RESUMO
Allergic asthma, driven by T helper 2 cell-mediated immune responses to common environmental antigens, remains the most common respiratory disease in children. Perfluorinated chemicals (PFCs) are environmental contaminants of great concern, because of their wide application, persistence in the environment, and bioaccumulation. PFCs associate with immunological disorders including asthma and attenuate immune responses to vaccines. The influence of PFCs on the immunological response to allergens during childhood is unknown. We report here that a major PFC, perfluorooctane sulfonate (PFOS), inactivates house dust mite (HDM) to dampen 5-wk-old, early weaned mice from developing HDM-induced allergic asthma. PFOS further attenuates the asthma protective effect of the microbial product lipopolysaccharide (LPS). We demonstrate that PFOS prevents desensitization of lung epithelia by LPS, thus abolishing the latter's protective effect. A close mechanistic study reveals that PFOS specifically binds the major HDM allergen Der p1 with high affinity as well as the lipid A moiety of LPS, leading to the inactivation of both antigens. Moreover, PFOS at physiological human (nanomolar) concentrations inactivates Der p1 from HDM and LPS in vitro, although higher doses did not cause further inactivation because of possible formation of PFOS aggregates. This PFOS-induced neutralization of LPS has been further validated in primary human cell models and extended to an in vivo bacterial infection mouse model. This study demonstrates that early life exposure of mice to a PFC blunts airway antigen bioactivity to modulate pulmonary inflammatory responses, which may adversely affect early pulmonary health.
Assuntos
Ácidos Alcanossulfônicos/farmacologia , Antígenos de Dermatophagoides/imunologia , Asma/imunologia , Asma/parasitologia , Fluorocarbonos/farmacologia , Hipersensibilidade/imunologia , Hipersensibilidade/parasitologia , Ácidos Alcanossulfônicos/química , Animais , Antígenos de Dermatophagoides/química , Asma/complicações , Asma/genética , Células Dendríticas/imunologia , Escherichia coli , Feminino , Fluorocarbonos/química , Perfilação da Expressão Gênica , Hipersensibilidade/complicações , Hipersensibilidade/genética , Imunomodulação/efeitos dos fármacos , Imunomodulação/genética , Lipopolissacarídeos , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/parasitologia , Pulmão/patologia , Camundongos Endogâmicos BALB C , Modelos Moleculares , Pseudomonas aeruginosa/fisiologia , Pyroglyphidae/fisiologiaRESUMO
Allergen-specific-immunotherapy (ASIT) can cause long-term resolution of allergic diseases, reduces drug use and chances of new allergen sensitization. Nevertheless, therapeutic vaccine and data on ASIT efficacy for cockroach (CR) allergy are relatively scarce. In this study, efficacy and mechanism of a novel intranasal vaccine consisting of liposome (L)-entrapped mixture of American CR (Periplaneta americana) major allergen (Per a 9) and immunosuppressive protein of Brugia malayi nematode named transforming growth factor-beta homologue (TGH) in treatment of CR allergy were investigated along with two other vaccines (L-Per a 9 alone and L-TGH alone). All three vaccines could reduce pathogenic type 2 response and lung immunopathology in the vaccines-treated CR-allergic mice, but by different mechanisms. L-Per a 9 caused a deviation of the pathogenic type 2 to type 1 response (IFN-γ-upregulation), whereas the L-(TGH + Per a 9) and L-TGH generated regulatory immune responses including up-expression of immunosuppressive cytokine genes and increment of serum adenosine and lung indoleamine-2,3-dioxygenase-1 which are signatures of regulatory T cells (Tregs) and tolerogenic dendritic cells, respectively. The L-(TGH + Per a 9) should be further evaluated towards clinical application, as this vaccine has a propensity to induce broadly effective therapeutic effects for inhalant allergies.
