature stages of B cell development. Bcl-xL but not Bcl-2 is rapidly induced in peripheral B cells upon surface immunoglobulin M (IgM) cross-linking, CD40 signaling, or LPS stimulation. Transgenic mice that overexpressed Bcl-xL within the B cell lineage exhibited marked accumulation of peripheral B cells in lymphoid organs and enhanced survival of developing and mature B cells. B cell survival was further increased by simultaneous expression of bcl-xL and bcl-2 transgenes. These studies demonstrate that Bcl-2 and Bcl-xL are regulated differentially during B cell development and activation of mature B cells. Induction of Bcl-xL after signaling through surface IgM and CD40 appears to provide mature B cells with an additional protective mechanism against apoptotic signals associated with antigen-induced activation and proliferation.

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Long noncoding RNAs in B-cell development and activation

Blood ◽

10.1182/blood-2015-11-680843 ◽

2016 ◽

Vol 128 (7) ◽

pp. e10-e19 ◽

Cited By ~ 48

Author(s):

Tiago F. Brazão ◽

Jethro S. Johnson ◽

Jennifer Müller ◽

Andreas Heger ◽

Chris P. Ponting ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

De Novo ◽

Lymphoblastic Leukemia ◽

Cell Lineage ◽

Noncoding Rnas ◽

Cell Development ◽

B Cell Development ◽

Long Noncoding Rnas ◽

Human B Cells

AbstractLong noncoding RNAs (lncRNAs) are potentially important regulators of cell differentiation and development, but little is known about their roles in B lymphocytes. Using RNA-seq and de novo transcript assembly, we identified 4516 lncRNAs expressed in 11 stages of B-cell development and activation. Most of these lncRNAs have not been previously detected, even in the closely related T-cell lineage. Comparison with lncRNAs previously described in human B cells identified 185 mouse lncRNAs that have human orthologs. Using chromatin immunoprecipitation-seq, we classified 20% of the lncRNAs as either enhancer-associated (eRNA) or promoter-associated RNAs. We identified 126 eRNAs whose expression closely correlated with the nearest coding gene, thereby indicating the likely location of numerous enhancers active in the B-cell lineage. Furthermore, using this catalog of newly discovered lncRNAs, we show that PAX5, a transcription factor required to specify the B-cell lineage, bound to and regulated the expression of 109 lncRNAs in pro-B and mature B cells and 184 lncRNAs in acute lymphoblastic leukemia.

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Transcription factor Zfx controls BCR-induced proliferation and survival of B lymphocytes

Blood ◽

10.1182/blood-2008-11-188888 ◽

2009 ◽

Vol 113 (23) ◽

pp. 5857-5867 ◽

Cited By ~ 15

Author(s):

Teresita L. Arenzana ◽

Matthew R. Smith-Raska ◽

Boris Reizis

Keyword(s):

Transcription Factor ◽

B Cells ◽

B Cell ◽

B Lymphocytes ◽

Cell Lineage ◽

Cell Development ◽

B Cell Development ◽

Stem Cell Maintenance ◽

And Function ◽

Cell Maintenance

Abstract The development, homeostasis, and function of B lymphocytes involve multiple rounds of B-cell receptor (BCR)–controlled proliferation and prolonged maintenance. We analyzed the role of transcription factor Zfx, a recently identified regulator of hematopoietic stem cell maintenance, in B-cell development and homeostasis. Panhematopoietic or B cell–specific deletion of Zfx in the bone marrow blocked B-cell development at the pre-BCR selection checkpoint. Zfx deficiency in peripheral B cells caused accelerated B-cell turnover, depletion of mature recirculating B cells, and delayed T-dependent antibody responses. In addition, the numbers and function of B-1 cell lineage were reduced. Zfx-deficient B cells showed normal proximal BCR signaling, but impaired BCR-induced proliferation and survival in vitro. This was accompanied by aberrantly enhanced and prolonged integrated stress response and by delayed induction of cyclin D2 and Bcl-xL proteins. Thus, Zfx restrains the stress response and couples antigen receptor signaling to cell expansion and maintenance during B-cell development and peripheral homeostasis. These results identify a novel transcriptional regulator of the B-cell lineage and highlight the common genetic control of stem cell maintenance and lymphocyte homeostasis.

