RESUMEN
The regulatory T (Treg) cells constitute a functionally defined subpopulation of T cells that modulate the immune system and maintain immune tolerance through suppression of the development of autoimmune responses to self-antigens and allergic reactions to external antigens. Reduction in the number or function of Treg cells has been suggested as a key immune abnormality underlying the development of autoimmune and allergic diseases. In vitro studies have demonstrated that purified polyvalent immunoglobulin G (IgG) from multiple healthy blood donors can exert immunomodulatory effects on Treg cells. Incubation of polyvalent human IgG with purified CD4+CD25high T cells increased the intracellular expression of interleukin (IL)-10. Intravenous administration of polyvalent human IgG induced significant expansions of CD4+ Foxp3+ Treg cells and clinical improvements in patients with autoimmune diseases. In human clinical trials, intramuscular administration of autologous total IgG significantly increased the percentage of IL-10-producing CD4+ Treg cells in the peripheral blood of healthy subjects and provided significant clinical improvements in patients with atopic dermatitis. These results suggest a clinical usefulness of polyvalent IgG-induced activation of Treg cells in human subjects. This review proposes a new hypothesis for immune tolerance mechanism by integrating the pre-existing "idiotypic network theory" and "Treg cell theory" into an "anti-idiotypic Treg cell theory." Based on this hypothesis, an "active anti-idiotypic therapy" for allergic and autoimmune diseases using autologous polyvalent IgG (as immunizing antigens) is suggested as follows: (1) Intramuscular or subcutaneous administration of autologous polyvalent IgG produces numerous immunogenic peptides derived from idiotypes of autologous IgG through processing of dendritic cells, and these peptides activate anti-idiotypic Treg cells in the same subject. (2) Activated anti-idiotypic Treg cells secrete IL-10 and suppress Th2 cell response to allergens and autoimmune T cell response to self-antigens. (3) These events can induce a long-term clinical improvements in patients with allergic and autoimmune diseases. Further studies are needed to evaluate the detailed molecular mechanism underlying polyvalent IgG-induced Treg cell activation and the clinical usefulness of this immunomodulatory therapy for autoimmune and allergic diseases.
Asunto(s)
Enfermedades Autoinmunes , Hipersensibilidad , Humanos , Linfocitos T Reguladores , Interleucina-10/metabolismo , Inmunoglobulina G/metabolismo , Tolerancia Inmunológica , Alérgenos , Hipersensibilidad/metabolismo , Enfermedades Autoinmunes/terapia , Enfermedades Autoinmunes/metabolismo , Autoantígenos/metabolismoRESUMEN
Objective: To evaluate the effect of pharmacological modulation of HIF-1 on the expression of IL-33 and IL-17 in a murine model of allergic pulmonary inflam- mation (API) with different degrees of severity. Methods: 5 mice/group received ovalbumin (OVA) 1(mild), 2(moderate) or 3(severe) challenges via i.t. prior to allergen sensitization, in addition to the HIF-1 induction or inhibition groups, received EDHB (OVA+EDHB) i.p. or 2ME (OVA+2ME) i.t. respectively. Control groups received saline solution (SS) in the same way. HE (inflammatory infiltrate), PAS (mucus production) and immunohistochemical staining for HIF-1a, IL-33, IL-17 were performed, quantitatively analyzing by digital pathology. Results: We obtained different degrees of severity with a greater number of challenges, increasing the expression of HIF-1, correlating with the expression of IL-33/IL-17. Increasing or decreasing, respectively by pharmacological modulation. Conclusions: The above suggests that the high expression of HIF-1 favors the production of IL-33 and IL-17 contributing to the damage in lung tissue and the severity of the disease and these can be regulated through the modulation of HIF- 1.
Objetivo: Evaluar el efecto de la modulación farmacológica de HIF-1 en la expresión de IL-33 e IL-17 en un modelo murino de inflamación alérgica pulmonar (IAP) con diferentes grados de severidad. Métodos: 5 ratones/grupo recibieron ovoalbúmina (OVA) 1(leve), 2(moderada) o 3(severa) retos vía i.t. previa sensibilización como alergeno, además los grupos de inducción o inhibición de HIF-1a, recibieron EDHB (OVA+EDHB) i.p. o 2ME (OVA+2ME) i.t. respectivamente. Los grupos controles recibieron solución salina (SS) de igual forma. Se realizaron tinciones de HE (infiltrado inflamatorio), PAS (producción de moco) e inmunohistoquímicas de HIF-1a, IL-33, IL-17, analizando cuantitativamente por patología digital. Resultados: Obtuvimos diferentes grados de severidad a mayor número de retos, incrementando la expresión de HIF-1, correlacionando con la expresión de IL- 33/IL-17. Aumentando o disminuyendo, respectivamente por la modulación farmacológica. Conclusiones: Lo anterior sugiere que la alta expresión de HIF-1 favorece la producción de IL-33 e IL-17 contribuyendo al daño en el tejido pulmonar y la severi- dad de la enfermedad y estas pueden ser reguladas a través de la modulación de HIF-1.