Assuntos
Alérgenos/imunologia , Arginina Quinase/imunologia , Brugia Malayi/imunologia , Dessensibilização Imunológica/métodos , Hipersensibilidade/imunologia , Hipersensibilidade/prevenção & controle , Imunossupressores/imunologia , Proteínas de Insetos/imunologia , Periplaneta/imunologia , Fator de Crescimento Transformador beta/imunologia , Vacinas/imunologia , Administração Intranasal , Alérgenos/sangue , Animais , Arginina Quinase/sangue , Células Dendríticas/imunologia , Modelos Animais de Doenças , Hipersensibilidade/sangue , Hipersensibilidade/parasitologia , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/sangue , Resultado do Tratamento , Vacinas/administração & dosagemRESUMO
Obesity is a risk factor for the development of asthma and represents a difficult-to-treat disease phenotype. Aerobic glycolysis is emerging as a key feature of asthma, and changes in glucose metabolism are linked to leukocyte activation and adaptation to oxidative stress. Dysregulation of PKM2 (pyruvate kinase M2), the enzyme that catalyzes the last step of glycolysis, contributes to house dust mite (HDM)-induced airway inflammation and remodeling in lean mice. It remains unclear whether glycolytic reprogramming and dysregulation of PKM2 also contribute to obese asthma. The goal of the present study was to elucidate the functional role of PKM2 in a murine model of obese allergic asthma. We evaluated the small molecule activator of PKM2, TEPP46, and assessed the role of PKM2 using conditional ablation of the Pkm2 allele from airway epithelial cells. In obese C57BL/6NJ mice, parameters indicative of glycolytic reprogramming remained unchanged in the absence of stimulation with HDM. Obese mice that were subjected to HDM showed evidence of glycolytic reprogramming, and treatment with TEPP46 diminished airway inflammation, whereas parameters of airway remodeling were unaffected. Epithelial ablation of Pkm2 decreased central airway resistance in both lean and obese allergic mice in addition to decreasing inflammatory cytokines in the lung tissue. Lastly, we highlight a novel role for PKM2 in the regulation of glutathione-dependent protein oxidation in the lung tissue of obese allergic mice via a putative IFN-γ-glutaredoxin1 pathway. Overall, targeting metabolism and protein oxidation may be a novel treatment strategy for obese allergic asthma.
Assuntos
Asma/enzimologia , Asma/patologia , Hipersensibilidade/enzimologia , Hipersensibilidade/patologia , Inflamação/enzimologia , Inflamação/patologia , Piruvato Quinase/metabolismo , Animais , Asma/complicações , Asma/parasitologia , Hiper-Reatividade Brônquica/complicações , Dieta Hiperlipídica , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Glutationa/metabolismo , Glicólise , Homeostase/efeitos dos fármacos , Hipersensibilidade/complicações , Hipersensibilidade/parasitologia , Mediadores da Inflamação/metabolismo , Pulmão/enzimologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Modelos Biológicos , Piridazinas/administração & dosagem , Piridazinas/farmacologia , Pyroglyphidae , Pirróis/administração & dosagem , Pirróis/farmacologiaRESUMO
Immune-mediated hypersensitivity reactions to ticks and other arthropods are well documented. Hypersensitivity to ixodid (hard bodied) ticks is especially important because they transmit infection to humans throughout the world and are responsible for most vector-borne diseases in the United States. The causative pathogens of these diseases are transmitted in tick saliva that is secreted into the host while taking a blood meal. Tick salivary proteins inhibit blood coagulation, block the local itch response and impair host anti-tick immune responses, which allows completion of the blood meal. Anti-tick host immune responses are heightened upon repeated tick exposure and have the potential to abrogate tick salivary protein function, interfere with the blood meal and prevent pathogen transmission. Although there have been relatively few tick bite hypersensitivity studies in humans compared with those in domestic animals and laboratory animal models, areas of human investigation have included local hypersensitivity reactions at the site of tick attachment and generalized hypersensitivity reactions. Progress in the development of anti-tick vaccines for humans has been slow due to the complexities of such vaccines but has recently accelerated. This approach holds great promise for future prevention of tick-borne diseases.
Assuntos
Hipersensibilidade/parasitologia , Picadas de Carrapatos/imunologia , Doenças Transmitidas por Carrapatos/imunologia , Carrapatos/imunologia , Animais , Humanos , Hipersensibilidade/imunologia , Saliva/microbiologia , Saliva/parasitologia , Proteínas e Peptídeos Salivares/imunologia , Proteínas e Peptídeos Salivares/fisiologia , Doenças Transmitidas por Carrapatos/prevenção & controle , Doenças Transmitidas por Carrapatos/transmissão , VacinasRESUMO
The high frequency of infection by Anisakis simplex (A. simplex) has led to an increase in IgE sensitization, turning allergy to this parasite a relevant contemporary health problem. Improving the lack of conventional diagnosis test specificity is crucial to better understand these clinical scenarios. Specific IgE (sIgE) to A. simplex extract by ImmunoCAP (Anisakis-sIgE) was determined in sera from 403 blood donors (BD) from Cantabria (North of Spain) of which 51 subjects resulted sensitized. Among these latter, 47 were asymptomatic (sABD). The values of total IgE, prick-test, Anisakis-sIgE, and sIgE to Ani s 1 (anti-rAni s 1) and Ani s 7 (anti-rAni s 7) were compared between 46 sABD and 49 A. simplex allergic patients. The IgE seroprevalence by ImmunoCAP among BD was 12.65%. Allergic patients and sABD showed significant differences in all serum biomarkers evaluated. The area under the curve was assessed for Anisakis-sIgE (0.892), sIgE-rAni s 1 (0.672) and sIgE-rAni s 7 (0.668). After a severe reaction, significantly higher levels of Anisakis-sIgE and sIgE anti-rAni s 1 were detected. Determinations of sIgE by ImmunoCAP, Ani s 1 and Ani s 7 presented different sensitization patterns between allergic and asymptomatic individuals. The Ani s 1 allergen arises as a possible biomarker to detect patients at risk of suffering severe allergic reactions.
