• B cells
• IL-10
• T cells
• Type 1 diabetes
• marginal zone B cells
• regulatory B cells

• Diabetes Mellitus, Type 1/immunology
• Diabetes Mellitus, Type 1/etiology
• Animals
• Humans
• B-Lymphocytes, Regulatory/immunology
• B-Lymphocytes, Regulatory/metabolism
• Immune Tolerance
• Autoantibodies/immunology
• B-Lymphocytes/immunology
• Insulin-Secreting Cells/immunology
• Insulin-Secreting Cells/pathology
• Insulin-Secreting Cells/metabolism
• Mice
• Mice, Inbred NOD

• Autoimmune diseases
• Breg makers
• Breg subsets
• Breg-based therapies
• Regulatory B cells

• Humans
• B-Lymphocytes, Regulatory/immunology
• B-Lymphocytes, Regulatory/metabolism
• Autoimmune Diseases/immunology
• Autoimmune Diseases/therapy
• Animals
• Signal Transduction
• Immune Tolerance

• Allergen-specific immunotherapy (AIT)
• B cells
• IL-10
• antibody-secreting cells
• regulatory B (Breg) cells

• Humans
• Allergens
• COVID-19
• Hypersensitivity
• Cytokines
• Immune Tolerance
• B-Lymphocytes, Regulatory
• Desensitization, Immunologic

• inflammation
• lymphocytes

• B-Lymphocytes, Regulatory/metabolism
• Glycolysis/genetics
• Humans
• Interleukin-10/genetics
• Lupus Erythematosus, Systemic/genetics
• Lymphocyte Count

• National Natural Science Foundation of China (National Science Foundation of China)
• Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)

• cell therapy
• graft tolerance
• immunosuppressive therapy
• kidney transplantation
• regulatory B cells

• B cells
• aging
• atherosclerosis
• autoimmune diseases
• immunosenescence
• inflammaging

• Aging/immunology
• Animals
• Antibody Formation
• Autoimmune Diseases/immunology
• B-Lymphocyte Subsets/immunology
• B-Lymphocytes/immunology
• Cellular Senescence
• Humans
• Inflammation/immunology
• Lymphocyte Activation

• I 4647 Austrian Science Fund FWF

• Breg cells
• IL-10
• allergy
• autoimmunity
• inflammation
• suppression
• tolerance

• CD1d
• IL-10
• IL-35
• PD-L1
• TGF-β
• TIM-1
• granzyme B
• regulatory B cells

• Apoptosis
• B lymphocytes
• Exosomes
• Fas ligand
• Immune regulation
• Interleukin-10

• Animals
• Antigens/metabolism
• Apoptosis/immunology
• B-Lymphocytes/immunology
• Cytokines/metabolism
• Exosomes/metabolism
• Fas Ligand Protein/isolation & purification
• Fas Ligand Protein/metabolism
• Female
• Flow Cytometry/methods
• Histocompatibility Antigens Class II/metabolism
• Immune Tolerance
• Interleukin-10/immunology
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred DBA
• Spleen/cytology
• fas Receptor/metabolism

• Breg cells
• IL-10
• allergen immunotherapy
• tolerance

• AhR ligands
• Autoimmunity

Regulatory B (Breg) cells represent a population of suppressor B cells that participate in immunomodulatory processes and inhibition of excessive inflammation. The regulatory function of Breg cells have been demonstrated in mice and human with inflammatory diseases, cancer, after transplantation, and particularly in autoinflammatory disorders. In order to suppress inflammation, Breg cells produce anti-inflammatory mediators, induce death ligand-mediated apoptosis, and regulate many kinds of immune cells such as suppressing the proliferation and differentiation of effector T cell and increasing the number of regulatory T cells. Central nervous system Inflammatory demyelinating diseases (CNS IDDs) are a heterogeneous group of disorders, which occur against the background of an acute or chronic inflammatory process. With the advent of monoclonal antibodies directed against B cells, breakthroughs have been made in the treatment of CNS IDDs. Therefore, the number and function of B cells in IDDs have attracted attention. Meanwhile, increasing number of studies have confirmed that Breg cells play a role in alleviating autoimmune diseases, and treatment with Breg cells has also been proposed as a new therapeutic direction. In this review, we focus on the understanding of the development and function of Breg cells and on the diversification of Breg cells in CNS IDDs.

