RESUMEN
Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell-dependent autoimmune diseases.
Asunto(s)
Acetatos/metabolismo , Linfocitos B/inmunología , Butiratos/metabolismo , Colon/metabolismo , Diabetes Mellitus Tipo 1/dietoterapia , Disbiosis/dietoterapia , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad , Linfocitos B/microbiología , Células Cultivadas , Colon/patología , Dietoterapia , Microbioma Gastrointestinal , Interleucinas/sangre , Ratones , Ratones Endogámicos NOD , Linfocitos T Reguladores/microbiologíaRESUMEN
This corrects the article DOI: 10.1038/ni.3713.
RESUMEN
One explanation for the increased incidence of allergies, asthma, and even some autoimmune diseases has been the hygiene hypothesis. However, recent studies also highlight an important role for diet and bacterial metabolites in controlling various immune pathways, including gut and immune homeostasis, regulatory T cell biology, and inflammation. Dietary-related metabolites engage "metabolite-sensing" G-protein-coupled receptors, such as GPR43, GPR41, GPR109A, GPR120, and GPR35. These receptors are expressed on immune cells and some gut epithelial cells and generally mediate a direct anti-inflammatory effect. Insufficient intake of "healthy foodstuffs" adversely affects the production of bacterial metabolites. These metabolites and those derived directly from food drive beneficial downstream effects on immune pathways. We propose that insufficient exposure to dietary and bacterial metabolites might underlie the development of inflammatory disorders in Western countries. This review highlights what is currently known about diet, metabolites, and their associated immune pathways in relation to the development of inflammatory disease.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Dieta , Hipersensibilidad/inmunología , Inflamación/inmunología , Estilo de Vida , Proteínas Bacterianas/inmunología , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/microbiología , Humanos , Inflamación/microbiología , Metaboloma/inmunología , Microbiota/inmunología , Receptores Acoplados a Proteínas G/inmunologíaRESUMEN
Environmental factors contribute to development of autoimmune diseases. For instance, human autoimmune arthritis can associate with intestinal inflammation, cigarette smoking, periodontal disease, and various infections. The cellular and, molecular pathways whereby such remote challenges might precipitate arthritis or flares remain unclear. Here, we used a transfer model of self-reactive arthritis-inducing CD4(+) cells from KRNtg mice that, upon transfer, induce a very mild form of autoinflammatory arthritis in recipient animals. This model enabled us to identify external factors that greatly aggravated disease. We show that several distinct challenges precipitated full-blown arthritis, including intestinal inflammation through DSS-induced colitis, and bronchial stress through Influenza infection. Both triggers induced strong IL-17 expression primarily in self-reactive CD4(+) cells in lymph nodes draining the site of inflammation. Moreover, treatment of mice with IL-1ß greatly exacerbated arthritis, while transfer of KRNtg CD4(+) cells lacking IL-1R significantly reduced disease and IL-17 expression. Thus, IL-1ß enhances the autoaggressive potential of self-reactive CD4(+) cells, through increased Th17 differentiation, and this influences inflammatory events in the joints. We propose that diverse challenges that cause remote inflammation (lung infection or colitis, etc.) result in IL-1ß-driven Th17 differentiation, and this precipitates arthritis in genetically susceptible individuals. Thus the etiology of autoimmune inflammatory arthritis likely relates to diverse triggers that converge to a common pathway involving IL-1ß production and Th17 cell distribution.
