RESUMEN
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(+)CD24(hi)CD38(hi) (immature) B cells into IL-10-producing CD24(+)CD38(hi) Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement. CD24(+)CD38(hi) 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(+)CD38(hi) Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation. Both altered pDC-CD24(+)CD38(hi) Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab. We propose that alteration in pDC-CD24(+)CD38(hi) Breg cell interaction contributes to the pathogenesis of SLE.
Asunto(s)
Linfocitos B Reguladores/inmunología , Células Dendríticas/inmunología , Lupus Eritematoso Sistémico/inmunología , Adulto , Anciano , Antígenos CD/metabolismo , Antirreumáticos/administración & dosificación , Linfocitos B Reguladores/efectos de los fármacos , Comunicación Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Células Dendríticas/efectos de los fármacos , Femenino , Homeostasis/efectos de los fármacos , Humanos , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Lupus Eritematoso Sistémico/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Rituximab/administración & dosificación , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Activación Transcripcional/efectos de los fármacos , Adulto JovenRESUMEN
Regulatory B cells have largely been reported as B cells at a developmental stage before plasma cell differentiation. Matsumoto et al. (2014) report that IL-10(+) plasmablasts restrain autoimmune inflammation and suggest an ontological connection between immature B cells and regulatory plasmablasts.
Asunto(s)
Linfocitos B Reguladores/inmunología , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Células Plasmáticas/fisiología , Linfocitos T/inmunología , Animales , HumanosRESUMEN
The immunosuppressive function of regulatory B cells has been shown in several murine models of chronic inflammation, including collagen-induced arthritis, inflammatory bowel disease, and experimental autoimmune encephalomyelitis. Despite interest in these cells, their relevance to the maintenance of peripheral tolerance in humans remains elusive. Here, we demonstrate that human CD19(+)CD24(hi)CD38(hi) B cells possessed regulatory capacity. After CD40 stimulation, CD19(+)CD24(hi)CD38(hi) B cells suppressed the differentiation of T helper 1 cells, partially via the provision of interleukin-10 (IL-10), but not transforming growth factor-beta (TGF-beta), and their suppressive capacity was reversed by the addition of CD80 and CD86 mAbs. In addition, CD19(+)CD24(hi)CD38(hi) SLE B cells isolated from the peripheral blood of systemic lupus erythematosus (SLE) patients were refractory to further CD40 stimulation, produced less IL-10, and lacked the suppressive capacity of their healthy counterparts. Altered cellular function within this compartment may impact effector immune responses in SLE and other autoimmune disorders.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Lupus Eritematoso Sistémico/inmunología , Transducción de Señal/inmunología , ADP-Ribosil Ciclasa 1/inmunología , ADP-Ribosil Ciclasa 1/metabolismo , Adulto , Anciano , Antígenos CD19/inmunología , Antígenos CD19/metabolismo , Subgrupos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Antígeno CD24/inmunología , Antígeno CD24/metabolismo , Diferenciación Celular/inmunología , Separación Celular , Citocinas/biosíntesis , Citocinas/inmunología , Femenino , Citometría de Flujo , Humanos , Lupus Eritematoso Sistémico/metabolismo , Masculino , Persona de Mediana Edad , Células TH1/inmunología , Células TH1/metabolismo , Adulto JovenRESUMEN
In humans, tolerance to renal transplants has been associated with alterations in B-cell gene transcription and maintenance of the numbers of circulating transitional B cells. Here, we use a mouse model of transplantation tolerance to investigate the contribution of B cells to allograft survival. We demonstrate that transfer of B cells from mice rendered tolerant to MHC class I mismatched skin grafts can prolong graft survival in a dose-dependent and antigen-specific manner to a degree similar to that afforded by graft-specific regulatory T (Treg) cells. Tolerance in this model was associated with an increase in transitional-2 (T2) B cells. Only T2 B cells from tolerized mice, not naïve T2 nor alloantigen experienced T2, were capable of prolonging skin allograft survival, and suppressing T-cell activation. Tolerized T2 B cells expressed lower levels of CD86, increased TIM-1, and demonstrated a preferential survival in vivo. Furthermore, we demonstrate a synergistic effect between tolerized B cells and graft-specific Treg cells. IL-10 production by T2 B cells did not contribute to tolerance, as shown by transfer of B cells from IL-10(-/-) mice. These results suggest that T2 B cells in tolerant patients may include a population of regulatory B cells that directly inhibit graft rejection.