Asunto(s)
Hipersensibilidad , Factor 1 Inducible por Hipoxia , Interleucina-17 , Interleucina-33 , Enfermedades Pulmonares , Animales , Ratones , Alérgenos , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Pulmón , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/metabolismo , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/metabolismo , Factor 1 Inducible por Hipoxia/metabolismoRESUMEN
Allergic reactions are highly prevalent pathologies initiated by the production of IgE antibodies against harmless antigens (allergens) and the activation of the high-affinity IgE receptor (FcεRI) expressed in the surface of basophils and mast cells (MCs). Research on the mechanisms of negative control of those exacerbated inflammatory reactions has been intense in recent years. Endocannabinoids (eCBs) show important regulatory effects on MC-mediated immune responses, mainly inhibiting the production of pro-inflammatory mediators. However, the description of the molecular mechanisms involved in eCB control of MC activation is far from complete. In this review, we aim to summarize the available information regarding the role of eCBs in the modulation of FcεRI-dependent activation of that cell type, emphasizing the description of the eCB system and the existence of some of its elements in MCs. Unique characteristics of the eCB system and cannabinoid receptors (CBRs) localization and signaling in MCs are mentioned. The described and putative points of cross-talk between CBRs and FcεRI signaling cascades are also presented. Finally, we discuss some important considerations in the study of the effects of eCBs in MCs and the perspectives in the field.
Asunto(s)
Hipersensibilidad , Receptores de IgE , Humanos , Receptores de IgE/metabolismo , Inmunoglobulina E/metabolismo , Inmunoglobulina E/farmacología , Endocannabinoides/metabolismo , Endocannabinoides/farmacología , Mastocitos/metabolismo , Hipersensibilidad/metabolismoRESUMEN
Programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2 are receptors that act in co-stimulatory and coinhibitory immune responses. Signaling the PD-1/PD-L1 or PD-L2 pathway is essential to regulate the inflammatory responses to infections, autoimmunity, and allergies, and it has been extensively studied in cancer. Allergic diseases include asthma, rhinoconjunctivitis, atopic dermatitis, drug allergy, and anaphylaxis. These overactive immune responses involve IgE-dependent activation and increased CD4+ T helper type 2 (Th2) lymphocytes. Recent studies have shown that PD-L1 and PD-L2 act to regulate T-cell activation and function. However, the main role of PD-1 and its ligands is to balance the immune response; however, the inflammatory process of allergic diseases is poorly understood. These immune checkpoint molecules can function as a brake or a kick-start to regulate the adaptive immune response. These findings suggest that PD-1 and its ligands may be a key factor in studying the exaggerated response in hypersensitivity reactions in allergies. This review summarizes the current understanding of the role of PD-1 and PD-L1 and PD-L2 pathway regulation in allergic diseases and how this immunomodulatory pathway is currently being targeted to develop novel therapeutic immunotherapy.
Asunto(s)
Antígeno B7-H1/metabolismo , Hipersensibilidad/patología , Inmunidad Innata/inmunología , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Animales , Antígeno B7-H1/inmunología , Humanos , Hipersensibilidad/etiología , Hipersensibilidad/metabolismo , Proteína 2 Ligando de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
Cancer is associated with immunodeficiency, while allergies result from immune system hyperactivity mediated by cytokines and immunoglobulins. The purpose of this study was to determine the relationship between immune environment of specific cancers and allergies, emphasizing cytokines related to Th1 and Th2 responses associated with IgE. 80 adults were distributed into two groups: control (n = 20) and cancer (n = 60), distributed in three subgroups (n = 20), head and neck, stomach, and prostate cancers. This study compared Th1 (IL-2) and Th2 (IL-4) parameters, anti-inflammatory, pro-inflammatory, or regulatory profile regarding both IgE levels and reported allergies, by means of clinical manifestations and IgE, IL-1ß, IL-2, IL-4, IL-17, and TGF-ß serum concentration. Clinically allergies were observed in 50% of the control group and in 20% of the cancer group (p = 0.009). IL-2 cytokine and TGF-ß concentrations were higher in the patients with cancer as compared to the control (p < 0.005). However, there were IL-4, IL-17, and IL-1ß decreases in the patients with cancer (p < 0.05). No correlation was observed between the cytokines studied and IgE and clinically proven allergies in both investigated groups. There was an inverse association between cancer and clinical allergy manifestations. In head and neck, stomach, and prostate cancers, an immunosuppressive serum tumor environment was predominant. There was no difference in cytokines related to Th1 and Th2 parameters in relation to IgE. No correlation was found between clinically proved allergies and immunity markers related to the same allergens.
