RESUMO
In the second of two linked articles, we describe the development in clinical as described by Clinical & Experimental Allergy and other journals in 2019. Epidemiology, clinical allergy, asthma and rhinitis are all covered. In this article, we described the development in the field of allergy as described by Clinical and Experimental Allergy in 2019. Epidemiology, clinical allergy, asthma and rhinitis are all covered.
Assuntos
Alérgenos/imunologia , Hipersensibilidade/imunologia , Sistema Imunitário/imunologia , Animais , Asma/epidemiologia , Asma/imunologia , Asma/metabolismo , Asma/terapia , Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/metabolismo , Hipersensibilidade Alimentar/terapia , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/metabolismo , Hipersensibilidade/terapia , Sistema Imunitário/metabolismo , Prognóstico , Rinite Alérgica/epidemiologia , Rinite Alérgica/imunologia , Rinite Alérgica/metabolismo , Rinite Alérgica/terapia , Fatores de RiscoRESUMO
In the first of two linked articles, we describe the development in the mechanisms underlying allergy as described by Clinical & Experimental Allergy and other journals in 2019. Experimental models of allergic disease, basic mechanisms, clinical mechanisms and allergens are all covered.
Assuntos
Alérgenos/imunologia , Hipersensibilidade/imunologia , Sistema Imunitário/imunologia , Animais , Modelos Animais de Doenças , Humanos , Hipersensibilidade/metabolismo , Sistema Imunitário/metabolismoRESUMO
In this article, we describe developments in the field of clinical allergy as described by Clinical and Experimental Allergy in 2018; epidemiology, asthma and rhinitis, clinical allergy and allergens are all covered.
Assuntos
Alérgenos/imunologia , Asma/imunologia , Rinite/imunologia , Animais , Asma/patologia , Humanos , Rinite/patologiaRESUMO
In this article, we described the development in the field of allergy as described by Clinical and Experimental Allergy in 2017. Experimental models of allergic disease, basic mechanisms, clinical mechanisms, allergens, asthma and rhinitis and clinical allergy are all covered.
Assuntos
Estudos Clínicos como Assunto , Hipersensibilidade/epidemiologia , Pesquisa , Alérgenos/imunologia , Animais , Gerenciamento Clínico , Suscetibilidade a Doenças , História do Século XXI , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/etiologia , Hipersensibilidade/história , Fenótipo , Pesquisa/tendências , Fatores de RiscoRESUMO
In this article, we described the development in the field of allergy as described by Clinical and Experimental Allergy in 2016. Experimental models of allergic disease, basic mechanisms, clinical mechanisms, allergens, asthma and rhinitis, and clinical allergy are all covered.
Assuntos
Hipersensibilidade/etiologia , Alérgenos/imunologia , Animais , Gerenciamento Clínico , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/epidemiologia , Hipersensibilidade/terapia , ImunizaçãoRESUMO
BACKGROUND: Clinical and experimental analyses have identified a central role for IgE/FcεRI/mast cells in promoting IgE-mediated anaphylaxis. Recent data from human studies suggest that bacterial infections can alter susceptibility to anaphylaxis. OBJECTIVE: We examined the effect of LPS exposure on the induction of IgE-mast cell (MC) mediated reactions in mice. METHODS: C57BL/6 WT, tlr4-/- and IL10-/- mice were exposed to LPS, and serum cytokines (TNF and IL-10) were measured. Mice were subsequently treated with anti-IgE, and the symptoms of passive IgE-mediated anaphylaxis, MC activation, Ca2+ -mobilization and the expression of FcεRI on peritoneal MCs were quantitated. RESULTS: We show that LPS exposure of C57BL/6 WT mice constraints IgE-MC-mediated reactions. LPS-induced suppression of IgE-MC-mediated responses was TLR-4-dependent and associated with increased systemic IL-10 levels, decreased surface expression of FcεRI on MCs and loss of sensitivity to IgE activation. Notably, LPS-induced desensitization of MCs was short term with MC sensitivity to IgE reconstituted within 48 hours, which was associated with recapitulation of FcεRI expression on the MCs. Mechanistic analyses revealed a requirement for IL-10 in LPS-mediated decrease in MC FcεRI surface expression. CONCLUSIONS & CLINICAL RELEVANCE: Collectively, these studies suggest that LPS-induced IL-10 promotes the down-regulation of MC surface FcεRI expression and leads to desensitization of mice to IgE-mediated reactions. These studies indicate that targeting of the LPS-TLR-4-IL-10 pathway may be used as a therapeutic approach to prevent adverse IgE-mediated reactions.