Assuntos
Alérgenos/imunologia , Anisaquíase/imunologia , Antígenos de Helmintos/imunologia , Biomarcadores/sangue , Proteínas de Ligação ao Cálcio/imunologia , Proteínas de Helminto/imunologia , Hipersensibilidade/parasitologia , Adulto , Idoso , Animais , Anisakis/imunologia , Estudos Transversais , Dermatophagoides pteronyssinus/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina E/imunologia , Masculino , Pessoa de Meia-Idade , Penaeidae/imunologia , Prevalência , Estudos Prospectivos , Curva ROC , Estudos SoroepidemiológicosRESUMO
Insect Bite Hypersensitivity (IBH) is a common cutaneous disease, affecting a large number of horses worldwide. Several studies have identified Culicoides spp. saliva as a clinically relevant allergen source. The prevalence of IBH in Portugal, particularly in Lusitano horses, is still not known. However, the environmental characteristics of the national territory are favorable to the activity of Culicoides, and several species of this genus can be found, namely C. imicola and C. obsoletus/C. scoticus. In this study we characterized the Culicoides population present in Lusitano stud farms with a history of IBH. Thirteen stud farms with Lusitano horses were selected in several regions of mainland Portugal for having a previous history of IBH-affected horses, with a minimum of 5 affected horses. Culicoides were collected in May and June 2016 using OVI traps, placed in these stud farms, and we were able to identify several Culicoides species. We could also verify that C. obsoletus/C. scoticus, and C. imicola were the ones most frequently found, but other species like C. pulicaris were also found.
Assuntos
Ceratopogonidae/fisiologia , Doenças dos Cavalos/parasitologia , Hipersensibilidade/veterinária , Mordeduras e Picadas de Insetos/veterinária , Animais , Ceratopogonidae/classificação , Fazendas , Feminino , Doenças dos Cavalos/epidemiologia , Cavalos , Hipersensibilidade/epidemiologia , Hipersensibilidade/imunologia , Hipersensibilidade/parasitologia , Incidência , Mordeduras e Picadas de Insetos/epidemiologia , Mordeduras e Picadas de Insetos/parasitologia , Masculino , Portugal/epidemiologiaRESUMO
Allergic asthma is a common chronic lung inflammatory disease and seriously influences public health. We aim to investigate the effects of formononetin (FMN) and calycosin (CAL), 2 flavonoids in Radix Astragali, on allergic asthma and elucidate possible therapeutic targets. A house dust mite (HDM)-induced allergic asthma mouse model and TNF-α and Poly(I:C) co-stimulated human bronchial epithelial cell line (16HBE) were performed respectively in vivo and in vitro. The role of G protein-coupled estrogen receptor (GPER) was explored by its agonist, antagonist, or GPER small interfering RNA (siGPER). E-cadherin, occludin, and GPER were detected by western blotting, immunohistochemistry, or immunofluorescence. The epithelial barrier integrity was assessed by trans-epithelial electric resistance (TEER). Cytokines were examined by enzyme-linked immunosorbent assay (ELISA). The results showed that flavonoids attenuated pulmonary inflammation and hyperresponsiveness in asthmatic mice. These flavonoids significantly inhibited thymic stromal lymphopoietin (TSLP), increased occludin and restored E-cadherin in vivo and in vitro. The effects of flavonoids on occludin and TSLP were not interfered by ICI182780 (estrogen receptor antagonist), while blocked by G15 (GPER antagonist). Furthermore, compared with PPT (ERα agonist) and DPN (ERß agonist), G1 (GPER agonist) significantly inhibited TSLP, up-regulated occludin, and restored E-cadherin. siGPER and TEER assays suggested that GPER was pivotal for the flavonoids on the epithelial barrier integrity. Finally, G1 attenuated allergic lung inflammation, which could be abolished by G15. Our data demonstrated that 2 flavonoids in Radix Astragali could alleviate allergic asthma by protecting epithelial integrity via regulating GPER, and activating GPER might be a possible therapeutic strategy against allergic inflammation.