Asunto(s)
Hipersensibilidad/epidemiología , Hipersensibilidad/etiología , Neoplasias/complicaciones , Neoplasias/epidemiología , Anciano , Biomarcadores , Comorbilidad , Citocinas/sangre , Citocinas/metabolismo , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Hipersensibilidad/diagnóstico , Hipersensibilidad/metabolismo , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/metabolismo , Neoplasias/patología , Medición de Riesgo , Factores de RiesgoRESUMEN
Exposure to different organisms (bacteria, mold, virus, protozoan, helminths, among others) can induce epigenetic changes affecting the modulation of immune responses and consequently increasing the susceptibility to inflammatory diseases. Epigenomic regulatory features are highly affected during embryonic development and are responsible for the expression or repression of different genes associated with cell development and targeting/conducting immune responses. The well-known, "window of opportunity" that includes maternal and post-natal environmental exposures, which include maternal infections, microbiota, diet, drugs, and pollutant exposures are of fundamental importance to immune modulation and these events are almost always accompanied by epigenetic changes. Recently, it has been shown that these alterations could be involved in both risk and protection of allergic diseases through mechanisms, such as DNA methylation and histone modifications, which can enhance Th2 responses and maintain memory Th2 cells or decrease Treg cells differentiation. In addition, epigenetic changes may differ according to the microbial agent involved and may even influence different asthma or allergy phenotypes. In this review, we discuss how exposure to different organisms, including bacteria, viruses, and helminths can lead to epigenetic modulations and how this correlates with allergic diseases considering different genetic backgrounds of several ancestral populations.
Asunto(s)
Asma/genética , Asma/inmunología , Epigénesis Genética , Hipersensibilidad/genética , Hipersensibilidad/inmunología , Fenómenos Inmunogenéticos , Microbiota/inmunología , Animales , Asma/metabolismo , Bacterias/inmunología , Ensamble y Desensamble de Cromatina , Metilación de ADN , Exposición a Riesgos Ambientales/efectos adversos , Predisposición Genética a la Enfermedad , Helmintos/inmunología , Interacciones Huésped-Patógeno , Humanos , Hipótesis de la Higiene , Hipersensibilidad/metabolismo , Medición de Riesgo , Factores de Riesgo , Virus/inmunologíaRESUMEN
The prevalence of food allergy has increased in recent years, especially among the pediatric population. Differences in the gut microbiota composition between children with FA and healthy children have brought this topic into the spotlight as a possible explanation for the increase in FA. The gut microbiota characteristics are acquired through environmental interactions starting early in life, such as type of delivery during birth and breastfeeding. The microbiota features may be shaped by a plethora of immunomodulatory mechanisms, including a predominant role of Tregs and the transcription factor FOXP3. Additionally, a pivotal role has been given to vitamin A and butyrate, the main anti-inflammatory metabolite. These observations have led to the study and development of therapies oriented to modifying the microbiota and metabolite profiles, such as the use of pre- and probiotics and the determination of their capacity to induce tolerance to allergens that are relevant to FA. To date, evidence supporting these approaches in humans is scarce and inconclusive. Larger cohorts and dose-titration studies are mandatory to evaluate whether the observed changes in gut microbiota composition reflect medical recovery and increased tolerance in pediatric patients with FA. In this article, we discuss the establishment of the microbiota, the immunological mechanisms that regulate the microbiota of children with food allergies, and the evidence in research focused on its regulation as a means to achieve tolerance to food allergens.
Asunto(s)
Microbioma Gastrointestinal , Interacciones Microbiota-Huesped/inmunología , Tolerancia Inmunológica , Factores de Edad , Animales , Biomarcadores , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Disbiosis , Metabolismo Energético , Femenino , Microbioma Gastrointestinal/inmunología , Humanos , Hipersensibilidad/diagnóstico , Hipersensibilidad/etiología , Hipersensibilidad/metabolismo , Hipersensibilidad/terapia , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Inmunidad Innata , Lactante , Recién Nacido , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Masculino , Mastocitos/inmunología , Mastocitos/metabolismo , Intercambio Materno-Fetal/inmunología , EmbarazoRESUMEN
Clinical and experimental studies show an association between maternal periodontitis and adverse outcomes during gestation. On the other hand, there were no studies evaluating the impact of maternal periodontitis on the offspring. Thus, our objective was to investigate the repercussion of maternal periodontitis on the development of asthma in the offspring. Pregnant rats were submitted or not to periodontitis by ligature technique. Thirty days after birth, the puppies were sensitized and challenged with ovalbumin (OVA) in order to induce asthmatic response. Our results showed that maternal periodontitis reduced cellular infiltrate in the parenchyma of offspring, tracheal responsiveness, lung edema, and anti-OVA antibodies, without alter mucus as well as cytokines production. We concluded that periodontitis has relevant impact on the offspring's immune system, blunting the response to allergic and inflammatory stimulus. This study shows the important role of oral health during pregnancy and opens possibilities for future studies in order to explain the effects of periodontitis during pregnancy in the offspring.