Assuntos
Imunoglobulina E/imunologia , Lipopolissacarídeos/imunologia , Mastócitos/imunologia , Anafilaxia/imunologia , Anafilaxia/metabolismo , Animais , Cálcio/metabolismo , Degranulação Celular/imunologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hematócrito , Interleucina-10/metabolismo , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Mastócitos/metabolismo , Camundongos , Camundongos Knockout , Receptores de IgE/genética , Receptores de IgE/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismoRESUMO
In the second of two papers, we describe developments in the field of clinical allergy as documented by Clinical and Experimental Allergy in 2015. Epidemiology, clinical allergy, asthma and rhinitis are all covered.
Assuntos
Hipersensibilidade/epidemiologia , Hipersensibilidade/etiologia , Alérgenos/imunologia , Animais , Asma/diagnóstico , Asma/epidemiologia , Asma/etiologia , Humanos , Hipersensibilidade/diagnóstico , Rinite/diagnóstico , Rinite/epidemiologia , Rinite/etiologiaRESUMO
In the first of two papers we described the development in the field of allergy mechanisms as described by Clinical and Experimental Allergy in 2015. Experimental models of allergic disease, basic mechanisms, clinical mechanisms and allergens are all covered. A second paper will cover clinical aspects.
Assuntos
Alergia e Imunologia/tendências , Hipersensibilidade/etiologia , Remodelação das Vias Aéreas , Alérgenos/imunologia , Animais , Modelos Animais de Doenças , Humanos , Hipersensibilidade/metabolismo , Hipersensibilidade/patologia , Hipersensibilidade/terapia , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Tolerância Imunológica , Imunoterapia , Inflamação/complicações , Inflamação/etiologia , Inflamação/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus featuring increased esophageal interleukin-13 (IL-13) levels and impaired barrier function. Herein, we investigated leucine-rich repeat-containing protein 31 (LRRC31) in human EoE esophageal tissue and IL-13-treated esophageal epithelial cells. LRRC31 had basal mRNA expression in colonic and airway mucosal epithelium. Esophageal LRRC31 mRNA and protein increased in active EoE and strongly correlated with esophageal eosinophilia and IL13 and CCL26 (chemokine (C-C motif) ligand 26) mRNA expression. IL-13 treatment increased LRRC31 mRNA and protein in air-liquid interface-differentiated esophageal epithelial cells (EPC2s). At baseline, differentiated LRRC31-overexpressing EPC2s had increased barrier function (1.9-fold increase in transepithelial electrical resistance (P<0.05) and 2.8-fold decrease in paracellular flux (P<0.05)). RNA sequencing analysis of differentiated LRRC31-overexpressing EPC2s identified 38 dysregulated genes (P<0.05), including five kallikrein (KLK) serine proteases. Notably, differentiated LRRC31-overexpressing EPC2s had decreased KLK expression and activity, whereas IL-13-treated, differentiated LRRC31 gene-silenced EPC2s had increased KLK expression and suprabasal epithelial detachment. We identified similarly dysregulated KLK expression in the esophagus of patients with active EoE and in IL-13-treated esophageal epithelial cells. We propose that LRRC31 is induced by IL-13 and modulates epithelial barrier function, potentially through KLK regulation.