• central nervous system
• inflammatory demyelinating diseases
• multiple sclerosis
• neuromyelitis optica
• regulatory B cells

Primary membranous nephropathy (PMN) is an autoimmune disease. Both T-regulatory cells (TREGs) and B-regulatory cells (BREGs) are decreased in patients with autoimmune disease. We evaluated the TREG and BREG population in patients of PMN treated with cyclical cyclophosphamide and steroid therapy (cCYC/GC).

Twenty-four patients with PMN resistant to a restrictive strategy and treated with cCYC/GC therapy and 10 healthy controls were enrolled. The proteinuria, serum creatinine, and serum albumin were tested at monthly intervals and blood samples were collected before starting cCYC/GC and at 6 and 8 (2 months wash out) months of therapy. The peripheral blood mononuclear cells (PBMCs) after staining with fluorochrome-conjugated antibodies were then subjected to flow cytometric analysis for detection of TREGs (CD3+CD4+CD25hiCD127loFoxP3+) and BREGs (CD19+CD5+CD1dhiIL10+). TREGs and BREGs are presented as the percentage of T and B cells, respectively. Cases with remission at month 18 were classified as responders, and those without any remission as nonresponders.

Patients with PMN had a lower percentage of TREGs (P = 0.07) and BREGs compared with healthy controls (P = 0.0007). As compared with baseline, there was a significant increase in both BREGs (P = 0.001) and TREGs (P = 0.02) with the treatment (8 months). Patients who responded to therapy by 18 months had an increase in TREG (P = 0.05) and BREG (P = 0.0001) at month 8 compared with baseline.

As compared with healthy controls, patients with PMN displayed a lower percentage of BREGs. Both TREGs and BREGs significantly improved with disease-specific therapy. BREGs had an association with clinical activity.

• BREG
• PLA2R
• TREG
• membranous nephropathy

Chronic obstructive pulmonary disease (COPD) is multifactorial disease, which is characterized by airflow limitation and can be provoked by genetic factors, including carriage of the PiZ allele of the protease inhibitor (Pi) gene, encoding alpha-1 antitrypsin (A1AT). Both homozygous and heterozygous PiZ allele carriers can develop COPD. It was found recently that normal A1AT regulates cytokine levels, including IL-17, which is involved in COPD progression. The aim of this study was to determine whether homozygous or heterozygous PiZ allele carriage leads to elevated level of IL-17 and other proinflammatory cytokines in COPD patients. Materials and Methods. Serum samples and clinical data were obtained from 44 COPD patients, who included 6 PiZZ, 8 PiMZ, and 30 PiMM A1AT phenotype carriers. Serum concentrations of IL-17, IL-6, IL-8, IFN-γ, and TNF-α were measured by the enzyme-linked immunosorbent assay (ELISA). All A1AT phenotypes were verified by narrow pH range isoelectrofocusing with selective A1AT staining. A turbidimetric method was used for quantitative A1AT measurements. Results. COPD patients with both PiZZ and PiMZ phenotypes demonstrated elevated IL-17 and decreased IFN-γ levels in comparison to patients with the PiMM phenotype of A1AT. Thereafter, the ratio IL-17/IFN-γ in PiZZ and PiMZ groups greatly exceeded the values of the PiMM group. Homozygous PiZ allele carriers also had significantly higher levels of IL-6 and lower levels of IL-8, and IL-6 values correlated negatively with A1AT concentrations. Conclusions. The presence of the PiZ allele in both homozygous and heterozygous states is associated with altered serum cytokine levels, including elevated IL-17, IL-17/IFN-γ ratio, and IL-6 (only PiZZ), but lower IFN-γ and IL-8.