Asunto(s)
Asma/patología , Hipersensibilidad/patología , Exposición Materna/efectos adversos , Periodontitis/complicaciones , Animales , Animales Recién Nacidos , Asma/etiología , Asma/metabolismo , Citocinas/metabolismo , Femenino , Hipersensibilidad/etiología , Hipersensibilidad/metabolismo , Masculino , Embarazo , Ratas , Ratas WistarRESUMEN
Insect venom can cause systemic allergic reactions, including anaphylaxis. Improvements in diagnosis and venom immunotherapy (VIT) are based on a better understanding of an immunological response triggered by venom allergens. Previously, we demonstrated that the recombinant phospholipase A1 (rPoly p 1) from Polybia paulista wasp venom induces specific IgE and IgG antibodies in sensitized mice, which recognized the native allergen. Here, we addressed the T cell immune response of rPoly p 1-sensitized BALB/c mice. Cultures of splenocytes were stimulated with Polybia paulista venom extract and the proliferation of CD8+ and CD4+ T cells and the frequency of T regulatory cells (Tregs) populations were assessed by flow cytometry. Cytokines were quantified in cell culture supernatants in ELISA assays. The in vitro stimulation of T cells from sensitized mice induces a significant proliferation of CD4+ T cells, but not of CD8+ T cells. The cytokine pattern showed a high concentration of IFN-γ and IL-6, and no significant differences to IL-4, IL-1ß and TGF-ß1 production. In addition, the rPoly p 1 group showed a pronounced expansion of CD4+CD25+FoxP3+ and CD4+CD25-FoxP3+ Tregs. rPoly p 1 sensitization induces a Th1/Treg profile in CD4+ T cell subset, suggesting its potential use in wasp venom immunotherapy.
Asunto(s)
Alérgenos/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Desensibilización Inmunológica , Proteínas de Insectos/farmacología , Fosfolipasas A1/farmacología , Venenos de Avispas/farmacología , Alérgenos/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Femenino , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Hipersensibilidad/terapia , Mordeduras y Picaduras de Insectos/inmunología , Mordeduras y Picaduras de Insectos/metabolismo , Mordeduras y Picaduras de Insectos/terapia , Proteínas de Insectos/inmunología , Activación de Linfocitos/efectos de los fármacos , Ratones Endogámicos BALB C , Fosfolipasas A1/inmunología , Venenos de Avispas/inmunologíaRESUMEN
Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that participates in innate and adaptive immune responses. MIF contributes to the resistance against infection agents, but also to the cellular and tissue damage in infectious, autoimmune, and allergic diseases. In the past years, several studies demonstrated a critical role for MIF in the pathogenesis of type-2-mediated inflammation, including allergy and helminth infection. Atopic patients have increased MIF amounts in affected tissues, mainly produced by immune cells such as macrophages, Th2 cells, and eosinophils. Increased MIF mRNA and protein are found in activated Th2 cells, while eosinophils stock pre-formed MIF protein and secrete high amounts of MIF upon stimulation. In mouse models of allergic asthma, the lack of MIF causes an almost complete abrogation of the cardinal signs of the disease including mucus secretion, eosinophilic inflammation, and airway hyper-responsiveness. Additionally, blocking the expression of MIF in animal models leads to significant reduction of pathological signs of eosinophilic inflammation such as rhinitis, atopic dermatitis, eosinophilic esophagitis and helminth infection. A number of studies indicate that MIF is important in the effector phase of type-2 immune responses, while its contribution to Th2 differentiation and IgE production is not consensual. MIF has been found to intervene in different aspects of eosinophil physiology including differentiation, survival, activation, and migration. CD4+ T cells and eosinophils express CD74 and CXCR4, receptors able to signal upon MIF binding. Blockage of these receptors with neutralizing antibodies or small molecule antagonists also succeeds in reducing the signals of inflammation in experimental allergic models. Together, these studies demonstrate an important contribution of MIF on eosinophil biology and in the pathogenesis of allergic diseases and helminth infection.