Assuntos
Esofagite Eosinofílica/imunologia , Epitélio/metabolismo , Esôfago/imunologia , Interleucina-13/metabolismo , Calicreínas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas/metabolismo , Adulto , Transporte Biológico , Diferenciação Celular , Linhagem Celular , Dextranos/farmacocinética , Impedância Elétrica , Epitélio/patologia , Esôfago/patologia , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/farmacocinética , Regulação da Expressão Gênica , Humanos , Interleucina-13/genética , Calicreínas/genética , Proteínas de Repetições Ricas em Leucina , Proteínas Nucleares/genética , Proteínas/genética , RNA Interferente Pequeno/genéticaRESUMO
The desmosomal cadherin desmoglein-1 (DSG1) is an essential intercellular adhesion molecule that is altered in various human cutaneous disorders; however, its regulation and function in allergic disease remains unexplored. Herein, we demonstrate a specific reduction in DSG1 in esophageal biopsies from patients with eosinophilic esophagitis (EoE), an emerging allergic disorder characterized by chronic inflammation within the esophageal mucosa. Further, we show that DSG1 gene silencing weakens esophageal epithelial integrity, and induces cell separation and impaired barrier function (IBF) despite high levels of desmoglein-3. Moreover, DSG1 deficiency induces transcriptional changes that partially overlap with the transcriptome of inflamed esophageal mucosa; notably, periostin (POSTN), a multipotent pro-inflammatory extracellular matrix molecule, is the top induced overlapping gene. We further demonstrate that IBF is a pathological feature in EoE, which can be partially induced through the downregulation of DSG1 by interleukin-13 (IL-13). Taken together, these data identify a functional role for DSG1 and its dysregulation by IL-13 in the pathophysiology of EoE and suggest that the loss of DSG1 may potentiate allergic inflammation through the induction of pro-inflammatory mediators such as POSTN.
Assuntos
Desmogleína 1/metabolismo , Esofagite Eosinofílica/imunologia , Esofagite Eosinofílica/metabolismo , Mucosa/imunologia , Mucosa/metabolismo , Diferenciação Celular/genética , Análise por Conglomerados , Desmogleína 1/deficiência , Desmogleína 1/genética , Esofagite Eosinofílica/genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Imunidade Inata/genética , Imuno-Histoquímica , Interleucina-13/metabolismo , Modelos Biológicos , Mucosa/patologia , Transcrição GênicaRESUMO
Interleukin 13 (IL-13)-induced epithelial gene and protein expression changes are central to the pathogenesis of multiple allergic diseases. Herein, using human esophageal squamous and bronchial columnar epithelial cells, we identified microRNAs (miRNAs) that were differentially regulated after IL-13 stimulation. Among the IL-13-regulated miRNAs, miR-375 showed a conserved pattern of downregulation. Furthermore, miR-375 was downregulated in the lung of IL-13 lung transgenic mice. We subsequently analyzed miR-375 levels in a human disease characterized by IL-13 overproduction--the allergic disorder eosinophilic esophagitis (EE)--and observed downregulation of miR-375 in EE patient samples compared with control patients. MiR-375 expression levels reflected disease activity, normalized with remission, and inversely correlated with the degree of allergic inflammation. Using a lentiviral strategy and whole-transcriptome analysis in epithelial cells, miR-375 overexpression was sufficient to markedly modify IL-13-associated immunoinflammatory pathways in epithelial cells in vitro, further substantiating interactions between miR-375 and IL-13. Taken together, our results support a key role of miRNAs, particularly miR-375, in regulating and fine-tuning IL-13-mediated responses.
Assuntos
Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Interleucina-13/farmacologia , MicroRNAs/genética , Transcriptoma , Animais , Linhagem Celular , Análise por Conglomerados , Esofagite Eosinofílica/genética , Esôfago/metabolismo , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismoAssuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Hiper-Reatividade Brônquica/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Chá , Animais , Asma/imunologia , Asma/fisiopatologia , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Humanos , Imunoglobulina E/sangue , Interferon gama/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/fisiopatologia , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Eosinofilia Pulmonar/tratamento farmacológico , Eosinofilia Pulmonar/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Nippostrongylus brasiliensis larvae are particularly susceptible to immunological attack during the pre-lung stage of primary and secondary infections in mice. Whilst most of the common laboratory strains of mice are permissive hosts for the parasite, in this study we report for the first time, the strong resistance of naive FVB/N mice to N. brasiliensis. Damage to larvae is evident within the first 24 h of infection and this may be critical to later larval development and reproductive success. Inflammatory responses in the skin, and larval escape from this tissue were comparable in susceptible CBA/Ca and resistant FVB/N mice, with most larvae exiting within 4 h of a primary infection. Lung larval burdens were also similar between strains, but larvae recovered from FVB/N mice were smaller and less motile. In FVB/N mice, larval colonization of the gut was impaired and worms produced very few eggs. However FVB/N mice did not show enhanced resistance to Heligmosomoides bakeri (also known as Heligmosomoides polygyrus), a nematode largely restricted to the gut. Damage done in the pre-lung or lung stages of infection with N. brasiliensis is likely to contribute to ongoing developmental and functional abnormalities, which are profoundly evident in the gut phase of infection.