Asunto(s)
Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/inmunología , Interleucina-1beta/metabolismo , Espondiloartritis/inmunología , Células Th17/inmunología , Traslado Adoptivo , Animales , Artritis Reumatoide/genética , Colitis/inducido químicamente , Colitis/inmunología , Sulfato de Dextran/toxicidad , Predisposición Genética a la Enfermedad , Virus de la Influenza A/inmunología , Interleucina-17/metabolismo , Articulaciones/inmunología , Klebsiella pneumoniae/inmunología , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/virología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Transgénicos , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Neumonía Bacteriana/inmunología , Neumonía Bacteriana/microbiología , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Células Th17/metabolismoRESUMEN
The dynamic interplay between regulatory T cells (T(regs)) and effector T cells (T(effs)) governs the balance between tolerance and effector immune responses. Perturbations of T(reg) frequency and function or imbalances in T(reg)/T(eff) levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. T(regs) displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to T(effs) (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient T(reg) control of T(effs) and induced autoimmunity. Moreover, a counterregulatory and probably IL-7-driven increase in thymic T(reg) production and recruitment to inflamed tissues was too slow for disease prevention. Increased T(eff) over T(reg) expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that T(reg) expansion mainly depended on this cytokine. IL-21R(-/-) cells were used to demonstrate that IL-21 promoted the maintenance of T(effs). Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 hampers T(reg) proliferation, whereas exaggerated IL-21 levels overwhelm T(reg) control by supporting T(eff) expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.
Asunto(s)
Artritis/inmunología , Autoinmunidad , Interleucina-2/inmunología , Interleucinas/inmunología , Linfopenia/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Animales , Artritis/complicaciones , Artritis/genética , Artritis/patología , Proliferación Celular , Regulación de la Expresión Génica , Tolerancia Inmunológica , Inflamación/complicaciones , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-2/genética , Interleucinas/genética , Linfopenia/complicaciones , Linfopenia/genética , Linfopenia/patología , Ratones , Ratones Transgénicos , Receptores de Interleucina-21/genética , Receptores de Interleucina-21/inmunología , Transducción de Señal , Linfocitos T Colaboradores-Inductores/patología , Linfocitos T Reguladores/patologíaRESUMEN
Certain autoimmune diseases as well as asthma have increased in recent decades, particularly in developed countries. The hygiene hypothesis has been the prevailing model to account for this increase; however, epidemiology studies also support the contribution of diet and obesity to inflammatory diseases. Diet affects the composition of the gut microbiota, and recent studies have identified various molecules and mechanisms that connect diet, the gut microbiota, and immune responses. Herein, we discuss the effects of microbial metabolites, such as short chain fatty acids, on epithelial integrity as well as immune cell function. We propose that dysbiosis contributes to compromised epithelial integrity and disrupted immune tolerance. In addition, dietary molecules affect the function of immune cells directly, particularly through lipid G-protein coupled receptors such as GPR43.
Asunto(s)
Bacterias/inmunología , Infecciones Bacterianas/inmunología , Ácidos Grasos/inmunología , Enfermedades del Sistema Inmune/inmunología , Mucosa Intestinal/inmunología , Animales , Bacterias/metabolismo , Infecciones Bacterianas/complicaciones , Infecciones Bacterianas/microbiología , Dieta , Suplementos Dietéticos , Ácidos Grasos/metabolismo , Humanos , Enfermedades del Sistema Inmune/etiología , Enfermedades del Sistema Inmune/microbiología , Tolerancia Inmunológica , Inflamación/inmunología , Inflamación/microbiología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Multipotent mesenchymal stromal cells (MSCs) possess reparative and immunoregulatory properties, making them attractive candidates for cellular therapy. However, the majority of MSCs administered i.v. encounter a pulmonary impasse and soon disappear from the lungs, raising the question of how they induce such durable immunosuppressive effects. Using a mouse model of allergic asthma, we show that administration of MSCs isolated from human bone marrow, umbilical cord, or adipose tissue provoked a pronounced increase in alveolar macrophages and inhibited hallmark features of asthma, including airway hyperresponsiveness, eosinophilic accumulation, and Th2 cytokine production. Importantly, selective depletion of this macrophage compartment reversed the therapeutic benefit of MSC treatment on airway hyperresponsiveness. Our data demonstrate that human MSCs exert cross-species immunosuppressive activity, which is mediated by alveolar macrophages in allergic asthma. As alveolar macrophages are the predominant immune effector cells at the air-tissue interface in the lungs, this study provides a compelling mechanism for durable MSC effects in the absence of sustained engraftment.
