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1.
Biomed Res Int ; 2019: 6012473, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341902

RESUMO

Objective: Studying correlative changes of Th1/Th2 (Th, Helper T cells) related factor Interferon-γ (IFN-γ) and Interleukin-4 (IL-4) in the progression of radiation pneumonia (RP) rats and the efficacy of Shashen-Maidong decoction on these indexes to explore the immune mechanism of the decoction on the prevention and treatment of RP. Methods: Male 60 Sprague-Dawley (SD) rats were randomly divided into four groups. In addition to the normal control group taking saline, the other rats were set up RP model treated with Shashen-Maidong decoction or dexamethasone (DXM), respectively. The IFN-γ and IL-4 concentrations in serum and bronchoalveolar lavage fluid (BALF) of rats were tested in the 2nd and 4th week after radiation, and the relative ratio of IFN-γ/IL-4 was calculated. Results: (1) There was significant difference of serum IL-4 concentrations in group B (p<0.01) and extreme difference in groups C and D (p<0.001) compared with group A in 4th week. Compared with group D, IL-4 concentrations in group B increased significantly in both 2nd and 4th week (p<0.01). Group B had significantly decreased IFN-γ concentrations in BALF (p<0.001) compared with group D in the 4th week. And IFN-γ concentrations in BALF in group B were increased compared with group C in the 4th week (p<0.05). (2) There was no difference of the relative ratio of IFN-γ/IL-4 at each time in groups B and A for both serum and BALF, while the ratios in groups C and D in 4th week in BALF were increased (p<0.05) compared to group A. Conclusion: Shashen-Maidong decoction can improve the immune function of RP rats by increasing IFN-γ concentration and decreasing IL-4 concentration, possibly by increasing the relative ratio of IFN-γ/IL-4 to regulate the immune imbalance of Th1/Th2.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Interferon gama/imunologia , Interleucina-4/imunologia , Lesões Experimentais por Radiação/imunologia , Pneumonite por Radiação/imunologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Dexametasona/farmacologia , Masculino , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/patologia , Pneumonite por Radiação/tratamento farmacológico , Pneumonite por Radiação/patologia , Ratos , Ratos Sprague-Dawley , Células Th1/patologia , Células Th2/patologia
2.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31285249

RESUMO

Granuloma formation is a key host immune response generated to confine invading pathogens and limit extensive host damage. It consists of an accumulation of host immune cells around a pathogen. This host response has been extensively studied in the context of inflammatory diseases. However, there is much less known about Th2-type granulomas generated in response to parasitic worms. Based on in vitro data, innate immune cells within the granuloma are thought to immobilize and kill parasites but also act to repair damaged tissue. Understanding this dual function is key. The two billion people and many livestock/wild animals infected with helminths demonstrate that granulomas are not effective at clearing infection. However, the lack of high mortality highlights their importance in ensuring that parasite migration/tissue damage is restricted and wound healing is effective. In this review, we define two key cellular players (macrophages and eosinophils) and their associated molecular players involved in Th2 granuloma function. To date, the underlying mechanisms remain poorly understood, which is in part due to a lack of conclusive studies. Most have been performed in vitro rather than in vivo, using cells that have not been obtained from granulomas. Experiments using genetically modified mouse strains and/or antibody/chemical-mediated cell depletion have also generated conflicting results depending on the model. We discuss the caveats of previous studies and the new tools available that will help fill the gaps in our knowledge and allow a better understanding of the balance between immune killing and healing.


Assuntos
Eosinófilos/imunologia , Granuloma/imunologia , Helmintíase/imunologia , Helmintos/imunologia , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Células Th2/imunologia , Animais , Comunicação Celular , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Eosinófilos/parasitologia , Eosinófilos/patologia , Granuloma/parasitologia , Granuloma/patologia , Helmintíase/parasitologia , Helmintíase/patologia , Helmintos/crescimento & desenvolvimento , Helmintos/patogenicidade , Interações Hospedeiro-Parasita/imunologia , Humanos , Imunidade Inata , Mucosa Intestinal/patologia , Macrófagos/parasitologia , Macrófagos/patologia , Camundongos , Células Th2/parasitologia , Células Th2/patologia , Cicatrização/imunologia
4.
Mol Immunol ; 109: 1-11, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30836204

RESUMO

Protease activity of allergens has been suggested to be involved in the pathogenesis of allergic diseases. The major allergen Der f 3 from Dermatophagoides farinae harbors serine protease activity, but its immunopathogenesis remains unclear. This study aims to explore the effect of Der f 3 on the airway epithelial barrier and on the molecular pathways by which Der f 3 induces inflammation. RNA-seq was performed to identify differentially expressed genes in bronchial airway epithelial cells (AEC) between native Der f 3 and heat-inactivated (H) Der f 3, coupled with real-time PCR (RT-PCR) and ELISA for validation. Unlike other protease allergens such as that induce Th2-promoting alarmins (IL-25, IL-33, TSLP) in AECs, Der f 3 induced pro-inflammatory cytokines and chemokines including IL-6, IL-8 and GM-CSF, which are known to promote Th17 response. These pro-inflammatory mediators were induced by Der f 3 via the MAPK and NF-κB pathways as well as the store-operated calcium signaling. Gene silencing with small interfering RNA in A549 and BEAS-2B cells indicated that activation of AECs by Der f 3 was mainly dependent on protease-activated receptor 2 (PAR-2), while PAR-1 was also required for the full activation of AECs. Double knock-down of PAR-1 and PAR-2 largely impaired Der f 3-inducecd IL-8 production and subsequent signaling pathways. Our data suggest that Der f 3 induces pro-inflammatory mediators in human epithelial cell lines via the PARs-MAPK-NF-κB axis. Our results provide a molecular mechanism by which Der f 3 may trigger the Th17-skewed allergic response toward house dust mites.