Asunto(s)
Susceptibilidad a Enfermedades , Eosinófilos/inmunología , Eosinófilos/metabolismo , Inflamación/etiología , Inflamación/metabolismo , Oxidorreductasas Intramoleculares/genética , Oxidorreductasas Intramoleculares/metabolismo , Factores Inhibidores de la Migración de Macrófagos/genética , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Animales , Biomarcadores , Médula Ósea/metabolismo , Médula Ósea/patología , Eosinófilos/patología , Interacciones Huésped-Parásitos , Interacciones Huésped-Patógeno , Humanos , Hipersensibilidad/etiología , Hipersensibilidad/metabolismo , Hipersensibilidad/patología , Inflamación/patología , Transducción de SeñalRESUMEN
Asthma allergic disease is caused by airway chronic inflammation. Some intracellular signaling pathways, such as MAPK and STAT3-SOCS3, are involved in the control of airway inflammation in asthma. The flavonoid sakuranetin demonstrated an anti-inflammatory effect in different asthma models. Our aim was to clarify how sakuranetin treatment affects MAPK and STAT3-SOCS3 pathways in a murine experimental asthma model. Mice were submitted to an asthma ovalbumin-induction protocol and were treated with vehicle, sakuranetin, or dexamethasone. We assayed the inflammatory profile, mucus production, and serum antibody, STAT3-SOCS3, and MAPK levels in the lungs. Morphological alterations were also evaluated in the liver. LPS-stimulated RAW 264.7 cells were used to evaluate the effects of sakuranetin on nitric oxide (NO) and cytokine production. In vivo, sakuranetin treatment reduced serum IgE levels, lung inflammation (eosinophils, neutrophils, and Th2/Th17 cytokines), and respiratory epithelial mucus production in ovalbumin-sensitized animals. Considering possible mechanisms, sakuranetin inhibits the activation of ERK1/2, JNK, p38, and STAT3 in the lungs. No alterations were found in the liver for treated animals. Sakuranetin did not modify in vitro cell viability in RAW 264.7 and reduced NO release and gene expression of IL-1ß and IL-6 induced by LPS in these cells. In conclusion, our data showed that the inhibitory effects of sakuranetin on eosinophilic lung inflammation can be due to the inhibition of Th2 and Th17 cytokines and the inhibition of MAPK and STAT3 pathways, reinforcing the idea that sakuranetin can be considered a relevant candidate for the treatment of inflammatory allergic airway disease.
Asunto(s)
Flavonoides/uso terapéutico , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Extractos Vegetales/uso terapéutico , Factor de Transcripción STAT3/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Animales , Western Blotting , Citocinas/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos BALB C , Células RAW 264.7RESUMEN
Both obesity and low vitamin D levels have been associated with allergic asthma (AA) severity. In the present study, severity of AA was associated with obesity but to the in vitro IgE production. In those patients, higher levels of IL-5, IL-6 and IL-17 were quantified in CD4+ T-cell cultures as compared with patients with mild and moderate AA. In addition, the lowest IL-10 levels were detected in the cell cultures from patients with a worse prognosis. Interestingly, the occurrence of AA elevates the plasma levels of leptin, and this adipokine was positively correlated with the release of IL-5, IL-6 and IL-17, but inversely correlated with IL-10 production, by CD4+ T-cells from patients. In AA-derived CD4+ T-cell cultures, 1,25(OH)2D3 was less efficient at inhibiting IL-5, IL-6 and IL-17 production, and up regulating IL-10 release, as those from healthy subjects. Interestingly, the in vitro immunomodulatory effects of vitamin D were inversely correlated with serum leptin levels. In summary, our findings suggested that obesity, probably due to the overproduction of leptin, negatively impacts AA as it favors imbalance between Th2/Th17 and regulatory phenotypes. The deleterious effects of leptin may also be due to its ability to counter-regulate the immunosuppressive effects of vitamin D.
Asunto(s)
Asma/inmunología , Linfocitos T CD4-Positivos/inmunología , Citocinas/inmunología , Hipersensibilidad/inmunología , Leptina/metabolismo , Obesidad/metabolismo , Adulto , Asma/metabolismo , Linfocitos T CD4-Positivos/efectos de los fármacos , Calcitriol/farmacología , Citocinas/efectos de los fármacos , Femenino , Humanos , Hipersensibilidad/metabolismo , Inmunoglobulina E/inmunología , Técnicas In Vitro , Interleucina-10/inmunología , Interleucina-17/inmunología , Interleucina-5/inmunología , Interleucina-6/inmunología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Vitamina D/metabolismo , Vitaminas/farmacología , Adulto JovenRESUMEN
Increased levels of ATP have been found in the bronchoalveolar lavage of patients with asthma, and subjects with this disease, but not healthy subjects, develop bronchospasm after nebulization with ATP. Because the main mechanism for controlling the noxious effects of extracellular ATP is its enzymatic hydrolysis, we hypothesized that allergic sensitization is accompanied by a decreased functioning of such hydrolysis. In the present study, peripheral blood leukocytes from sensitized and non-sensitized guinea pigs were used for determining the extracellular metabolism (as assessed by inorganic phosphate production) of ATP, ADP, AMP, or adenosine, and for detecting possible changes in the expression (qPCR and Western blot) of major ectonucleotidases (NTPDase1, NTPDase3, and NPP1) and purinoceptors (P2X1, P2X7, P2Y4, and P2Y6). Contrary to our hypothesis, we found that leukocytes from allergic animals produced higher amounts of inorganic phosphate after stimulation with ATP and ADP, as compared with leukocytes from non-sensitized animals. Although at first glance, this result suggested that sensitization caused higher efficiency of ectonucleotidases, their mRNA and protein expressions were unaffected. On the other hand, after sensitization, we found a significant increase in the protein expression of P2X7 and P2Y4, two purinoceptors known to be responsible for ATP release after activation. We concluded that allergic sensitization increased the amount of ATP hydrolyzed by ectonucleotidases, the latter probably not due to the enhanced efficiency of its enzymatic breakdown, but rather due to an increased release of endogenous ATP or other nucleotides, partly mediated by enhanced expression or P2X7 and P2Y4 receptors.