Assuntos
Asma/tratamento farmacológico , Células Epiteliais/patologia , Hipersensibilidade/tratamento farmacológico , Inflamação/complicações , Isoflavonas/uso terapêutico , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Junções Aderentes/efeitos dos fármacos , Junções Aderentes/metabolismo , Animais , Asma/complicações , Asma/parasitologia , Astragalus propinquus , Caderinas/metabolismo , Citocinas/metabolismo , Medicamentos de Ervas Chinesas/química , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/parasitologia , Isoflavonas/química , Isoflavonas/farmacologia , Camundongos Endogâmicos BALB C , Modelos Biológicos , Ocludina/metabolismo , Pneumonia/complicações , Pneumonia/tratamento farmacológico , Pneumonia/parasitologia , Pyroglyphidae/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Regulação para Cima/efeitos dos fármacos , Linfopoietina do Estroma do TimoRESUMO
The parasites and eggs of helminths, including schistosomes, are associated with factors that can modulate the nature and outcomes of host immune responses, particularly enhancing type 2 immunity and impairing the effects of type 1 and type 17 immunity. The main species of schistosomes that cause infection in humans are capable of generating a microenvironment that allows survival of the parasite by evasion of the immune response. Schistosome infections are associated with beneficial effects on chronic immune disorders, including allergies, autoimmune diseases, and alloimmune responses. Recently, there has been increasing research interest in the role of schistosomes in immunoregulation during human infection, and the mechanisms underlying these roles continue to be investigated. Further studies may identify potential opportunities to develop new treatments for immune disease. In this review, we provide an update on the advances in our understanding of schistosome-associated modulation of the cells of the innate and adaptive immune systems as well as the potential role of schistosome-associated factors as therapeutic modulators of immune disorders, including allergies, autoimmune diseases, and transplant immunopathology. We also discuss potential opportunities for targeting schistosome-induced immunoregulation for future translation to the clinical setting.
Assuntos
Doenças Autoimunes/terapia , Hipersensibilidade/terapia , Fatores Imunológicos/uso terapêutico , Schistosoma japonicum/imunologia , Schistosoma mansoni/imunologia , Esquistossomose/terapia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/parasitologia , Doenças Autoimunes/patologia , Hipersensibilidade/imunologia , Hipersensibilidade/parasitologia , Hipersensibilidade/patologia , Evasão da Resposta Imune , Imunidade Inata/efeitos dos fármacos , Imunomodulação , Imunoterapia/métodos , Transplante de Órgãos/reabilitação , Schistosoma japonicum/química , Schistosoma mansoni/química , Esquistossomose/imunologia , Esquistossomose/parasitologia , Esquistossomose/patologia , Células Th1/imunologia , Células Th1/parasitologia , Células Th17/imunologia , Células Th17/parasitologia , Células Th2/imunologia , Células Th2/parasitologia , Zigoto/química , Zigoto/imunologiaRESUMO
Allergies to food and environmental antigens have steeply grown to epidemic proportions. IgE antibodies are key mediators of allergic disease, including life-threatening anaphylaxis. There is now compelling evidence that one of the hallmarks of anaphylaxis-inducing IgE molecules is their high affinity for allergen, and the cellular pathway to high-affinity IgE is typically through sequential switching of IgG B cells. Further, in contrast to the previously held paradigm that a subset of CD4+ T cells called Th2 cells promotes IgE responses, recent studies suggest that T follicular helper cells are crucial for inducing anaphylactic IgE. Here we discuss recent studies that have enabled us to understand the nature, induction, and regulation of this enigmatic antibody isotype in allergic sensitization.
Assuntos
Imunoglobulina E/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Anafilaxia/imunologia , Anafilaxia/parasitologia , Animais , Diferenciação Celular , Plasticidade Celular , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade/parasitologiaRESUMO
Lung immune responses to respiratory pathogens and allergens are initiated in early life which will further influence the later onset of asthma. The airway epithelia form the first mechanical physical barrier to allergic stimuli and environmental pollutants, which is also the key regulator in the initiation and development of lung immune response. However, the epithelial regulation mechanisms of early-life lung immune responses are far from clear. Our previous study found that integrin ß4 (ITGB4) is decreased in the airway epithelium of asthma patients with specific variant site. ITGB4 deficiency in adult mice aggravated the lung Th2 immune responses and enhanced airway hyper-responsiveness (AHR) with a house dust mite (HDM)-induced asthma model. However, the contribution of ITGB4 to the postnatal lung immune response is still obscure. Here, we further demonstrated that ITGB4 deficiency following birth mediates spontaneous lung inflammation with ILC2 activation and increased infiltration of eosinophils and lymphocytes. Moreover, ITGB4 deficiency regulated thymic stromal lymphopoietin (TSLP) production in airway epithelial cells through EGFR pathways. Neutralization of TSLP inhibited the spontaneous inflammation significantly in ITGB4-deficient mice. Furthermore, we also found that ITGB4 deficiency led to exaggerated lung allergic inflammation response to HDM stress. In all, these findings indicate that ITGB4 deficiency in early life causes spontaneous lung inflammation and induces exaggerated lung inflammation response to HDM aeroallergen.