Asunto(s)
Supervivencia de Injerto/inmunología , Activación de Linfocitos , Células Precursoras de Linfocitos B/inmunología , Trasplante de Piel , Linfocitos T Reguladores/inmunología , Tolerancia al Trasplante , Aloinjertos , Animales , Supervivencia de Injerto/genética , Interleucina-10/genética , Interleucina-10/inmunología , Ratones , Ratones NoqueadosRESUMEN
Common variable immunodeficiency (CVID) refers to primary hypogammaglobulinemia with unknown pathogenesis. Although there is evidence for intrinsic B cell defects in some CVID patient groups, various abnormalities in cytokine production by T cells in CVID patients are frequently observed. Here, we demonstrate a relationship in the production of pro-inflammatory Th1 cytokines and regulatory B cells producing IL-10 between CVID patients and healthy controls. We describe CD19(+)CD24(hi)CD38(hi)IL-10(+) regulatory B cells generated after T cell stimulation of human peripheral blood lymphocytes ex vivo are able to suppress IFN-γ(+)TNF-α(+) producing CD4(+) T cells. This process is impaired in CVID patients, who present with both low numbers of CD19(+)CD24(hi)CD38(hi)IL-10(+) B cells and increased numbers of IFN-γ(+)TNF-α(+)CD4(+) T cells. Disruption of the regulatory B cell response to T cell stimulation explains the excessive T cell activation regarded as an immunoregulatory abnormality that is a frequent finding in CVID patients.
Asunto(s)
Linfocitos B Reguladores/inmunología , Linfocitos T CD4-Positivos/inmunología , Inmunodeficiencia Variable Común/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular/inmunología , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Citometría de Flujo , Humanos , Interferón gamma/inmunología , Interferón gamma/metabolismo , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
We have previously reported that IL-10(+) regulatory B cells, known to play an important role in controlling autoimmunity and inflammatory disorders, are contained within the transitional 2 immature (T2) B cell pool (T2 Bregs). Therapeutic strategies facilitating their enrichment or enhancing their suppressive activity are highly attractive. In this study, we report that agonistic anti-CD40 specifically targets T2 B cells and enriches Bregs upon short-term in vitro culture. Although transfer of unmanipulated T2 B cells, isolated from mice with established lupus, failed to confer protection to diseased mice, transfer of in vitro anti-CD40-generated T2 B cells (T2-like-Bregs) significantly improved renal disease and survival by an IL-10-dependent mechanism. T2-like-Bregs readily accumulated in the spleen after transfer, suppressed Th1 responses, induced the differentiation of IL-10(+)CD4(+)T cells, and conveyed a regulatory effect to CD4(+)T cells. In addition, in vivo administration of agonistic anti-CD40, currently on trial for the treatment of cancer, halted and reversed established lupus. Taken together, our results suggest a novel cellular approach for the amelioration of experimental lupus.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Subgrupos de Linfocitos B/inmunología , Antígenos CD40/agonistas , Antígenos CD40/inmunología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/terapia , Animales , Anticuerpos Monoclonales/uso terapéutico , Subgrupos de Linfocitos B/patología , Subgrupos de Linfocitos B/trasplante , Diferenciación Celular/inmunología , Proliferación Celular , Células Cultivadas , Lupus Eritematoso Sistémico/patología , Recuento de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos MRL lpr , Ratones Transgénicos , Células TH1/inmunología , Células TH1/patologíaRESUMEN
BACKGROUND: Evidence suggests an important role for gut-microbiota dysbiosis in the development of rheumatoid arthritis (RA). The link between changes in gut bacteria and the development of joint inflammation is missing. Here, we address whether there are changes to the gut environment and how they contribute to arthritis pathogenesis. METHODS: We analyzed changes in markers of gut permeability, damage, and inflammation in peripheral blood and serum of RA patients. Serum, intestines, and lymphoid organs isolated from K/BxN mice with spontaneous arthritis or from wild-type, genetically modified interleukin (IL)-10R-/-or claudin-8-/-mice with induced arthritis were