Asunto(s)
Asma/terapia , Terapia de Inmunosupresión/métodos , Macrófagos Alveolares/fisiología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/fisiología , Tejido Adiposo/citología , Animales , Asma/etiología , Asma/inmunología , Asma/patología , Asma/fisiopatología , Células de la Médula Ósea/citología , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/etiología , Líquido del Lavado Bronquioalveolar , Ácido Clodrónico/farmacología , Eosinofilia/etiología , Eosinofilia/inmunología , Femenino , Genes Reporteros , Supervivencia de Injerto , Xenoinjertos , Humanos , Inmunización , Interleucina-10/biosíntesis , Interleucina-10/genética , Pulmón/patología , Linfocinas/biosíntesis , Linfocinas/genética , Macrófagos Alveolares/efectos de los fármacos , Cloruro de Metacolina , Ratones , Ratones Endogámicos BALB C , Especificidad de Órganos , Ovalbúmina/inmunología , Ovalbúmina/toxicidad , Especificidad de la Especie , Organismos Libres de Patógenos Específicos , Células Th2/metabolismo , Transducción Genética , Cordón Umbilical/citologíaRESUMEN
The induction of regulatory T cells (Tregs) to suppress aberrant inflammation and immunity has potential as a therapeutic strategy for asthma. Recently, we identified key immunoregulatory components of Streptococcus pneumoniae, type 3 polysaccharide and pneumolysoid (T+P), which suppress allergic airways disease (AAD) in mouse models of asthma. To elucidate the mechanisms of suppression, we have now performed a thorough examination of the role of Tregs. BALB/c mice were sensitized to OVA (day 0) i.p. and challenged intranasal (12-15 d later) to induce AAD. T+P was administered intratracheally at the time of sensitization in three doses (0, 12, and 24 h). T+P treatment induced an early (36 h-4 d) expansion of Tregs in the mediastinal lymph nodes, and later (12-16 d) increases in these cells in the lungs, compared with untreated allergic controls. Anti-CD25 treatment showed that Treg-priming events involving CD25, CCR7, IL-2, and TGF-ß were required for the suppression of AAD. During AAD, T+P-induced Tregs in the lungs displayed a highly suppressive phenotype and had an increased functional capacity. T+P also blocked the induction of IL-6 to prevent the Th17 response, attenuated the expression of the costimulatory molecule CD86 on myeloid dendritic cells (DCs), and reduced the number of DCs carrying OVA in the lung and mediastinal lymph nodes. Therefore, bacterial components (T+P) drive the differentiation of highly suppressive Tregs, which suppress the Th2 response, prevent the Th17 response and disable the DC response resulting in the effective suppression of AAD.
Asunto(s)
Asma/inmunología , Polisacáridos Bacterianos/inmunología , Streptococcus pneumoniae/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígeno B7-2/biosíntesis , Células Cultivadas , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Inflamación/inmunología , Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Interleucina-6/biosíntesis , Pulmón/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Polisacáridos Bacterianos/administración & dosificación , Receptores CCR7/metabolismo , Células Th17/inmunología , Células Th2/inmunología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Asthma is an allergic airways disease (AAD) caused by dysregulated immune responses and characterized by eosinophilic inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). NKT cells have been shown to contribute to AHR in some mouse models. Conversely, regulatory T cells (Tregs) control aberrant immune responses and maintain homeostasis. Recent evidence suggests that Streptococcus pneumoniae induces Tregs that have potential to be harnessed therapeutically for asthma. In this study, mouse models of AAD were used to identify the S. pneumoniae components that have suppressive properties, and the mechanisms underlying suppression were investigated. We tested the suppressive capacity of type-3-polysaccharide (T3P), isolated cell walls, pneumolysoid (Ply) and CpG. When coadministered, T3P + Ply suppressed the development of: eosinophilic inflammation, Th2 cytokine release, mucus hypersecretion, and AHR. Importantly, T3P + Ply also attenuated features of AAD when administered during established disease. We show that NKT cells contributed to the development of AAD and also were suppressed by T3P + Ply treatment. Furthermore, adoptive transfer of NKT cells induced AHR, which also could be reversed by T3P + Ply. T3P + Ply-induced Tregs were essential for the suppression of NKT cells and AAD, which was demonstrated by Treg depletion. Collectively, our results show that the S. pneumoniae components T3P + Ply suppress AAD through the induction of Tregs that blocked the activity of NKT cells. These data suggest that S. pneumoniae components may have potential as a therapeutic strategy for the suppression of allergic asthma through the induction of Tregs and suppression of NKT cells.