Assuntos
Células Epiteliais/metabolismo , Hipersensibilidade/complicações , Hipersensibilidade/imunologia , Integrina beta4/metabolismo , Pulmão/patologia , Pneumonia/complicações , Animais , Animais Recém-Nascidos , Hiper-Reatividade Brônquica/complicações , Citocinas/metabolismo , Células Epiteliais/patologia , Receptores ErbB/metabolismo , Hipersensibilidade/parasitologia , Hipersensibilidade/fisiopatologia , Pulmão/parasitologia , Linfócitos/imunologia , Camundongos Transgênicos , Fosforilação , Pyroglyphidae/fisiologia , Linfopoietina do Estroma do TimoRESUMO
Background: The hygiene hypothesis suggests a link between parasitic infections and immune disorders, such as allergic diseases. We previously showed that infection with Toxoplasma gondii or systemic application of T. gondii tachyzoites lysate antigen (TLA) in a prophylactic, but not therapeutic protocol, prevented allergic airway inflammation in mice. Here we tested the effect of prophylactic and therapeutic application of TLA via the mucosal route. Methods: Mice were intranasally treated with TLA either i) prior to sensitization, ii) during sensitization and challenge, or iii) after sensitization with ovalbumin (OVA). Recruitment of inflammatory cells to the lung, cytokine levels in restimulated lung and spleen cell cultures as well as levels of OVA-specific antibodies in serum were measured. In parallel, the effect of native TLA, heat-inactivated (hiTLA) or deglycosylated TLA (dgTLA) on sensitized splenocytes was evaluated ex vivo. Results: When applied together with OVA i) during systemic sensitization and local challenge or ii) exclusively during local challenge, TLA reduced infiltration of eosinophils into the lung, OVA-specific type 2 cytokines in restimulated lung cell cultures, and partially, type 2 cytokines in restimulated spleen cell cultures in comparison to allergic controls. No beneficial effect was observed when TLA was applied prior to the start of sensitization. Analysis of epitope sugars on TLA indicated a high abundance of mannose, fucose, N-acetylglucosamine, and N-acetylgalactosamine. Deglycosylation of TLA, but not heat-inactivation, abolished the potential of TLA to reduce type 2 responses ex vivo, suggesting a significant role of carbohydrates in immunomodulation. Conclusion: We showed that mucosal application of TLA reduced the development of experimental allergy in mice. The beneficial effects depended on the timing of the application in relation to the time point of sensitization. Not only co-application, but also therapy in sensitized/allergic animals with native TLA reduced local allergic responses. Furthermore, we show that TLA is highly glycosylated and glycoconjugates seem to play a role in anti-allergic effects. In summary, given the powerful modulatory effect that TLA exhibits, understanding its exact mechanisms of action may lead to the development of novel immunomodulators in clinical application.
Assuntos
Carboidratos/imunologia , Hipersensibilidade/imunologia , Pneumopatias/imunologia , Mucosa Respiratória/imunologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Alérgenos/imunologia , Animais , Antígenos de Protozoários/imunologia , Linhagem Celular , Chlorocebus aethiops , Citocinas/imunologia , Feminino , Hipersensibilidade/parasitologia , Fatores Imunológicos/imunologia , Pulmão/imunologia , Pulmão/parasitologia , Pneumopatias/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Mucosa Respiratória/parasitologia , Baço/imunologia , Baço/parasitologia , Toxoplasmose/parasitologia , Células VeroRESUMO
The relationship between the cellular immune response during Trichuris trichiura infection and asthma has not yet been established. In this study, the cytokines interleukin (IL)-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ and IL-17A were evaluated in asthmatic children harboring T.â¯trichiura. For this assessment, asthmatic and non-asthmatic children (ISAAC questionnaire) were submitted to parasitological tests and blood samples were cultured (mitogen stimulation) for cytokine measurements in the supernatant. Asthma frequencies were similar in infected and uninfected children, but IL-4, IL-6, TNF-α and IL-10 levels were high in the infected asthmatic children. Additionally, infected non-asthmatic children exhibited high levels of these cytokines in relation to uninfected non-asthmatic children; however, cytokine levels were lower when compared with infected and asthmatic children. Therefore, T.â¯trichiura infection positively modulated the pro- and anti-inflammatory cytokines in asthmatic children, but a background of asthma seemed to narrow the production of cytokines induced by this helminth.