Asunto(s)
Adenosina Trifosfato/metabolismo , Hipersensibilidad/metabolismo , Leucocitos/metabolismo , Animales , Cobayas , Hidrólisis , Masculino , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7/metabolismoRESUMEN
To elucidate the proteomic responses of shrimp hemocytes to white spot syndrome virus (WSSV) infection at the proteome level, a quantitative shotgun proteomic analysis was performed to detect differentially synthesized proteins in infected hemocytes of white shrimp (Litopenaeus vannamei). We identified 1528 proteins associated to 203 gene ontology (GO) categories. The most representative GO categories were regulation of cellular processes, organic substance metabolic processes and nitrogen compound metabolic processes. Most of the 83 detected up-regulated proteins are involved in DNA regulation and organization and cell signaling. In contrast, most of the 40 down-regulated proteins were related to immune defense processes, protein folding, and development. Differentially induced proteins were further analyzed at the transcript level by RT-qPCR to validate the results. This work provides new insights into the alterations of L. vannamei hemocytes at the protein level at 12â¯h post-infection with WSSV. Interestingly, several of the up-regulated proteins are allergy-related proteins in humans. Based on our results, we suggest a deeper analysis of the effects of this interaction on the regulation of allergy related-proteins as their up-regulation during WSSV could represent a threat to human health.
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Proteínas de Artrópodos/metabolismo , Infecciones por Virus ADN/inmunología , Hemocitos/fisiología , Hipersensibilidad/metabolismo , Penaeidae/inmunología , Virus del Síndrome de la Mancha Blanca 1/inmunología , Animales , Proteínas de Artrópodos/genética , Perfilación de la Expresión Génica , Ontología de Genes , Humanos , Hipersensibilidad/genética , Inmunidad Innata/genética , Penaeidae/genética , Penaeidae/virología , ProteomaRESUMEN
Background. CrataBL is a protein isolated from Crataeva tapia bark. It has been shown to exhibit several biological properties, including anti-inflammatory, analgesic, antitumor, and insecticidal activities. There are no studies evaluating the role of CrataBL in experimental asthma models. Aim. To evaluate the effects of CrataBL on lung mechanics, inflammation, remodeling, and oxidative stress activation of mice with allergic pulmonary inflammation. Materials and Methods. BALB/c mice (6-7 weeks old, 25-30g) were divided into four groups: nonsensitized and nontreated mice (C group, n=8); ovalbumin- (OVA-) sensitized and nontreated mice (OVA group, n=8); nonsensitized and CrataBL-treated mice (C+CR group, n=8); OVA-sensitized and CrataBL-treated mice (OVA+CR group, n=8). We evaluated hyperresponsiveness to methacholine, bronchoalveolar lavage fluid (BALF), pulmonary inflammation, extracellular matrix remodeling, and oxidative stress markers. Results. CrataBL treatment in OVA-sensitized mice (OVA+CR group) attenuated the following variables compared to OVA-sensitized mice without treatment (OVA group) (all p<0.05): (1) respiratory system resistance (Rrs) and elastance (Ers) after methacholine challenge; (2) total cells, macrophages, polymorphonuclear cells, and lymphocytes in BALF; (3) eosinophils and volume fraction of collagen and elastic fibers in the airway and alveolar wall according to histopathological and morphometry analysis; (4) IL-4-, IL-5-, IL-13-, IL-17-, IFN-γ-, MMP-9-, TIMP-1-, TGF-ß-, iNOS-, and NF-kB-positive cells and volume of 8-iso-PGF2α in airway and alveolar septa according to immunohistochemistry; and (5) IL-4, IL-5, and IFN-γ according to an ELISA. Conclusion. CrataBL contributes to the control of hyperresponsiveness, pulmonary inflammation, extracellular matrix remodeling, and oxidative stress responses in an animal model of chronic allergic pulmonary inflammation.