Assuntos
Imunidade Inata/genética , Nippostrongylus/fisiologia , Infecções por Strongylida/genética , Infecções por Strongylida/imunologia , Animais , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Imunidade Celular , Imunidade Inata/imunologia , Intestinos/parasitologia , Larva/fisiologia , Leucócitos/imunologia , Pulmão/parasitologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos CBA , Camundongos Endogâmicos , Camundongos Transgênicos , Nematospiroides/fisiologia , Contagem de Ovos de ParasitasRESUMO
BACKGROUND: Colon epithelial cell (CEC) apoptosis and nuclear factor-kappaB (NF-kappaB) activation may compromise barrier function, and it has been reported that signal transducer and activator of transcription 5b (STAT5b)-deficient mice exhibit increased susceptibility to colitis. It is hypothesised that the growth hormone (GH) target STAT5b maintains mucosal barrier integrity by promoting CEC survival and inhibiting NF-kappaB activation. METHODS: The GH effect upon mucosal injury due to 2,4,6-trinitro-benzenesulfonic acid (TNBS) administration was determined in STAT5b-deficient mice and wild-type (WT) controls. The effect of STAT5b deficiency upon CEC survival and NF-kappaB activation was determined and related to differences in intestinal permeability and bacterial translocation. RNA interference (RNAi) was used to knock down STAT5b expression in the T84 CEC line, and the effect upon basal and GH-dependent regulation of proapoptotic and inflammatory pathways induced by tumour necrosis factor alpha (TNFalpha) was determined. RESULTS: GH suppression of mucosal inflammation in TNBS colitis was abrogated in STAT5b-deficient mice. STAT5b deficiency led to activation of a proapoptotic pattern of gene expression in the colon, and increased mucosal permeability. The frequency of apoptotic CECs was increased in STAT5b-deficient mice while tight junction protein abundance was reduced. This was associated with upregulation of CEC Toll-like receptor 2 expression and NF-kappaB activation. STAT5b knockdown in T84 CEC increased TNFalpha-dependent NF-kappaB and caspase-3 activation. GH inhibition of TNFalpha signalling was prevented by STAT5b knockdown. CONCLUSION: STAT5b maintains colonic barrier integrity by modulating CEC survival and NF-kappaB activation. STAT5b activation may therefore represent a novel therapeutic target in inflammatory bowel disease.
Assuntos
Colite/fisiopatologia , Colo/fisiopatologia , Fator de Transcrição STAT5/fisiologia , Animais , Apoptose , Caspase 3/metabolismo , Células Cultivadas , Colite/induzido quimicamente , Colite/prevenção & controle , Colo/metabolismo , Citocinas/biossíntese , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Hormônio do Crescimento/farmacologia , Mediadores da Inflamação/metabolismo , Absorção Intestinal , Mucosa Intestinal/patologia , Mucosa Intestinal/fisiopatologia , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Permeabilidade/efeitos dos fármacos , Fator de Transcrição STAT5/deficiência , Transdução de Sinais , Receptor 2 Toll-Like/metabolismo , Ácido Trinitrobenzenossulfônico , Regulação para CimaAssuntos
Alérgenos/imunologia , Proteínas Alimentares/imunologia , Hipersensibilidade Alimentar/imunologia , Tolerância Imunológica , Intestinos/imunologia , Administração Oral , Alérgenos/administração & dosagem , Animais , Proteínas Alimentares/administração & dosagem , Humanos , Imunização , CamundongosRESUMO
BACKGROUND: IL-25, a novel member of the IL-17 cytokine family, promotes CD4+ T-helper 2 lymphocyte-like (Th type-2) inflammatory responses in the lung. Although IL-25 up-regulates IL-13 in the lung, the contribution of this and other type 2 cytokine signalling pathways to the induction and persistence of airways hyper-reactivity (AHR) and allergic inflammation are unclear. OBJECTIVE: To determine the downstream factors employed by IL-25 to induce Th type-2 pulmonary inflammation and AHR. METHODS: IL-25 was delivered to the airways of BALB/c mice by intra-tracheal (i.t.) instillation and AHR and Th type-2 inflammatory