• Toll-like receptors
• homeostasis
• immune regulation
• immunogenicity
• inflammatory bowel disease (IBD)
• interleukin 10 (IL-10)
• microbiota
• regulatory B cells (Bregs)

• Asymmetric antibodies
• B cell
• IL-10
• hormones
• pregnancy

• Allergies
• Autoimmunity
• Chronic infectious disease
• Malignancies
• Primary immunodeficiencies
• Regulatory B cells

• B cell
• autoimmunity
• viral load

• contact hypersensitivity
• interleukin-10
• peroxisome proliferator-activated receptor γ
• regulatory B cell

• Breg cell
• autoimmune diseases
• immunoregulation
• infectious diseases

B cells possess various immuno regulatory functions. However, research about their participation in tolerance induction toward the fetus is just emerging. Accumulating evidence supports the idea that B cells can play seemingly conflicting roles during pregnancy, either protecting or harming the fetus. Previous findings indicated the presence of two different peritoneal B cell subsets, defined by the expression of the plasma cell alloantigen 1 (PC1) and with distinct immune modulatory functions. Here, we aimed to study the participation of these two B cell subsets, on pregnancy outcome in a murine model of disturbed fetal tolerance. The frequencies and cell numbers of peritoneal and splenic CD19⁺IL-10⁺ and CD19⁺CD5⁺IL-10⁺PC1⁺ cells were assessed in virgin as well as normal pregnant (NP) and abortion-prone (AP) females during the course of gestation. Peritoneal PC1^low or PC1^high B1a B cells were sorted, analyzed for their ability to secrete IL-10 and adoptively transferred into NP or AP females. On gestation day (gd) 12, the abortion rate as well as the frequencies and cell numbers of regulatory T cells, TH1 and TH17 cells were determined in spleens and decidua. In addition, mRNA expression of IL-10, TGF-β, IFN-γ, and TNF-α was analyzed in decidual tissue. Peritoneal CD19⁺IL-10⁺ and CD19⁺CD5⁺IL-10⁺PC1⁺ frequencies fluctuated during the progression of normal pregnancies while no significant changes were observed in spleen. AP females showed significantly reduced frequencies of both B cell populations and exhibited an altered peritoneal PC1^high/PC1^low ratio at gd10. Adoptive transfers of PC1^low B1a B cells into NP females increased the abortion rate in association with a reduced splenic regulatory T/TH17 ratio. By contrast, the transfer of PC1^high B1a B cells into AP females significantly diminished the fetal rejection rate and significantly reduced the numbers of splenic TH17 cells. Our results suggest that the peritoneum harbors two distinct B1a B cell subsets that can be distinguished by their PC1 expression. Whereas PC1^high B1a B cells seem to support fetal survival, PC1^low cells B1a B cells may compromise fetal well-being.

• B cells
• B1a B cells
• fetal tolerance
• interleukin-10
• peritoneum
• plasma cell alloantigen 1
• pregnancy

• Adaptive immunity
• B cells
• Immunology
• Inflammation
• Tolerance

• Cancer vaccine
• Colon carcinoma
• Interleukin-9
• Membrane-bound
• Toxicity

Kidney transplantation is the optimal treatment for end-stage renal diseases. Although great improvement has been achieved, immune tolerance is still the Holy Grail that every organ transplant practitioner pursues. The role of B cells in transplantation has long been considered simply to serve as precursors of plasma cells, which produce alloantibodies and induce antibody-mediated rejection. Recent research indicates that a specialized subset of B cells plays an important role in immune regulation, which has been well demonstrated in autoimmune diseases, infections, and cancers. This category of regulatory B cells (Bregs) differs from conventional B cells, and they may help develop a novel immunomodulatory therapeutic strategy to achieve immune tolerance in transplantation. Here, we review the latest evidence regarding phenotypes, functions, and effectors of Bregs and discuss their diverse effects on kidney transplantation.