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Comprehensive analyses of B-cell compartments across the human body reveal novel subsets and a gut-resident memory phenotype

Blood ◽

10.1182/blood.2019002782 ◽

2020 ◽

Vol 136 (24) ◽

pp. 2774-2785 ◽

Cited By ~ 2

Author(s):

Nadine M. Weisel ◽

Florian J. Weisel ◽

Donna L. Farber ◽

Lisa A. Borghesi ◽

Yufeng Shen ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Surface Expression ◽

Gene Signature ◽

Organ Donors ◽

Cell Compartments ◽

Human B Cells ◽

Donor Variability ◽

And Function ◽

Human B Cell

Abstract Although human B cells have been extensively studied, most reports have used peripheral blood as a source. Here, we used a unique tissue resource derived from healthy organ donors to deeply characterize human B-cell compartments across multiple tissues and donors. These datasets revealed that B cells in the blood are not in homeostasis with compartments in other tissues. We found striking donor-to-donor variability in the frequencies and isotype of CD27+ memory B cells (MBCs). A comprehensive antibody-based screen revealed markers of MBC and allowed identification of novel MBC subsets with distinct functions defined according to surface expression of CD69 and CD45RB. We defined a tissue-resident MBC phenotype that was predominant in the gut but absent in blood. RNA-sequencing of MBC subsets from multiple tissues revealed a tissue-resident MBC gene signature as well as gut- and spleen-specific signatures. Overall, these studies provide novel insights into the nature and function of human B-cell compartments across multiple tissues.

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Shared transcriptional profiles of atypical B cells suggest common drivers of expansion and function in malaria, HIV, and autoimmunity

Science Advances ◽

10.1126/sciadv.abg8384 ◽

2021 ◽

Vol 7 (22) ◽

pp. eabg8384

Author(s):

Prasida Holla ◽

Brian Dizon ◽

Abhijit A. Ambegaonkar ◽

Noga Rogel ◽

Ella Goldschmidt ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Lineage ◽

Cell Receptor ◽

Interferon Γ ◽

Substantial Impact ◽

Transcriptional Profiles ◽

Receptor Repertoire ◽

And Function ◽

Human B Cell

Chronic infectious diseases have a substantial impact on the human B cell compartment including a notable expansion of B cells here termed atypical B cells (ABCs). Using unbiased single-cell RNA sequencing (scRNA-seq), we uncovered and characterized heterogeneities in naïve B cell, classical memory B cells, and ABC subsets. We showed remarkably similar transcriptional profiles for ABC clusters in malaria, HIV, and autoimmune diseases and demonstrated that interferon-γ drove the expansion of ABCs in malaria. These observations suggest that ABCs represent a separate B cell lineage with a common inducer that further diversifies and acquires disease-specific characteristics and functions. In malaria, we identified ABC subsets based on isotype expression that differed in expansion in African children and in B cell receptor repertoire characteristics. Of particular interest, IgD+IgMlo and IgD−IgG+ ABCs acquired a high antigen affinity threshold for activation, suggesting that ABCs may limit autoimmune responses to low-affinity self-antigens in chronic malaria.

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Publisher Correction to: Direct contact between Plasmodium falciparum and human B-cells in a novel co-culture increases parasite growth and affects B-cell growth

Malaria Journal ◽

10.1186/s12936-021-03853-5 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Sreenivasulu B. Reddy ◽

Noemi Nagy ◽

Caroline Rönnberg ◽

Francesca Chiodi ◽

Allan Lugaajju ◽

...

Keyword(s):

Plasmodium Falciparum ◽

B Cells ◽

Cell Growth ◽

B Cell ◽

Direct Contact ◽

Parasite Growth ◽

Human B Cells

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AB0024 IN VITRO CHARACTERIZATION OF CENERIMOD, A POTENT AND SELECTIVE SPHINGOSINE 1-PHOSPHATE RECEPTOR 1 (S1P1) MODULATOR IN PREVENTING MIGRATION OF NON-ACTIVATED AND ACTIVATED PRIMARY HUMAN B CELLS IN THE PRESENCE OR ABSENCE OF GLUCOCORTICOIDS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2482 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1046.1-1046

Author(s):

L. Schlicher ◽

P. Kulig ◽

M. Murphy ◽

M. Keller

Keyword(s):