analyzed by immunofluorescence/histology, ELISA, and flow cytometry. FINDINGS: RA patients display increased levels of serum markers of gut permeability and damage and cellular gut-homing markers, both parameters positively correlating with disease severity. Arthritic mice display increased gut permeability from early stages of disease, as well as bacterial translocation, inflammatory gut damage, increases in interferon γ (IFNγ)+and decreases in IL-10+intestinal-infiltrating leukocyte frequency, and reduced intestinal epithelial IL-10R expression. Mechanistically, both arthritogenic bacteria and leukocytes are required to disrupt gut-barrier integrity. We show that exposing intestinal organoids to IFNγ reduces IL-10R expression by epithelial cells and that mice lacking epithelial IL-10R display increased intestinal permeability and exacerbated arthritis. Claudin-8-/-mice with constitutively increased gut permeability also develop worse joint disease. Treatment of mice with AT-1001, a molecule that prevents development of gut permeability, ameliorates arthritis. CONCLUSIONS: We suggest that breakdown of gut-barrier integrity contributes to arthritis development and propose restoration of gut-barrier homeostasis as a new therapeutic approach for RA. FUNDING: Funded by Versus Arthritis (21140 and 21257) and UKRI/MRC (MR/T000910/1).
Asunto(s)
Artritis Reumatoide , Microbioma Gastrointestinal , Enfermedades Intestinales , Animales , Artritis Reumatoide/metabolismo , Disbiosis/metabolismo , Humanos , Inflamación/metabolismo , Enfermedades Intestinales/metabolismo , Mucosa Intestinal/metabolismo , RatonesRESUMEN
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.
Asunto(s)
Artritis Reumatoide/metabolismo , Linfocitos B Reguladores/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Butiratos/farmacología , Ácidos Grasos Volátiles/metabolismo , Receptores de Hidrocarburo de Aril , Animales , Linfocitos B Reguladores/citología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Cultivadas , Femenino , Microbioma Gastrointestinal , Humanos , Ácido Hidroxiindolacético/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Receptores de Hidrocarburo de Aril/metabolismoRESUMEN
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.
Asunto(s)
Linfocitos B/inmunología , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Hígado/inmunología , Activación de Linfocitos , Adulto , Anciano , Linfocitos B/patología , Femenino , Anticuerpos contra la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/inmunología , Hepatitis B Crónica/patología , Hepatitis B Crónica/terapia , Humanos , Hígado/patología , Hígado/virología , Masculino , Persona de Mediana EdadRESUMEN
Whilst innate B1-B cells are atheroprotective, adaptive B2-B cells are considered pro-atherogenic. Different subsets of B regulatory cells (B(reg)) have been described. In experimental arthritis and lupus-like disease, B(reg) are contained within the CD21(hi)CD23(hi)CD24(hi) B cell pool. The existence and role of B(reg) in vascular disease is not known. We sought to investigate the existence, identity and location of B(reg) in vascular disease. The representation of B2-B cell subsets in the spleens and lymph nodes (LNs) of Apolipoprotein E(-/-) (ApoE(-/-)) mice compared to controls was characterised by flow cytometry. Additionally, we utilised a model of neointima formation based on the placement of a perivascular collar around the carotid artery in ApoE(-/-) mice to ascertain whether B cells and B cell subsets confer protection against lesion development. Adoptive transfer of B cells was performed from wild type or genetically modified mice. We showed that CD21(hi)CD23(hi)CD24(hi) B cells are unexpectedly increased in the draining LNs of ApoE(-/-) mice. Adoptive transfer of LN-derived B2-B cells or purified CD21(hi)CD23(hi)CD24(hi) B cells to syngeneic mice reduced lesion size and inflammation without changing serum cholesterol levels. Follicular B2-B cells did not confer protection. IL-10 blockade or transfer of IL10-deficient B cells prevented LN-derived B cell-mediated protection. This is the first identification of a specific LN-derived B2-B(reg) subset that confers IL-10 mediated protection from neointima formation. This may open the way for immune modulatory approaches in cardiovascular disease.