Regulatory B cells (Bregs) modulate immune responses predominantly, although not exclusively, via the release of IL-10. The importance of human Bregs in the maintenance of immune homeostasis comes ...from a variety of immune-related pathologies, such as autoimmune diseases, cancers, and chronic infections that are often associated with abnormalities in Breg numbers or function. A continuous effort toward understanding Breg biology in healthy individuals will provide new opportunities to develop Breg immunotherapy that could prove beneficial in treating various immune-mediated pathologies. In this Review, we discuss findings regarding human Bregs, including their mechanisms of suppression and role in different disease settings. We also propose several therapeutic strategies targeting Bregs for better management of immune disorders.
Over the last decade it has become evident that in addition to producing antibody, B cells activate the immune system by producing cytokines and via antigen presentation. In addition, B cells also ...exhibit immunosuppressive functions via diverse regulatory mechanisms. This subset of B cells, known as regulatory B cells (Bregs), contributes to the maintenance of tolerance, primarily via the production of IL-10. Studies in experimental animal models, as well as in patients with autoimmune diseases, have identified multiple Breg subsets exhibiting diverse mechanisms of immune suppression. In this review, we describe the different Breg subsets identified in mice and humans, and their diverse mechanisms of suppression in different disease settings.
B cells are regarded for their capacity to produce antibody. However, recent advances in B cell biology have capitalized on old findings and demonstrated that B cells also release a broad variety of ...cytokines. As with T helper cells, B cells can be classified into subsets according to the cytokine milieu that they produce. One functional B cell subset, regulatory B cells (Bregs), has recently been shown to contribute to the maintenance of the fine equilibrium required for tolerance. Bregs restrain the excessive inflammatory responses that occur during autoimmune diseases or that can be caused by unresolved infections. Pivotal to Breg function is interleukin-10 (IL-10), which inhibits proinflammatory cytokines and supports regulatory T cell differentiation. This review reports and discusses the factors that are important for Breg differentiation and for their effector function in both mouse and human.
B cells have a central role in many autoimmune diseases, including in those with renal involvement, as well as in the immunological response to kidney transplantation. The majority of B cell studies ...have focused on their pathological role as antibody producers. However, these cells have broad functions in immune responses beyond immunoglobulin secretion, including antigen presentation to T cells and cytokine production. Importantly, not all B cell subsets enhance immune responses. Regulatory B (B
) cells attenuate inflammation and contribute to the maintenance of immune tolerance. B
cells are numerically deficient and/or dysfunctional in several autoimmune diseases that can affect the kidneys, including systemic lupus erythematosus and anti-neutrophil cytoplasmic antibody-associated vasculitis, as well as in some groups of renal transplant recipients with alloimmune graft damage. B cell-targeting biologics have been trialled with promising results in diverse immune-mediated renal conditions. These therapies can affect both pro-inflammatory B cells and B
cells, potentially limiting their long-term efficacy. Future strategies might involve the modulation of pro-inflammatory B cells in combination with the stimulation of regulatory subsets. Additionally, the monitoring of individual B cell subsets in patients may lead to the discovery of novel biomarkers that could help to predict disease relapse or progression.
Signals controlling the generation of regulatory B (Breg) cells remain ill-defined. Here we report an “auto”-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells. ...In healthy individuals, pDCs drive the differentiation of CD19+CD24hiCD38hi (immature) B cells into IL-10-producing CD24+CD38hi Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement. CD24+CD38hi Breg cells conversely restrained IFN-α production by pDCs via IL-10 release. In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells. This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α. Defective pDC-mediated expansion of CD24+CD38hi Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation. Both altered pDC-CD24+CD38hi Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab. We propose that alteration in pDC-CD24+CD38hi Breg cell interaction contributes to the pathogenesis of SLE.
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•pDCs induce the differentiation of Breg cells in an IFN-α-dependent manner•Breg cells limit pDC-derived IFN-α in an IL-10-dependent mechanism•pDCs are hyperactivated in SLE and fail to induce Breg cells•Patients responding to rituximab display a normalized pDC-Breg cell interaction
The signals required for Breg cell differentiation in humans are currently unknown. Mauri and colleagues show that plasmacytoid dendritic cells, via the provision of IFN-α, govern the differentiation of immature B cells into regulatory B cells that restrain inflammation.