Asunto(s)
Asma/tratamiento farmacológico , Cápsulas Bacterianas/farmacología , Células T Asesinas Naturales/inmunología , Streptococcus pneumoniae/química , Estreptolisinas/farmacología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Asma/inmunología , Asma/metabolismo , Asma/patología , Cápsulas Bacterianas/química , Cápsulas Bacterianas/inmunología , Proteínas Bacterianas/química , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/farmacología , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos BALB C , Moco/inmunología , Moco/metabolismo , Células T Asesinas Naturales/metabolismo , Células T Asesinas Naturales/patología , Oligodesoxirribonucleótidos/farmacología , Streptococcus pneumoniae/inmunología , Estreptolisinas/química , Estreptolisinas/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/patologíaRESUMEN
Regulatory T cells (Tregs) play an essential role in maintaining the homeostatic balance of immune responses. Asthma is an inflammatory condition of the airways that is driven by dysregulated immune responses toward normally innocuous antigens. Individuals with asthma have fewer and less functional Tregs, which may lead to uncontrolled effector cell responses and promote proasthmatic responses of T helper type 2, T helper 17, natural killer T, antigen-presenting, and B cells. Tregs have the capacity to either directly or indirectly suppress these responses. Hence, the induced expansion of functional Tregs in predisposed or individuals with asthma is a potential approach for the prevention and treatment of asthma. Infection by a number of micro-organisms has been associated with reduced prevalence of asthma, and many infectious agents have been shown to induce Tregs and reduce allergic airways disease in mouse models. The translation of the regulatory and therapeutic properties of infectious agents for use in asthma requires the identification of key modulatory components and the development and trial of effective immunoregulatory therapies. Further translational and clinical research is required for the induction of Tregs to be harnessed as a therapeutic strategy for asthma.
Asunto(s)
Asma/inmunología , Asma/terapia , Linfocitos T Reguladores/inmunología , Animales , Biomarcadores , Humanos , Tolerancia Inmunológica/inmunologíaRESUMEN
BACKGROUND: Infections with some bacteria, including Streptococcus pneumoniae, have been associated with a reduced incidence of asthma. Components of S pneumoniae may have the potential to modulate allergic inflammatory responses and suppress the development of asthma. OBJECTIVES: To determine if human S pneumoniae vaccines have the potential to suppress asthma by elucidating their effect on allergic airways disease (AAD) in mouse models. METHODS: AAD was induced in BALB/c mice by intraperitoneal sensitisation and intranasal challenge with ovalbumin. Pneumococcal conjugate or polysaccharide vaccines were administered at the time of sensitisation or during established AAD. Hallmark features of AAD were assessed. Levels of regulatory T cells (Tregs) were quantified by fluorescence-activated cell sorting, and their immunoregulatory capacity was assessed using proliferation assays and anti-CD25 antibody treatment. RESULTS: Intranasal administration of the conjugate vaccine, but not the polysaccharide vaccine, suppressed the hallmark features of AAD, including: eosinophilic and T helper 2-mediated inflammation; airway hyper-responsiveness; circulating immunoglobulin E (IgE) levels; and mucus hypersecretion. Intramuscular administration of the conjugate vaccine had limited protective effects. The conjugate vaccine increased Tregs in the lung-draining lymph nodes, lung and spleen. Furthermore, conjugate vaccine-induced Tregs had an enhanced capacity to suppress T effector responses. Anti-CD25 administration reversed the suppressive effects of the conjugate vaccine. CONCLUSIONS: A currently available human conjugate vaccine suppresses the hallmark features of AAD through the induction of Tregs. Thus targeted administration may provide a novel immunoregulatory treatment for asthma.