responses were characterized in wild type (WT) and Th type-2-cytokine and -signalling pathway-deficient (-/-) mice. RESULTS: IL-25 treatment resulted in AHR, eosinophilic inflammation, mucus hypersecretion and a progressive increase in the production of Th type-2 cytokines in the lungs. Levels of arginase-I (arg-I) and eotaxin were also elevated by IL-25 treatment. A significant reduction in AHR, and attenuation of mucus production was observed in IL-25-treated IL-13-/-, IL-4 receptor alpha (IL-4Ralpha-/-)- and signal-transducer-and-activator-of-transcription-factor-6 (STAT6-/-)-deficient mice. AHR was also inhibited in IL-4(-/-)- and IL-5/eotaxin(1)(-/-)- deficient mice treated with IL-25, however, mucus hypersecretion was not completely ablated. IL-25 promoted Th type-2 responses by directly acting on naïve T cells. CONCLUSION: IL-25 potently (single dose) induces sustained AHR and acute pulmonary inflammation with eosinophilia. IL-25-induced AHR is dependent on the production of Th type-2 cytokines, and removal of IL-13 and its signal transduction pathway prevents IL-25-induced airways inflammation and AHR. IL-25 potently induces inflammatory cascades that may exacerbate allergic airways inflammation by promoting Th type-2 cytokine responses in conjunction with the up-regulation of factors (eotaxin and arg-I) that can amplify inflammation associated with allergic disorders. Dysregulation in IL-25 production may predispose to features of allergic airways disease.
Assuntos
Citocinas/imunologia , Interleucina-17/farmacologia , Pulmão/imunologia , Pneumonia/imunologia , Células Th2/imunologia , Animais , Arginase/análise , Arginase/genética , Asma/imunologia , Biomarcadores/análise , Hiper-Reatividade Brônquica/imunologia , Testes de Provocação Brônquica , Células Cultivadas , Quimiocina CCL11 , Quimiocinas CC/análise , Quimiocinas CC/genética , Citocinas/genética , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-17/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Pulmão/patologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Muco/metabolismo , Pneumonia/patologia , RNA Mensageiro/análise , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/imunologia , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Of the numerous adhesion molecules expressed by eosinophils, the alpha4-integrin has been identified as critically involved in eosinophil trafficking in the lung. Most studies have focused on the role of the alpha4beta1-adhesion complex, but eosinophils also express the alpha4beta7-integrin complex. OBJECTIVE: To investigate the role of alpha4beta7, by assessing its membrane expression on eosinophils from different compartments using allergen-challenged mice and IL-4/IL-5 bi-transgenic mice. In addition, we aim to determine the impact of beta7-integrin deficiency on eosinophil recruitment to the lungs and intestine in specific experimental allergic models. RESULTS: Evaluation of alpha4beta7 expression on bronchoalveolar lavage fluid (BALF) and lung tissue eosinophils revealed a down-regulation of this integrin as eosinophils migrate through the lungs. Indeed eosinophils isolated from the BALF and lung of allergic mice had low expression of the alpha4beta7-complex. While expression of the alpha4-chain remained unchanged, a significant decrease in beta7-surface expression was observed. Intestinal eosinophils, isolated from Peyer's patches, also displayed a down-regulation of the alpha4beta7-integrin, albeit only modest. In contrast, circulating eosinophils, isolated from the blood and spleen, expressed high levels of the alpha4beta7-integrin. However, eosinophil trafficking into the lungs of beta7-integrin-deficient mice was not significantly impaired in response to respiratory allergen challenges. In contrast, beta7-deficient mice had impaired eosinophil recruitment to the intestine. CONCLUSION: Taken together, these results identify differential expression of the alpha4beta7-integrin on eosinophils and its critical role in regulating eosinophil responses in the intestine.