Assuntos
Asma/parasitologia , Citocinas/sangue , Tricuríase/imunologia , Animais , Asma/imunologia , Brasil , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade/parasitologia , Imunidade Celular , Masculino , TrichurisAssuntos
Herpesvirus Humano 4/isolamento & purificação , Hipersensibilidade/diagnóstico , Mordeduras e Picadas de Insetos/imunologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfoma de Células T/diagnóstico , Adolescente , Animais , Medula Óssea/patologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Culicidae/imunologia , Rearranjo Gênico da Cadeia gama dos Receptores de Antígenos dos Linfócitos T/genética , Humanos , Hipersensibilidade/parasitologia , Hipersensibilidade/patologia , Linfo-Histiocitose Hemofagocítica/complicações , Linfoma de Células T/complicações , Linfoma de Células T/virologia , Masculino , República da Coreia , Índice de Gravidade de DoençaRESUMO
The majority of experiments investigating the immune response to gastrointestinal helminth infection use a single bolus infection. However, in situ individuals are repeatedly infected with low doses. Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with low doses of Trichuris muris. Trickle infection resulted in the slow acquisition of immunity reflected by a gradual increase in worm burden followed by partial expulsion. Flow cytometry revealed that the CD4+ T cell response shifted from Th1 dominated to Th2 dominated, which coincided with an increase in Type 2 cytokines. The development of resistance following trickle infection was associated with increased worm expulsion effector mechanisms including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turn over. Depletion of CD4+ T cells reversed resistance confirming their importance in protective immunity following trickle infection. In contrast, depletion of group 2 innate lymphoid cells did not alter protective immunity. T. muris trickle infection resulted in a dysbiotic mircrobiota which began to recover alpha diversity following the development of resistance. These data establish trickle infection as a robust and informative model for analysis of immunity to chronic intestinal helminth infection more akin to that observed under natural infection conditions and confirms the importance of CD4+ T cell adaptive immunity in host protection.
Assuntos
Anticorpos Anti-Helmínticos/imunologia , Hipersensibilidade/imunologia , Imunidade Inata/imunologia , Intestinos/imunologia , Pulmão/imunologia , Tricuríase/imunologia , Trichuris/imunologia , Imunidade Adaptativa , Animais , Anticorpos Anti-Helmínticos/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/parasitologia , Hipersensibilidade/parasitologia , Intestinos/parasitologia , Intestinos/patologia , Pulmão/parasitologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th2/imunologia , Células Th2/parasitologia , Tricuríase/sangue , Tricuríase/parasitologiaRESUMO
The prevalence of allergic asthma and incidences of helminth infections in humans are inversely correlated. Although experimental studies have established the causal relation between parasite infection and allergic asthma, the mechanism of the parasite-associated immunomodulation is not fully elucidated. Using a murine model of asthma and nematode parasite Heligmosomoides polygyrus, we investigated the roles of regulatory B cells (Breg ) and T cells (Treg ) in mediation of the protection against allergic asthma by parasite. H. polygyrus infection significantly suppressed ovalbumin (OVA)-induced allergic airway inflammation (AAI) evidenced by alleviated lung histopathology and reduced numbers of bronchoalveolar inflammatory cell infiltration, and induced significant responses of interleukin (IL)-10+ Breg , IL-10+ Treg and forkhead box protein 3 (FoxP3)+ Treg in mesenteric lymph node and spleen of the mice. Adoptive transfer of IL-10+ Breg and IL-10+ Treg cell prevented the lung immunopathology in AAI mice. Depletion of FoxP3+ Treg cells in FoxP3-diphtheria toxin (DT) receptor transgenic mice by diphtheria toxin (DT) treatment exacerbated airway inflammation in parasite-free AAI mice and partially abrogated the parasite-induced protection against AAI. IL-10+ Breg cells were able to promote IL-10+ Treg expansion and maintain FoxP3+ Treg cell population. These two types of Tregs failed to induce CD19+ B cells to transform into IL-10+ Breg cells. These results demonstrate that Breg , IL-10+ Treg and FoxP3+ Treg cells contribute in A discrepant manner to the protection against allergic airway immunopathology by parasiteS. Breg cell might be a key upstream regulatory cell that induces IL-10+ Treg response and supports FoxP3+ Treg cell population which, in turn, mediate the parasite-imposed immunosuppression of allergic airway inflammation. These results provide insight into the immunological relationship between parasite infection and allergic asthma.