The differentiation of IL-10-producing regulatory B cells (Bregs) in response to gut-microbiota-derived signals supports the maintenance of tolerance. However, whether microbiota-derived metabolites ...can modulate Breg suppressive function remains unknown. Here, we demonstrate that rheumatoid arthritis (RA) patients and arthritic mice have a reduction in microbial-derived short-chain fatty acids (SCFAs) compared to healthy controls and that in mice, supplementation with the SCFA butyrate reduces arthritis severity. Butyrate supplementation suppresses arthritis in a Breg-dependent manner by increasing the level of the serotonin-derived metabolite 5-Hydroxyindole-3-acetic acid (5-HIAA), which activates the aryl-hydrocarbon receptor (AhR), a newly discovered transcriptional marker for Breg function. Thus, butyrate supplementation via AhR activation controls a molecular program that supports Breg function while inhibiting germinal center (GC) B cell and plasmablast differentiation. Our study demonstrates that butyrate supplementation may serve as a viable therapy for the amelioration of systemic autoimmune disorders.
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•Stool butyrate levels are reduced in patients with RA compared to healthy controls•Supplementation with butyrate suppresses arthritis severity in a mouse model•Suppression of arthritis by butyrate supplementation depends upon AhR+Bregs•Butyrate increases serotonin-derived 5-HIAA, which directly activates AhR+Bregs
The environmental signals that influence Breg function are not yet fully defined. Here, Rosser et al. demonstrate that the short-chain fatty acid butyrate supports Breg function by increasing the level of the serotonin-derived metabolite 5-Hydroxyindole-3-acetic acid (5-HIAA). 5-HIAA, in turn, activates the aryl-hydrocarbon receptor, a newly discovered transcriptional regulator for Bregs.
B cells are increasingly recognized as playing an important role in the ongoing control of hepatitis B virus (HBV). The development of antibodies against the viral surface antigen (HBV surface ...antigen HBsAgs) constitutes the hallmark of resolution of acute infection and is a therapeutic goal for functional cure of chronic HBV (CHB). We characterized B cells directly ex vivo from the blood and liver of patients with CHB to investigate constraints on their antiviral potential. Unexpectedly, we found that HBsAg-specific B cells persisted in the blood and liver of many patients with CHB and were enriched for T-bet, a signature of antiviral potential in B cells. However, purified, differentiated HBsAg-specific B cells from patients with CHB had defective antibody production, consistent with undetectable anti-HBs antibodies in vivo. HBsAg-specific and global B cells had an accumulation of CD21-CD27- atypical memory B cells (atMBC) with high expression of inhibitory receptors, including PD-1. These atMBC demonstrated altered signaling, homing, differentiation into antibody-producing cells, survival, and antiviral/proinflammatory cytokine production that could be partially rescued by PD-1 blockade. Analysis of B cells within healthy and HBV-infected livers implicated the combination of this tolerogenic niche and HBV infection in driving PD-1hiatMBC and impairing B cell immunity.
Over a decade has now passed since the concept of B cells with a regulatory function was resurrected--B cells that produce antibodies with a suppressive effect were first reported in the 1960s and ...suppressor B cells in the 2000s. In the meantime, some aspects of regulatory B (B(REG))-cell biology have been elucidated. Not only have scientists begun to unravel the mechanism of how B(REG) cells suppress immune responses and which cells they target, but their ontogeny and development has also begun to be determined. To date, key roles for B(REG) cells have been identified in the regulation of several immune-mediated processes, including autoimmunity and responses to infectious disease and cancer. This Review highlights these advances in the study of B(REG) cells, and outlines what is known about their phenotype as well as their suppressive role in autoimmunity from studies in both mice and humans. A particular emphasis is placed on B(REG)-cell function in rheumatic diseases.
Regulatory B cells (Bregs) play a critical role in the control of autoimmunity and inflammation. IL-10 production is the hallmark for the identification of Bregs. However, the molecular determinants ...that regulate the transcription of IL-10 and control the Breg developmental program remain unknown. Here, we demonstrate that aryl hydrocarbon receptor (AhR) regulates the differentiation and function of IL-10-producing CD19+CD21hiCD24hiBregs and limits their differentiation into B cells that contribute to inflammation. Chromatin profiling and transcriptome analyses show that loss of AhR in B cells reduces expression of IL-10 by skewing the differentiation of CD19+CD21hiCD24hiB cells into a pro-inflammatory program, under Breg-inducing conditions. B cell AhR-deficient mice develop exacerbated arthritis, show significant reductions in IL-10-producing Bregs and regulatory T cells, and show an increase in T helper (Th) 1 and Th17 cells compared with B cell AhR-sufficient mice. Thus, we identify AhR as a relevant contributor to the transcriptional regulation of Breg differentiation.
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•IL-10+ Bregs are identified by high expression of AhR•B cell AhR deficiency leads to exacerbated arthritis and impaired Breg function•AhR directly binds to and regulates the expression of IL-10 in Bregs•AhR maintains Breg phenotype by suppressing pro-inflammatory gene expression
The transcriptional control of interleukin-10 (IL-10) in regulatory B cells (Bregs) remains undefined. Piper et al. identify the aryl hydrocarbon receptor (AhR) as an important transcription factor involved in Breg differentiation and show a direct role of AhR in the regulation of IL-10 transcription.
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