• Epigenetics
• Immunosuppression
• Regulatory B cell
• Regulatory T cell

• Animals
• B-Lymphocytes, Regulatory/immunology
• Biodiversity
• Cell Differentiation
• Cell Lineage
• Epigenesis, Genetic
• Forkhead Transcription Factors/metabolism
• Humans
• Immunity, Cellular
• Immunosuppression Therapy
• Phenotype
• Receptors, Antigen, B-Cell/metabolism
• Receptors, Antigen, T-Cell/metabolism
• T-Lymphocytes, Regulatory/immunology

• Anti-CD40
• Contact hypersensitivity
• FasL
• Regulatory B cell
• TLR4
• TLR9

Fas-mediated apoptosis contributes to physiological and pathological cellular processes, such as differentiation and survival. In particular, the roles of Fas in immune cells are complex and critical for the maintenance of immune tolerance. The precise pathways and unique functions associated with Fas/FasL-mediated signaling in the immune system are known. The dual character of Fas/FasL-mediated immune regulation that induces beneficial or harmful effects is associated with the onset or development of immune disorders. Studies on mutations in genes encoding Fas and FasL gene of humans and mice contributed to our understanding of the pathogenesis of autoimmune diseases. Here, we review the opposing functions of Fas/FasL-mediated signaling, bilateral effects of Fas/FasL on in immune cells, and complex pathogenesis of autoimmunity mediated by Fas/FasL.

• B cell
• Fas
• FasL
• T cell
• activation-induced cell death
• apoptosis
• autoimmunity
• immune tolerance

• autoimmunity
• cancer
• estrogen
• pregnancy
• progesterone
• regulatory B cells
• regulatory T cells
• tolerance

• B cell
• autoimmunity
• immune regulation
• inflammation

• R56 AI122655 NIAID NIH HHS
• R56 AI129348 NIAID NIH HHS

• Animals
• Antibody Formation
• Atherosclerosis/immunology
• Atherosclerosis/metabolism
• B-Lymphocyte Subsets/immunology
• B-Lymphocyte Subsets/metabolism
• Humans
• Immunity, Innate
• Interleukin-10/metabolism

Induction of tolerance remains a major goal in transplantation. Indeed, despite potent immunosuppression, chronic rejection is still a real problem in transplantation. The humoral response is an important mediator of chronic rejection, and numerous strategies have been developed to target either B cells or plasma cells. However, the use of anti-CD20 therapy has highlighted the beneficial role of subpopulation of B cells, termed regulatory B cells. These cells have been characterized mainly in mice models of auto-immune diseases but emerging literature suggests their role in graft tolerance in transplantation. Regulatory B cells seem to be induced following inflammation to restrain excessive response. Different phenotypes of regulatory B cells have been described and are functional at various differentiation steps from immature to plasma cells. These cells act by multiple mechanisms such as secretion of immuno-suppressive cytokines interleukin-10 (IL-10) or IL-35, cytotoxicity, expression of inhibitory receptors or by secretion of non-inflammatory antibodies. Better characterization of the development, phenotype and mode of action of these cells seems urgent to develop novel approaches to manipulate the different B cell subsets and the response to the graft in a clinical setting.

• Regulatory B cells
• Suppression
• Immuno-suppressive cytokines interleukin-10
• Antibodies
• Tolerance

• CIA
• EAE
• GVHD
• SLE
• autoimmunity
• colitis
• diabetes
• regulatory B cell

• Animals
• B-Lymphocytes, Regulatory/immunology
• B-Lymphocytes, Regulatory/pathology
• B7-H1 Antigen/genetics
• B7-H1 Antigen/immunology
• Cell Lineage/immunology
• Disease Models, Animal
• Encephalomyelitis, Autoimmune, Experimental/genetics
• Encephalomyelitis, Autoimmune, Experimental/immunology
• Encephalomyelitis, Autoimmune, Experimental/pathology
• Fas Ligand Protein/genetics
• Fas Ligand Protein/immunology
• Gene Expression Regulation/immunology
• Graft vs Host Disease/genetics
• Graft vs Host Disease/immunology
• Graft vs Host Disease/pathology
• Humans
• Interleukin-10
• Interleukins/genetics
• Interleukins/immunology
• Mice
• Signal Transduction
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/pathology
• Transforming Growth Factor beta/genetics
• Transforming Growth Factor beta/immunology

• R01 AI069358 NIAID NIH HHS
• NIH

• B cell
• Bregs
• IL-10
• human
• immune-suppression
• mouse
• regulation
• regulatory B cells
• subsets