Asunto(s)
Asma/prevención & control , Vacunas Neumococicas/inmunología , Linfocitos T Reguladores/inmunología , Animales , Asma/inmunología , Antígenos CD2/inmunología , Modelos Animales de Enfermedad , Femenino , Tolerancia Inmunológica , Inyecciones Intramusculares , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Células Th2/inmunología , Vacunas Conjugadas/inmunologíaRESUMEN
Recently, obinutuzumab was included in the Australian Pharmaceutical Benefits Scheme for use in first line, advanced or bulky stage 2, follicular lymphoma, providing more immunochemotherapy treatment options available than ever before. Rituximab with chemotherapy has been the standard of care since reimbursement in the late 1990s; however, obinutuzumab-based regimens have shown superior progression-free survival in comparison to rituximab-based options, albeit at an increased risk of grade ≥3 adverse events. As median overall survival approaches 20 years or more, the long-term effects and sequencing of any strategy should be considered. Here we discuss the considerations for selection of front-line therapy, based on evidence and local Australian clinician experience, in the management of first line follicular lymphoma.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Guías de Práctica Clínica como Asunto/normas , Australia , Manejo de la Enfermedad , Humanos , Linfoma Folicular/patología , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: Exposure to non-pathogenic Streptococcus pneumoniae and vaccination are inversely associated with asthma. Studies in animal models demonstrate that airway administration of S. pneumoniae (live or killed), or its vaccines or components, suppresses the characteristic features of asthma in mouse models of allergic airway disease (AAD). These components could be developed into immunoregulatory therapies. S. pneumoniae components are recognized by Toll-like receptors (TLR) 2 and TLR4, and both induce inflammatory cell responses through the adaptor protein myeloid differentiation primary response gene 88 (MyD88). The involvement of TLR2, TLR4 and MyD88 in the pathogenesis of AAD and asthma is incompletely understood, and has not been studied in S. pneumoniae-mediated suppression of AAD. We investigated the role of TLR2, TLR4 and MyD88 in the development of AAD and S. pneumoniae-mediated suppression of AAD. METHODS AND FINDINGS: OVA-induced AAD and killed S. pneumoniae-mediated suppression of AAD were assessed in wild-type, TLR2-/-, TLR4-/-, TLR2/4-/- and MyD88-/- BALB/c mice. During OVA-induced AAD, TLR2, TLR4 and MyD88 were variously involved in promoting eosinophil accumulation in bronchoalveolar lavage fluid and blood, and T-helper type (Th)2 cytokine release from mediastinal lymph node T cells and splenocytes. However, all were required for the induction of airways hyperresponsiveness (AHR). In S. pneumoniae-mediated suppression of AAD, TLR2, TLR4 and MyD88 were variously involved in the suppression of eosinophilic and splenocyte Th2 responses but all were required for the reduction in AHR. CONCLUSIONS: These results highlight important but complex roles for TLR2, TLR4 and MyD88 in promoting the development of OVA-induced AAD, but conversely in the S. pneumoniae-mediated suppression of AAD, with consistent and major contributions in both the induction and suppression of AHR. Thus, TLR signaling is likely required for both the development of asthma and the suppression of asthma by S. pneumoniae, and potentially other immunoregulatory therapies.