Asunto(s)
Asma/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Lectinas de Plantas/farmacología , Proteínas de Plantas/farmacología , Animales , Asma/metabolismo , Pruebas de Provocación Bronquial/métodos , Líquido del Lavado Bronquioalveolar/química , Capparaceae/química , Modelos Animales de Enfermedad , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/farmacología , Neumonía/tratamiento farmacológico , Neumonía/metabolismoRESUMEN
Asthma is an allergic inflammation driven by the Th2 immune response with release of cytokines such as IL-4 and IL-13, which contribute to the airflow limitations and airway hyperresponsiveness (AHR). The involvement of oxidative stress in this process is well-established, but the specific role of the superoxide anion and nitric oxide in asthma are poorly understood. Thus, the aim of this study was to investigate the mechanisms underlying the superoxide anion/nitric oxide production and detoxification in a murine asthma model. BALB/c male mice were sensitised and challenged with ovalbumin (OVA). Pretreatments with either apocynin (14 mg/kg) or allopurinol (25 mg/kg) (superoxide anion synthesis inhibitors), aminoguanidine (50 mg/kg) (nitric oxide synthesis inhibitor) or diethyldithiocarbamate (100 mg/kg) (superoxide dismutase inhibitor) were performed 1 h before the challenge. Our data showed that apocynin and allopurinol ameliorated AHR and reduced eosinophil peroxidase, as well as IL-4 and IL-13 levels. Apocynin also abrogated leukocyte peribronchiolar infiltrate and increased IL-1ß secretion. Aminoguanidine preserved lung function and shifted the Th2 to the Th1 response with a reduction of IL-4 and IL-13 and increase in IL-1ß production. Diethyldithiocarbamate prevented neither allergen-induced AHR nor eosinophil peroxidase (EPO) generation. All treatments protected against oxidative damage observed by a reduction in TBARS levels. Taken together, these results suggest that AHR in an asthma model can be avoided by the down-regulation of superoxide anion and nitric oxide synthesis in a mechanism that is independent of a redox response. This down-regulation is also associated with a transition in the typical immunological Th2 response toward the Th1 profile.
Asunto(s)
Asma/inmunología , Inflamación/inmunología , Óxido Nítrico/antagonistas & inhibidores , Hipersensibilidad Respiratoria/inmunología , Superóxidos/antagonistas & inhibidores , Acetofenonas/administración & dosificación , Alopurinol/administración & dosificación , Animales , Asma/metabolismo , Asma/patología , Modelos Animales de Enfermedad , Peroxidasa del Eosinófilo/inmunología , Peroxidasa del Eosinófilo/metabolismo , Guanidinas/administración & dosificación , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Hipersensibilidad/patología , Inflamación/metabolismo , Inflamación/patología , Interleucina-13/inmunología , Interleucina-13/metabolismo , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Interleucina-4/inmunología , Interleucina-4/metabolismo , Ratones , Óxido Nítrico/inmunología , Ovalbúmina/inmunología , Estrés Oxidativo/inmunología , Especies Reactivas de Oxígeno/inmunología , Especies Reactivas de Oxígeno/metabolismo , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/patología , Superóxidos/inmunología , Células TH1/inmunología , Células Th2/inmunologíaRESUMEN
IL-9 is a pleiotropic cytokine produced in different amounts by a wide variety of cells including mast cells, NKT cells, Th2, Th17, Treg, ILC2, and Th9 cells. Th9 cells are considered to be the main CD4+ T cells that produce IL-9. IL-9 exerts its effects on multiple types of cells and different tissues. To date, its main role has been found in the immune responses against parasites and pathogenesis of allergic diseases such as asthma and bronchial hyperreactivity. Additionally, it induces the proliferation of hematologic neoplasias, including Hodgkin's lymphoma in humans. However, IL-9 also has antitumor properties in solid tumors such as melanoma. The objective of this review is to describe IL-9, its function, sources, and methods of detection.
Asunto(s)
Interleucina-9/metabolismo , Asma/metabolismo , Citocinas/metabolismo , Humanos , Hipersensibilidad/metabolismo , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo , Células Th2/metabolismoRESUMEN
Asthma is a chronic inflammation of the airways affecting over 300 million people worldwide. As in the autoimmune diseases, it is well described that women are the most affected by asthma. The higher number of women presenting this pathology suggests the involvement of female sex hormones in the construction of the allergic immune response. Female Balb / c mice were used for the experiments. Thirty-eight animals were separated into four groups: OVX-Ova; Sham-Ova; OVX-Sal; Sham-Sal. Then animals underwent acute allergic induction protocol by Ovalbulmin (OVA). Ovariectomized animals showed greater number of leukocytes in bronchoalveolar lavage (BAL) and elevated white blood cells recruitment to the lung environment observed by histological analysis. There was a significant increase of eosinophils and mast cells in inflammatory sites at pulmonary tissue. The relative uterine and body weight were lower in ovariectomized animals and higher in Sham mice, respectively. Moreover, the lack of the sex hormones induced an increase in interleukin (IL)-4 and titers of immunoglobulin G1 (IgG1) antibodies. However, increased production of IL-17A was only observed in Sham animals. Altogether, data this study suggest that ovariectomy induces the formation of a stronger Th2 response in allergic animal. However, the immune processes involved in the allergic response in females currently remain unclear.