B Cells ◽

B Cell ◽

B Lymphocytes ◽

Cell Activation ◽

Surface Expression ◽

Cell Surface Expression ◽

B Cell Activation ◽

Human B Cells ◽

Circulating Lymphocytes

Background:Cenerimod is a potent, selective, and orally active sphingosine 1-phosphate receptor 1 (S1P1) modulator that is currently being evaluated in a Phase 2b study in patients with systemic lupus erythematosus (SLE) (NCT03742037). S1P1 receptor modulators sequester circulating lymphocytes within lymph nodes, thereby reducing pathogenic autoimmune cells (including B lymphocytes) in the blood stream and in inflamed tissues. Extensive clinical experience has become available for the nonselective S1P receptor modulator fingolimod in relapsing forms of multiple sclerosis, supporting this therapeutic concept for the treatment of autoimmune disorders.Objectives:Although the effect of S1P-receptor modulators in reducing peripheral B cells is well documented1,2, the role of the S1P1 receptor on this cell type is only incompletely understood. In this study, the mode of action of cenerimod on primary human B cells was investigated in a series of in vitro experiments, including S1P1 receptor cell surface expression and chemotaxis towards S1P. Moreover, S1P1 expression following B cell activation in vitro was studied. As glucocorticoids (GC) are frequently used in the treatment of patients with autoimmune disorders including SLE, the potential influence of GC on the mode of action of cenerimod was evaluated.Methods:Primary human B lymphocytes from healthy donors were isolated from whole blood. In one set of experiments, cells were treated with different concentrations of cenerimod to measure S1P1 receptor internalization by flow cytometry. In a second set of experiments, isolated B cells were activated using different stimuli or left untreated. Cells were then analysed for S1P1 and CD69 cell surface expression and tested in a novel real-time S1P-mediated migration assay. In addition, the effect of physiological concentrations of GCs (prednisolone and prednisone) on cenerimod activity in preventing S1P mediated migration was tested.Results:In vitro, cenerimod led to a dose-dependent internalization of the S1P1 receptor on primary human B lymphocytes. Cenerimod also blocked migration of nonactivated and activated B lymphocytes towards S1P in a concentration-dependent manner, which is in line with the retention of lymphocytes in the lymph node and the reduction of circulating lymphocytes observed in the clinical setting. Upon B cell activation, which was monitored by CD69 upregulation, a simultaneous downregulation of S1P1 expression was detected, leading to less efficient S1P-directed cell migration. Importantly, physiological concentrations of GC did not affect the inhibitory activity of cenerimod on B cell migration.Conclusion:These results show that cenerimod, by modulating S1P1, blocks B lymphocyte migration towards its natural chemoattractant S1P and demonstrate compatibility of cenerimod with GC. These results are consistent with results of comparable experiments done previously using primary human T lymphocytes.References:[1]Nakamura M et al., Mult Scler. 2014 Sep; 20(10):1371-80.[2]Strasser DS et al., RMD Open 2020;6:e001261.Disclosure of Interests:None declared

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WASP confers selective advantage for specific hematopoietic cell populations and serves a unique role in marginal zone B-cell homeostasis and function

Blood ◽

10.1182/blood-2008-02-140715 ◽

2008 ◽

Vol 112 (10) ◽

pp. 4139-4147 ◽

Cited By ~ 71

Author(s):

Lisa S. Westerberg ◽

Miguel A. de la Fuente ◽

Fredrik Wermeling ◽

Hans D. Ochs ◽

Mikael C. I. Karlsson ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Marginal Zone ◽

Hematopoietic Cells ◽

Selective Advantage ◽

Relative Contribution ◽

B Cell Homeostasis ◽

And Function

Abstract Development of hematopoietic cells depends on a dynamic actin cytoskeleton. Here we demonstrate that expression of the cytoskeletal regulator WASP, mutated in the Wiskott-Aldrich syndrome, provides selective advantage for the development of naturally occurring regulatory T cells, natural killer T cells, CD4+ and CD8+ T lymphocytes, marginal zone (MZ) B cells, MZ macrophages, and platelets. To define the relative contribution of MZ B cells and MZ macrophages for MZ development, we generated wild-type and WASP-deficient bone marrow chimeric mice, with full restoration of the MZ. However, even in the presence of MZ macrophages, only 10% of MZ B cells were of WASP-deficient origin. We show that WASP-deficient MZ B cells hyperproliferate in vivo and fail to respond to sphingosine-1-phosphate, a crucial chemoattractant for MZ B-cell positioning. Abnormalities of the MZ compartment in WASP−/− mice lead to aberrant uptake of Staphylococcus aureus and to a reduced immune response to TNP-Ficoll. Moreover, WASP-deficient mice have increased levels of “natural” IgM antibodies. Our findings reveal that WASP regulates both development and function of hematopoietic cells. We demonstrate that WASP deficiency leads to an aberrant MZ that may affect responses to blood-borne pathogens and peripheral B-cell tolerance.

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