• Animals
• Antigen Presentation
• Antigens, CD/genetics
• Antigens, CD/immunology
• Autoimmune Diseases/genetics
• Autoimmune Diseases/immunology
• Autoimmune Diseases/pathology
• B-Lymphocytes, Regulatory/immunology
• B-Lymphocytes, Regulatory/pathology
• Cell Communication
• Cell Lineage/immunology
• Disease Models, Animal
• Gene Expression Regulation/immunology
• Humans
• Immune Tolerance
• Immunity, Humoral
• Interleukin-10/genetics
• Interleukin-10/immunology
• Mice
• Signal Transduction
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/pathology

• Wellcome Trust
• 17707 Arthritis Research UK
• 17707 Versus Arthritis
• 090406/Z/09/Z Wellcome Trust

Induction of immune tolerance is a key process by which the immune system is educated to modulate reactions against benign stimuli such as self-antigens and commensal microbes. Understanding and harnessing the natural mechanisms of immune tolerance may become an increasingly useful strategy for treating many types of allergic and autoimmune diseases, as well as for improving the acceptance of solid organ transplants. Our laboratory and others have been interested in the natural ability of some B lymphocytes to express the death-inducing molecule Fas ligand (FasL), and their ability to kill T helper (T_H) lymphocytes. We have recently shown that experimental transformation of human B cells by a non-replicative variant of Epstein-Barr virus (EBV) consistently resulted in high expression of functional FasL protein. The production and release of FasL⁺ exosomes that co-expressed major histocompatibility complex (MHC) class II molecules and had the capacity to kill antigen-specific T_H cells was also observed. Several lines of evidence indicate that FasL+ B cells and FasL⁺MHCII⁺ exosomes have important roles in natural immune tolerance and have a great deal of therapeutic potential. Taken together, these findings suggest that EBV-immortalized human B lymphoblastoid cell lines could be used as cellular factories for FasL⁺ exosomes, which would be employed to therapeutically establish and/or regain immune tolerance toward specific antigens. The goals of this review are to summarize current knowledge of the roles of FasL⁺ B cells and exosomes in immune regulation, and to suggest methods of manipulating killer B cells and FasL⁺ exosomes for clinical purposes.

• EBV
• TH cells
• allergy
• apoptosis
• autoimmunity
• immune regulation
• transplantation

• Animals
• B-Lymphocytes/cytology
• B-Lymphocytes/immunology
• Blotting, Western/methods
• CD5 Antigens/analysis
• CD5 Antigens/immunology
• Cell Culture Techniques/methods
• Cell Separation/methods
• Cytotoxicity, Immunologic
• Fas Ligand Protein/analysis
• Fas Ligand Protein/immunology
• Flow Cytometry/methods
• Interleukin-10/analysis
• Interleukin-10/immunology
• Mice
• Mice, Inbred BALB C
• T-Lymphocytes, Helper-Inducer/cytology
• T-Lymphocytes, Helper-Inducer/immunology

Patients deficient in the cytoskeletal regulator Wiskott–Aldrich syndrome protein (WASp) are predisposed to varied autoimmunity, suggesting it has an important controlling role in participating cells. IL-10-producing regulatory B (Breg) cells are emerging as important mediators of immunosuppressive activity. In experimental, antigen-induced arthritis WASp-deficient (WASp knockout [WAS KO]) mice developed exacerbated disease associated with decreased Breg cells and regulatory T (Treg) cells, but increased Th17 cells in knee-draining LNs. Arthritic WAS KO mice showed increased serum levels of B-cell-activating factor, while their B cells were unresponsive in terms of B-cell-activating factor induced survival and IL-10 production. Adoptive transfer of WT Breg cells ameliorated arthritis in WAS KO recipients and restored a normal balance of Treg and Th17 cells. Mice with B-cell-restricted WASp deficiency, however, did not develop exacerbated arthritis, despite exhibiting reduced Breg- and Treg-cell numbers during active disease, and Th17 cells were not increased over equivalent WT levels. These findings support a contributory role for defective Breg cells in the development of WAS-related autoimmunity, but demonstrate that functional competence in other regulatory populations can be compensatory. A properly regulated cytoskeleton is therefore important for normal Breg-cell activity and complementation of defects in this lineage is likely to have important therapeutic benefits.