Asunto(s)
Hipersensibilidad/inmunología , Recuento de Linfocitos , Ovariectomía , Células Th17/inmunología , Células Th2/inmunología , Animales , Anticuerpos/sangre , Anticuerpos/inmunología , Quimiotaxis de Leucocito/inmunología , Citocinas/metabolismo , Eosinófilos/inmunología , Eosinófilos/metabolismo , Eosinófilos/patología , Femenino , Hormonas Esteroides Gonadales/metabolismo , Hipersensibilidad/metabolismo , Inmunoglobulina G/inmunología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Células Th17/metabolismo , Células Th2/metabolismoRESUMEN
Airway inflammation is the most common hallmark of allergic asthma. Chemokine receptors involved in leukocyte recruitment are closely related to the pathology in asthma. CCR9 has been described as a homeostatic and inflammatory chemokine receptor, but its role and that of its ligand CCL25 during lung inflammation remain unknown. To investigate the role of CCR9 as a modulator of airway inflammation, we established an OVA-induced allergic inflammation model in CCR9-deficient mice. Here, we report the expression of CCR9 and CCL25 as early as 6 hours post-OVA challenge in eosinophils and T-lymphocytes. Moreover, in challenged CCR9-deficient mice, cell recruitment was impaired at peribronchial and perivenular levels. OVA-administration in CCR9-deficient mice leads to a less inflammatory cell recruitment, which modifies the expression of IL-10, CCL11, and CCL25 at 24 hours after OVA challenge. In contrast, the secretion of IL-4 and IL-5 was not affected in CCR9-deficient mice compared to WT mice. These results demonstrate for the first time that CCR9 and CCL25 expressions are induced in the early stages of airway inflammation and they have an important role modulating eosinophils and lymphocytes recruitment at the first stages of inflammatory process, suggesting that they might be a potential target to regulate inflammation in asthma.
Asunto(s)
Quimiocinas CC/metabolismo , Regulación de la Expresión Génica , Hipersensibilidad/metabolismo , Inflamación/metabolismo , Receptores CCR/metabolismo , Animales , Líquido del Lavado Bronquioalveolar , Separación Celular , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Eosinófilos/citología , Femenino , Citometría de Flujo , Inmunoglobulina E/sangre , Leucocitos/citología , Pulmón/fisiopatología , Linfocitos/citología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Linfocitos T/citologíaRESUMEN
BACKGROUND: The mosquito Aedes aegypti is a potential source of important clinically relevant allergens. However, the allergenicity and cross-reactivity of most of these has not been fully described. METHODS: Natural wild-type mosquito tropomyosin was purified by size exclusion and anionic-exchange chromatography from an A. aegypti extract. Further characterization was accomplished by MALDI-TOF/TOF. Two recombinant variants of tropomyosin were obtained by expression in Escherichia coli. Specific IgE measurement by ELISA and skin tests for mosquito extract were performed in 12 patients with asthma or allergy rhinitis residing on the Caribbean island of Martinique. Cross-reactivity between natural A. aegypti tropomyosin and recombinant tropomyosins from A. aegypti, house dust mite, shrimp and Ascaris lumbricoides was analyzed by ELISA competition. RESULTS: Four variants of natural tropomyosin were purified. A band of 32 kDa in SDS-PAGE representing 2 tropomyosin variants (Aed a 10.0101 and Aed a 10.0201) reacted with specific IgE of 4 of the 12 (33%) allergic patients and with rabbit polyclonal anti-shrimp tropomyosin. A high degree of cross-reactivity (60-70%) was detected between natural mosquito tropomyosin and Blo t 10, Der p 10 and Lit v 1, and a lower degree with Asc l 3 from A. lumbricoides (<30%). rAed a 10.0101 inhibited IgE binding to natural A. aegypti tropomyosin; however, rAed a 10.0201 showed a low inhibitory capacity. CONCLUSION: Tropomyosin is a new IgE-binding protein from A. aegypti. Two of the 4 variants identified showed different degree of cross-reactivity with tropomyosins from other arthropods. The potential allergenic role of each variant should be further investigated.