Asunto(s)
Inmunoterapia/métodos , Factor 88 de Diferenciación Mieloide/inmunología , Hipersensibilidad Respiratoria/prevención & control , Streptococcus pneumoniae/inmunología , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 4/inmunología , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/microbiología , Eosinófilos/inmunología , Eosinófilos/patología , Femenino , Regulación de la Expresión Génica , Calor , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Ratones , Ratones Endogámicos BALB C , Factor 88 de Diferenciación Mieloide/genética , Ovalbúmina , Factores Protectores , Hipersensibilidad Respiratoria/inducido químicamente , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/patología , Transducción de Señal , Bazo/inmunología , Bazo/patología , Streptococcus pneumoniae/química , Células Th2/inmunología , Células Th2/patología , Receptor Toll-Like 2/genética , Receptor Toll-Like 4/genéticaRESUMEN
OBJECTIVE: Antibody-mediated autoimmunity involves cognate interactions between self-reactive T cells and B cells during germinal center (GC) reactions. The aim of this study was to determine the role of essential follicular helper T (Tfh) cell molecules (CXCR5, signaling lymphocytic activation molecule-associated protein) on autoreactive CD4+ cells and the role of certain environmental influences that may determine GC-driven autoantibody production and arthritis development. METHODS: We transferred self-reactive CD4+ cells from KRN-Tg mice into recipient mice, which induced autoantibodies and autoinflammatory arthritis. This model allowed manipulation of environmental effects, such as inflammation, and use of transferred cells that were genetically deficient in important Tfh cell-associated molecules. RESULTS: A deficiency of signaling lymphocytic activation molecule-associated protein (SAP) in CD4+ cells from KRN-Tg mice completely protected against arthritis, indicating that stable T cell-B cell interactions are required for GC formation, autoantibody production, and arthritis induction. In contrast, a CXCR5 deficiency in CD4+ cells from KRN-Tg mice still induced disease when these cells were transferred into wild-type mice, suggesting that T cell help for B cells could rely on other migration mechanisms. However, various manipulations influenced this system, including elimination of bystander effects through use of CD28(-/-) recipient mice (reduced disease) or use of inflammation-inducing Freund's complete adjuvant (progression to arthritis). We also examined the capacity of preexisting GCs with a nonautoimmune specificity to co-opt autoimmune T cells and observed no evidence for any influence. CONCLUSION: In addition to the quality and quantity of cognate CD4+ cell help, external factors such as inflammation and noncognate CD4+ cell bystander activation trigger autoimmunity by shaping events within autoimmune GC responses. SAP is an essential molecule for autoimmune antibody production, whereas the importance of CXCR5 varies depending on the circumstances.
Asunto(s)
Artritis Reumatoide/inmunología , Autoanticuerpos/biosíntesis , Ambiente , Péptidos y Proteínas de Señalización Intracelular/inmunología , Receptores CXCR5/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Artritis Psoriásica/inmunología , Artritis Reumatoide/genética , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Centro Germinal/citología , Glucosa-6-Fosfato Isomerasa/inmunología , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores CXCR5/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína Asociada a la Molécula de Señalización de la Activación LinfocitariaRESUMEN
Asthma is prevalent in Western countries, and recent explanations have evoked the actions of the gut microbiota. Here we show that feeding mice a high-fibre diet yields a distinctive gut microbiota, which increases the levels of the short-chain fatty acid, acetate. High-fibre or acetate-feeding led to marked suppression of allergic airways disease (AAD, a model for human asthma), by enhancing T-regulatory cell numbers and function. Acetate increases acetylation at the Foxp3 promoter, likely through HDAC9 inhibition. Epigenetic effects of fibre/acetate in adult mice led us to examine the influence of maternal intake of fibre/acetate. High-fibre/acetate feeding of pregnant mice imparts on their adult offspring an inability to develop robust AAD. High fibre/acetate suppresses expression of certain genes in the mouse fetal lung linked to both human asthma and mouse AAD. Thus, diet acting on the gut microbiota profoundly influences airway responses, and may represent an approach to prevent asthma, including during pregnancy.