• Arthritis
• Immune regulation
• Regulatory B cells
• Regulatory T cell
• Th17 cells
• Wiskott-Aldrich syndrome protein

Immune suppression mediated by exosomes is an emerging concept with potentially immense utility for immunotherapy in a variety of inflammatory contexts, including allogeneic transplantation. Exosomes containing the apoptosis-inducing molecule Fas ligand (FasL) have demonstrated efficacy in inhibiting antigen-specific immune responses upon adoptive transfer in animal models. We report here that a very high frequency of human B cell-derived lymphoblastoid cell lines (LCL) constitutively produce MHCII⁺FasL⁺ exosomes that can induce apoptosis in CD4⁺ T cells. All LCL tested for this study (>20 independent cell lines) showed robust expression of FasL, but had no detectable FasL on the cell surface. Given this intracellular sequestration, we hypothesized that FasL in LCL was retained in the secretory lysosome and secreted via exosomes. Indeed, we found both MHCII and FasL proteins present in LCL-derived exosomes, and using a bead-based exosome capture assay demonstrated the presence of MHCII⁺FasL⁺ exosomes among those secreted by LCL. Using two independent experimental approaches, we demonstrated that LCL-derived exosomes were capable of inducing antigen-specific apoptosis in autologous CD4⁺ T cells. These results suggest that LCL-derived exosomes may present a realistic source of immunosuppressive exosomes that could reduce or eliminate T cell-mediated responses against donor-derived antigens in transplant recipients.

• Epstein–Barr virus
• T cell apoptosis
• killer B cells
• lethal exosomes
• microvesicles
• regulatory B cells
• transplant tolerance

Beyond their critical role in humoral immunity, B lymphocytes can employ a variety of immunomodulatory mechanisms including expression of the apoptosis-inducing molecule Fas ligand (FasL; CD178). Here, we extensively characterized the surface phenotype of FasL⁺ killer B cells, showing they are enriched in the IgM^highCD5⁺CD1d^high B cell subset previously reported to contain a higher frequency of B cells producing interleukin-10 (IL-10). A rare population of B cells expressing IL-10 was present among FasL⁺ B cells, but most FasL⁺ B cells did not produce IL-10. We also identify interleukin-5 (IL-5) as a novel inducer of killer B cell function. Constitutively FasL⁺ B cells expressed higher levels of the IL-5 receptor, and treating B cells with IL-5 and CD40L resulted in the expansion of a B cell population enriched for FasL⁺ cells. B cells stimulated with IL-5 and CD40L were potent inducers of apoptosis in activated primary CD4⁺ T cells, and this killing function was antigen-specific and dependent upon FasL. IL-5 also enhanced IL-10 secretion in B cells stimulated with CD40L. Taken together these findings elucidate the relationship of FasL⁺ B cells and IL-10-producing B cells and demonstrate that IL-5 can induce or enhance both killer B cell activity and IL-10 secretion in B cells. Finally, we found that the killer B cell activity induced by IL-5 was completely blocked by IL-4, suggesting the existence of a previously unknown antagonistic relationship between these type-2 cytokines in modulating the activity of killer B cells. Targeting this IL-5/IL-4 signaling axis may therefore represent a novel area of drug discovery in inflammatory disorders.

• Animals
• Apoptosis/drug effects
• B-Lymphocytes/drug effects
• B-Lymphocytes/metabolism
• Cell Proliferation/drug effects
• Cells, Cultured
• Enzyme-Linked Immunosorbent Assay
• Fas Ligand Protein/metabolism
• Flow Cytometry
• Immunoblotting
• Interleukin-10/metabolism
• Interleukin-5/pharmacology
• Mice

• K01 AR053846 NIAMS NIH HHS
• 5K01 AR-053846 NIAMS NIH HHS

• T helper lymphocytes
• hygiene hypothesis
• immune regulation
• sialyl Lewis glycans
• soluble egg antigen