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Enfermedades de las Arterias Carótidas/prevención & control , Traumatismos de las Arterias Carótidas/prevención & control , Proliferación Celular , Hipercolesterolemia/inmunología , Interleucina-10/inmunología , Ganglios Linfáticos/inmunología , Activación de Linfocitos , Inmunidad Adaptativa , Traslado Adoptivo , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Subgrupos de Linfocitos B/metabolismo , Subgrupos de Linfocitos B/trasplante , Antígeno CD24/inmunología , Antígeno CD24/metabolismo , Antígenos CD40/inmunología , Antígenos CD40/metabolismo , Arterias Carótidas/inmunología , Arterias Carótidas/metabolismo , Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/genética , Enfermedades de las Arterias Carótidas/inmunología , Enfermedades de las Arterias Carótidas/metabolismo , Enfermedades de las Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas/genética , Traumatismos de las Arterias Carótidas/inmunología , Traumatismos de las Arterias Carótidas/metabolismo , Traumatismos de las Arterias Carótidas/patología , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Genotipo , Hipercolesterolemia/complicaciones , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Ganglios Linfáticos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Neointima , Fenotipo , Factores Protectores , Receptores de Complemento 3d/inmunología , Receptores de Complemento 3d/metabolismo , Receptores de IgE/inmunología , Receptores de IgE/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Factores de TiempoRESUMEN
Regulatory B cells (Bregs) are defined by their ability to restrain inflammatory responses both in vivo and in vitro. Interleukin 10 (IL-10) production by Bregs is thought to be central to their ability to regulate inflammation, largely due to IL-10s' ability to suppress pro-inflammatory cytokine production by effector lymphocytes and to maintain the differentiation of regulatory T cells (Tregs). However, with an increase in available published data, it has become evident that Bregs utilize a number of suppressive mechanisms in order to alter the activation of a variety of different lymphocytes. Here, we summarize the multiplicity of cellular targets of Breg-mediated suppression and describe the mechanisms employed by Bregs to suppress chronic inflammatory responses.
Asunto(s)
Linfocitos B Reguladores/inmunología , Inmunosupresores/inmunología , Animales , Humanos , Inflamación/inmunología , Interleucina-10/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
We have tracked the fate of immature human B cells at a critical stage in their development when the mature B cell repertoire is shaped. We show that a major subset of bone marrow emigrant immature human B cells, the transitional 2 (T2) B cells, homes to gut-associated lymphoid tissue (GALT) and that most T2 B cells isolated from human GALT are activated. Activation in GALT is a previously unknown potential fate for immature human B cells. The process of maturation from immature transitional B cell through to mature naive B cell includes the removal of autoreactive cells from the developing repertoire, a process which is known to fail in systemic lupus erythematosus (SLE). We observe that immature B cells in SLE are poorly equipped to access the gut and that gut immune compartments are depleted in SLE. Thus, activation of immature B cells in GALT may function as a checkpoint that protects against autoimmunity. In healthy individuals, this pathway may be involved in generating the vast population of IgA plasma cells and also the enigmatic marginal zone B cell subset that is poorly understood in humans.
Asunto(s)
Linfocitos B/inmunología , Tracto Gastrointestinal/inmunología , Tejido Linfoide/inmunología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/patología , Secuencia de Bases , Tracto Gastrointestinal/patología , Humanos , Cadenas beta de Integrinas/metabolismo , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/patología , Activación de Linfocitos/inmunología , Metagenoma/inmunología , Datos de Secuencia Molecular , Células Plasmáticas/inmunología , Células Precursoras de Linfocitos B/inmunología , Células Precursoras de Linfocitos B/patologíaRESUMEN
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.