Assuntos
Linfócitos B Reguladores/imunologia , Hipersensibilidade/imunologia , Nematospiroides dubius/imunologia , Pneumonia/imunologia , Infecções por Strongylida/imunologia , Animais , Asma/imunologia , Asma/metabolismo , Asma/parasitologia , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Humanos , Hipersensibilidade/metabolismo , Hipersensibilidade/parasitologia , Tolerância Imunológica/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nematospiroides dubius/fisiologia , Pneumonia/metabolismo , Pneumonia/parasitologia , Infecções por Strongylida/parasitologia , Linfócitos T Reguladores/imunologiaRESUMO
Blomia tropicalis mite is highly prevalent in tropical and subtropical regions and it is associated with allergic diseases such as rhinitis and asthma. By using an OVA-model of allergic lung disease, we have previously shown that sensitization in the presence of toll like receptors (TLRs) agonists attenuates subsequent OVA-induced allergic responses. Here, we evaluated the effect of CpG-ODN, a specific synthetic TLR-9 agonist, on the development of experimental asthma induced by Blomia tropicalis extract, a relevant source of aeroallergens. Among different protocols of Blomia tropicalis extract sensitization, the subcutaneous sensitization in the presence of alum adjuvant induced the highest Th2 responses, including high IgE levels. Adsorption of CpG to Blomia tropicalis extract/Alum attenuated the airway hyperreactivity, the infiltration of inflammatory cells including eosinophils, and the IL-5 content in BAL. In addition, lung peribronchial inflammatory infiltrate, mucus production and IL-5-producing CD3+ CD4+ T cells were significantly reduced in the Blomia tropicalis extract/Alum+CpG group. Importantly, CpG inhibited total IgE production as well as active systemic or cutaneous anaphylaxis reactions. Inhibition of pulmonary Th2 responses was associated with increased IL-10 production but not with IFN-γ production. Notably, in IL-10-deficient mice, sensitization with OVA/Alum+CpG resulted in intense lung neutrophilia and IFN-γ production, indicating that IL-10 is necessary to inhibit subsequent Th1 immunity. Our work highlights the mechanisms of allergy attenuation by CpG and it indicates the potential use of Alum-based formulation with CpG to treat allergic processes.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Compostos de Alúmen/química , Asma/prevenção & controle , Asma/parasitologia , Pyroglyphidae/fisiologia , Receptor Toll-Like 9/agonistas , Adjuvantes Imunológicos/farmacologia , Adsorção , Anafilaxia/complicações , Anafilaxia/imunologia , Anafilaxia/parasitologia , Animais , Asma/complicações , Citocinas/biossíntese , Modelos Animais de Doenças , Eosinófilos/patologia , Feminino , Hipersensibilidade/complicações , Hipersensibilidade/imunologia , Hipersensibilidade/parasitologia , Imunidade/efeitos dos fármacos , Imunização , Interleucina-10/metabolismo , Interleucina-4/biossíntese , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfonodos/patologia , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Camundongos Endogâmicos C57BL , Neutrófilos/patologia , Oligodesoxirribonucleotídeos/farmacologia , Pyroglyphidae/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Receptor Toll-Like 9/metabolismoRESUMO
BACKGROUND: Topical application of polyunsaturated fatty acids (PUFAs) has shown satisfactory results in dogs and humans with allergic skin diseases. Urea and glycolic acid act as keratolytics and moisturizers. Culicoides hypersensitivity is the most common equine hypersensitivity disorder and only limited treatment options exist. OBJECTIVES: To evaluate the effect of a cream containing topical PUFAs, humectants and emollients on clinical signs of equine Culicoides hypersensitivity. ANIMALS: Privately owned horses (n = 28) with clinical signs of Culicoides hypersensitivity. METHODS AND MATERIALS: For a period of four weeks, one half of the horse's body (left or right) was treated with a cream containing concentrated fish oil and several moisturizing and emollient ingredients in a randomized, single-blinded fashion to evaluate the influence of the treatment on skin lesions. In the subsequent four weeks, the lesional areas of the entire body were treated to assess the treatment effect on pruritus. Additionally, the quality of the hair coat, an overall assessment and adverse effects were recorded. RESULTS: Twenty-one horses completed the study. Skin lesions on the treated side improved significantly between days 0 and 28 (P < 0.0001) in comparison to the untreated side. Neither pruritus scores nor coat quality improved significantly between days 0 and 56. Overall condition improved during the study. Five horses showed adverse effects. CONCLUSIONS AND CLINICAL IMPORTANCE: The cream improved Culicoides-induced skin lesions in affected horses, but anti-pruritic effects were less prominent.