Asunto(s)
Acetatos/metabolismo , Asma/metabolismo , Dieta , Fibras de la Dieta/metabolismo , Microbioma Gastrointestinal , Efectos Tardíos de la Exposición Prenatal/metabolismo , Linfocitos T Reguladores/inmunología , Acetatos/farmacología , Acetilación/efectos de los fármacos , Animales , Asma/inmunología , Modelos Animales de Enfermedad , Epigénesis Genética/efectos de los fármacos , Ácidos Grasos Volátiles/metabolismo , Ácidos Grasos Volátiles/farmacología , Femenino , Factores de Transcripción Forkhead/efectos de los fármacos , Factores de Transcripción Forkhead/genética , Histona Desacetilasas/efectos de los fármacos , Histona Desacetilasas/metabolismo , Ratones , Embarazo , Efectos Tardíos de la Exposición Prenatal/inmunología , Regiones Promotoras Genéticas , Proteínas Represoras/efectos de los fármacos , Proteínas Represoras/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
Diet and the gut microbiota may underpin numerous human diseases. A major metabolic product of commensal bacteria are short-chain fatty acids (SCFAs) that derive from fermentation of dietary fibre. Here we show that diets deficient or low in fibre exacerbate colitis development, while very high intake of dietary fibre or the SCFA acetate protects against colitis. SCFAs binding to the 'metabolite-sensing' receptors GPR43 and GPR109A in non-haematopoietic cells mediate these protective effects. The inflammasome pathway has hitherto been reported as a principal pathway promoting gut epithelial integrity. SCFAs binding to GPR43 on colonic epithelial cells stimulates K(+) efflux and hyperpolarization, which lead to NLRP3 inflammasome activation. Dietary fibre also shapes gut bacterial ecology, resulting in bacterial species that are more effective for inflammasome activation. SCFAs and metabolite receptors thus explain health benefits of dietary fibre, and how metabolite signals feed through to a major pathway for gut homeostasis.
Asunto(s)
Proteínas Portadoras/efectos de los fármacos , Colitis/metabolismo , Colon/efectos de los fármacos , Fibras de la Dieta/farmacología , Ácidos Grasos Volátiles/metabolismo , Inflamasomas/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Acetatos/metabolismo , Animales , Butiratos/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Colon/metabolismo , Fermentación , Microbioma Gastrointestinal , Homeostasis/efectos de los fármacos , Inflamasomas/metabolismo , Ratones , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Receptores Acoplados a Proteínas G/genética , Receptores Nicotínicos/genéticaRESUMEN
There is now an abundance of evidence to show that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and the development of disease. SCFAs are a subset of fatty acids that are produced by the gut microbiota during the fermentation of partially and nondigestible polysaccharides. The highest levels of SCFAs are found in the proximal colon, where they are used locally by enterocytes or transported across the gut epithelium into the bloodstream. Two major SCFA signaling mechanisms have been identified, inhibition of histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs). Since HDACs regulate gene expression, inhibition of HDACs has a vast array of downstream consequences. Our understanding of SCFA-mediated inhibition of HDACs is still in its infancy. GPCRs, particularly GPR43, GPR41, and GPR109A, have been identified as receptors for SCFAs. Studies have implicated a major role for these GPCRs in the regulation of metabolism, inflammation, and disease. SCFAs have been shown to alter chemotaxis and phagocytosis; induce reactive oxygen species (ROS); change cell proliferation and function; have anti-inflammatory, antitumorigenic, and antimicrobial effects; and alter gut integrity. These findings highlight the role of SCFAs as a major player in maintenance of gut and immune homeostasis. Given the vast effects of SCFAs, and that their levels are regulated by diet, they provide a new basis to explain the increased prevalence of inflammatory disease in Westernized countries, as highlighted in this chapter.
Asunto(s)
Ácidos Grasos Volátiles/fisiología , Animales , Citocinas/antagonistas & inhibidores , Citocinas/biosíntesis , Citocinas/fisiología , Ácidos Grasos Volátiles/biosíntesis , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/prevención & control , Microbiota/inmunología , Microbiota/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Transducción de Señal/inmunología , Especificidad por Sustrato/inmunologíaRESUMEN
BACKGROUND: Asthma is a common global health problem. Environmental exposures such as bacteria may protect against asthma development. OBJECTIVE: This review aims to examine the possible protective role of pneumococcal infection and vaccination in asthma. METHODS: A review of known experimental biology and human epidemiology relating to asthma and pneumococcal infection was performed. RESULTS: Pneumococcal infection can modulate components of allergic airways disease such as airways hyperresponsiveness and airway eosinophilia. Exposure to killed pneumococcus can reproduce these effects and the mechanism may involve control by T regulatory cells. CONCLUSIONS: Pneumococcal immunoregulatory therapy is a potentially important approach to asthma management that requires further evaluation in well-designed research studies.