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Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.

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 (Breg) cells attenuate inflammation and contribute to the maintenance of immune tolerance. Breg 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 Breg 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.

The gut microbiota promotes regulatory B cell development and function through interleukin-1β and interleukin-6. Regulatory B cells (B reg cells) differentiate in response to inflammation and subsequently restrain excessive immune responses via the release of interleukin-10 (IL-10) 1 . However, the precise inflammatory signals governing their differentiation remain to be elucidated. Here we show that the gut microbiota promotes the differentiation of B reg cells in the spleen as well as in the mesenteric lymph nodes. Perturbation of the gut microbiome imposed either by antibiotic treatment or by changes in the sterility of housing conditions reduces the number and function of B reg cells. Following the induction of arthritis, IL-1β and IL-6 are produced only in conventionally housed mice and both cytokines directly promote B reg cell differentiation and IL-10 production. Mice lacking IL-6 receptor (IL-6R) or IL-1 receptor 1 (IL-1R1) specifically on B cells have a reduced number of IL-10–producing B cells and develop exacerbated arthritis compared to control animals. Thus, in response to inflammatory signals induced by both the gut flora and arthritis, B reg cells increase in number and restrain excessive inflammation.

Chronic lymphocytic leukemia (CLL) is associated with immune dysfunction, but how disease-intrinsic mechanisms in treatment-naive patients influence the coordination of adaptive responses to novel antigens remains unclear. Here, we assessed SARS-CoV-2-specific antibody and T cell immunity in 38 treatment-naive CLL patients and 13 healthy controls (HCs) following vaccination. Despite significantly reduced total immunoglobulin levels compared to HCs, 94.7% of CLL patients developed SARS-CoV-2-specific IgG, and 89.5% mounted IgA responses, with serum titers comparable to those of HCs. Virus-specific T cell responses, measured by IFN-γ release following antigen stimulation, were detected in 78.9% of patients. CLL patients had significantly more circulating CD4+ T follicular helper (Tfh) and T follicular regulatory (Tfr) cells than HCs. These expansions correlated with B cell abundance, which, in untreated CLL, predominantly reflects malignant B cells. Notably, Tfh cell frequencies and absolute counts were highest in patients lacking a SARS-CoV-2-specific T cell response, indicating a decoupling between Tfh expansion and functional antiviral immunity. Overall, these findings demonstrate that while SARS-CoV-2-specific immune responses are largely preserved in treatment-naive CLL patients, disease-driven alterations in T cell composition may compromise the coordination and quality of antigen-specific T cell-mediated immunity.

Gut-associated lymphoid tissue is central to the production of galactose-deficient IgA1 (Gd-IgA1), a key factor in immunoglobulin A nephropathy (IgAN). Although no major differences in gut microbiome diversity have been reported across IgAN cohorts, functional alterations in microbial composition may contribute to disease pathogenesis. The study was designed as a cross-sectional study with an embedded prospective cohort component. Forty-eight adults with biopsy-confirmed IgAN—categorized as progressors (eGFR decline > 5 ml/min/1.73 m²/year, n = 23) or nonprogressors (n = 23)—and 23 healthy controls (HC) were recruited. Stool samples underwent metagenomic and functional profiling. Alpha diversity did not differ significantly between IgAN patients and HC. However, butyrate-producing bacteria (Butyrococcus, Agathobacter rectalis) were less abundant in IgAN patients. The sulfoquinovose degradation I pathway, associated with these bacteria, was also reduced. Nucleotide- and nucleoside-biosynthesis pathways were elevated in IgAN. Gd-IgA1 levels correlated with variations in metabolic pathways. Progressors demonstrated enhanced activity in isopropanol biosynthesis, biotin biosynthesis II, and phospholipid biosynthesis pathways. IgAN patients show reduced butyrate-producing bacteria and distinct functional changes in the gut microbiome suggestive of immune activation and inflammation. Progressors exhibit additional metabolic shifts linked to bacterial membrane stabilization.

Regulatory B cells (Bregs) express high levels of CD1d that presents lipid antigens to invariant natural killer T (iNKT) cells. The role of CD1d in Breg biology and the specific contribution to iNKT cell function and in suppressing inflammation remains unknown. Combining chimeric mice, cell depletion and adoptive transfer strategies, we show that CD1d lipid presentation by B cells to iNKT cells is critical for the induction of iNKT cells that down-regulate Th1 and Th17 adaptive immune responses and arthritis, whilst dispensable for Breg development. Mice lacking CD1d-expressing B cells developed exacerbated arthritis compared to wild-type mice and failed to respond to α-GalCer treatment. Absence of lipid presentation by B cells led to altered activation of iNKT cells, with disruption of regulatory pathways including those involved in metabolism and cytokine responses. Thus, we have identified a novel mechanism by which Bregs via CD1d, in an IL-10 independent manner, control and restrain excessive inflammation.

The gut microbiota promotes regulatory B cell development and function through interleukin-1[beta] and interleukin-6. Regulatory B cells (B.sub.reg cells) differentiate in response to inflammation and subsequently restrain excessive immune responses via the release of interleukin-10 (IL-10).sup.1. However, the precise inflammatory signals governing their differentiation remain to be elucidated. Here we show that the gut microbiota promotes the differentiation of B.sub.reg cells in the spleen as well as in the mesenteric lymph nodes. Perturbation of the gut microbiome imposed either by antibiotic treatment or by changes in the sterility of housing conditions reduces the number and function of B.sub.reg cells. Following the induction of arthritis, IL-1[beta] and IL-6 are produced only in conventionally housed mice and both cytokines directly promote B.sub.reg cell differentiation and IL-10 production. Mice lacking IL-6 receptor (IL-6R) or IL-1 receptor 1 (IL-1R1) specifically on B cells have a reduced number of IL-10-producing B cells and develop exacerbated arthritis compared to control animals. Thus, in response to inflammatory signals induced by both the gut flora and arthritis, B.sub.reg cells increase in number and restrain excessive inflammation.