Assuntos
Ceratopogonidae , Emolientes/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Doenças dos Cavalos/parasitologia , Higroscópicos/uso terapêutico , Hipersensibilidade/veterinária , Administração Tópica , Animais , Emolientes/administração & dosagem , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Doenças dos Cavalos/tratamento farmacológico , Cavalos/parasitologia , Higroscópicos/administração & dosagem , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/parasitologia , Masculino , Pomadas/uso terapêutico , Projetos Piloto , Prurido/tratamento farmacológico , Prurido/veterinária , Distribuição Aleatória , Método Simples-Cego , Pele/efeitos dos fármacos , Pele/patologiaRESUMO
Population studies from the African continent have observed a marked increase in the prevalence of allergy-related diseases over the past few decades, but the cause of this rise is not fully understood. The most investigated potential risk factor has been the relationship between exposure to helminths and allergy-related outcomes. Immunologically, parallels exist between responses to helminths and to allergens as both are associated with elevated levels of immunoglobulin E, increased numbers of T helper 2 cells and other immune cells. However, epidemiological studies from the African continent have found inconsistent results. In this review, observations from population studies carried out in Africa over the last decade that focus on the relationship between helminth infections and allergy-related outcomes are examined. How these findings advance our understanding of the complex interactions between helminths and allergies at the population level is also explored as well as some of the underlying immune mechanisms involved. This knowledge is important for better diagnosis, treatment and prevention of allergy-related diseases and has wider global significance.
Assuntos
Helmintíase/imunologia , Helmintos/imunologia , Hipersensibilidade/imunologia , África , Animais , Helmintíase/parasitologia , Humanos , Hipersensibilidade/parasitologia , Imunoglobulina E/imunologia , Estudos Observacionais como Assunto , Células Th2/imunologiaRESUMO
Ascariasis is the most frequent soil transmitted helminthiasis and, as well as other helminth infections, is expected to influence the clinical presentation of allergic diseases such as asthma. Indeed, several clinical and experimental works have shown an important impact either increasing or suppressing symptoms, and the same effects have been detected on the underlying immune responses. In this review we analyze the work on this field performed in Colombia, a Latin American tropical country, including aspects such as the molecular genetics of the IgE response to Ascaris; the allergenic activity of Ascaris IgE-binding molecular components and the immunological and clinical influences of ascariasis on asthma. The analysis allows us to conclude that the impact of ascariasis on the inception and evolution of allergic diseases such as asthma deserves more investigation, but advances have been made during the last years. The concurrent parasite-induced immunostimulatory and immunosuppressive effects during this helminthiasis do modify the natural history of asthma and some aspects of the practice of allergology in the tropics. Theoretically it can also influence the epidemiological trends of allergic diseases either by its absence or presence in different regions and countries.
Assuntos
Ascaríase/imunologia , Ascaris/imunologia , Hipersensibilidade/imunologia , Animais , Ascaríase/parasitologia , Modelos Animais de Doenças , Humanos , Hipersensibilidade/parasitologia , Imunoglobulina E/imunologiaRESUMO
There is considerable interest as to potential protective effects of soil-transmitted helminths (STH) against allergy and allergic diseases. Here, we discuss findings of studies done of the effects of STH parasites on atopy and allergic diseases in Ecuador. While cross-sectional studies have consistently shown a reduced prevalence of allergen skin prick test (SPT) reactivity among infected schoolchildren, the removal of these infections by repeated deworming did not affect SPT prevalence over the short-term (ie, 12 months) but may have increased SPT prevalence over the long-term (ie, 15-17 years). In the case of allergic symptoms, cross-sectional studies have generally not shown associations with STH and intervention studies showed no impact on prevalence. However, a birth cohort suggested that early STH infections might reduce wheeze by 5 years. Allergic sensitization to Ascaris, however, explained a significant proportion of wheezing among rural schoolchildren. Studies of the effects of STH on immune and inflammatory responses indicated a potential role of STH in contributing to more robust regulation. The effects of STH on allergy are likely to be determined by history of exposure over the life-course and by interactions with a wide variety of other infectious and non-infectious factors.