Assuntos
Alérgenos/imunologia , Proteínas de Artrópodes/imunologia , Células Epiteliais/imunologia , Pyroglyphidae/imunologia , Receptor PAR-1/imunologia , Receptor PAR-2/imunologia , Mucosa Respiratória/imunologia , Serina Endopeptidases/imunologia , Células A549 , Alérgenos/farmacologia , Animais , Proteínas de Artrópodes/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/genética , Sinalização do Cálcio/imunologia , Citocinas/genética , Citocinas/imunologia , Células Epiteliais/patologia , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Mediadores da Inflamação/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Receptor PAR-1/genética , Receptor PAR-2/genética , Serina Endopeptidases/farmacologia , Células Th17/imunologia , Células Th17/patologia , Células Th2/imunologia , Células Th2/patologia
5.
PLoS One ; 14(3): e0213536, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30849108

RESUMO

A safe and effective adjuvant is necessary to induce reliable protective efficacy of the protein-based vaccines against tuberculosis (TB). Mycobacterial components, such as synthetic cord factor and arabinogalactan, have been used as one of the adjuvant components. Mycobacterium bovis bacillus Calmette- Guérin cell-wall skeleton (BCG-CWS) has been used as an effective immune-stimulator. However, it is not proven whether BCG-CWS can be an effective adjuvant for the subunit protein vaccine of TB. In this study, we demonstrated that the BCG-CWS effectively coupled with Ag85B and enhanced the conjugated Ag85B activity on the maturation of dendritic cells (DCs). Ag85B-BCG-CWS-matured DCs induced significant Th1 and Th17 responses when compared to BCG-CWS or Ag85B alone. In addition, significant Ag85B-specific Th1 and Th17 responses were induced in Ag85B-BCG-CWS-immunized mice before infection with M. tuberculosis and maintained after infection. Moreover, Ag85B-BCG-CWS showed significant protective effect comparable to live BCG at 6 weeks after infection and maintained its protective efficacy at 32 weeks post-challenge, whereas live BCG did not. These results suggest that the BCG-CWS may be an effective adjuvant candidate for a protein-based vaccine against TB.


Assuntos
Antígenos de Bactérias/imunologia , Parede Celular/imunologia , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Células Th1/imunologia , Células Th2/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Antígenos de Bactérias/farmacologia , Feminino , Camundongos , Células Th2/patologia , Tuberculose/patologia , Tuberculose/prevenção & controle , Vacinas contra a Tuberculose/farmacologia
6.
J Biol Chem ; 294(14): 5438-5455, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30745361

RESUMO

Asthma is a common inflammatory pulmonary disorder involving a diverse array of immune cells such as proinflammatory T helper 2 (Th2) cells. We recently reported that intraperitoneal injection of α-galactosylceramide (α-GalCer) can stimulate the lung invariant natural killer T (iNKT) cells and does not lead to airway inflammation in WT mice. Other studies indicate that iNKT cells play an important role in inducing regulatory T cells (Treg cells) and peripheral tolerance. Using iNKT cell- knockout mice, functional inactivation of Treg cells, and co-culture experiments in murine asthma models, we investigated the immunoregulatory effects of α-GalCer treatment before allergen sensitization on Th2 cell responses. We also studied whether α-GalCer's effects require lung Treg cells induced by activated iNKT cells. Our results disclosed that intraperitoneal administration of α-GalCer before allergen sensitization could promote the expansion and suppressive activity of lung CD4+FoxP3+ Treg cells. These effects were accompanied by down-regulated Th2 cell responses and decreased immunogenic maturation of lung dendritic cells in WT mice. However, these changes were absent in CD1d-/- mice immunized and challenged with ovalbumin or house dust mites, indicating that the effects of α-GalCer on Treg cells mainly require iNKT cells. Moreover, functional inactivation of Treg cells could reverse the inhibitory ability of this α-GalCer therapy on Th2 cell responses in a murine asthma model. Our findings indicate that intraperitoneal administration of α-GalCer before the development of asthma symptoms induces the generation of lung Treg cells via iNKT cells and may provide a potential therapeutic strategy to prevent allergic asthma.


Assuntos
Alérgenos/toxicidade , Asma/prevenção & controle , Galactosilceramidas/farmacologia , Células T Matadoras Naturais/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Alérgenos/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células T Matadoras Naturais/patologia , Pyroglyphidae/imunologia , Linfócitos T Reguladores/patologia , Células Th2/patologia
7.
Pancreas ; 48(3): 367-373, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30768574

RESUMO

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a peritumoral proliferation of fibroblasts and extracellular matrix production known as desmoplasia. We aimed to study desmoplasia in PDAC lymph node (LN) metastases. METHODS: We evaluated LNs from 66 patients with PDAC and LN metastases. We used immunohistochemistry and real-time polymerase chain reaction to phenotype the desmoplastic response. RESULTS: Desmoplasia was identified in 57% of patients with LN metastases (Des+). Cancer-associated fibroblasts (CAFs) in Des+ expressed α-smooth muscle actin and collagen 11A1. The latter expression was present only in CAFs but not in LN stroma or in LN metastases without desmoplasia (Des-). Desmoplasia was associated with upregulation of transforming growth factor ß messenger RNA. Whereas numbers of CD8+ in tumor vicinity were not different between Des+ and Des- patients (78 [standard deviation {SD}, 57] vs 92 [SD, 52], P = 0.48, respectively), the numbers of GATA-3+ cells, a marker of T-helper 2 immune response was significantly increased (3.7 [SD, 6.3] for Des+ vs 1.3 [SD, 2.7] for Des-, P < 0.05). CONCLUSIONS: Lymph node desmoplasia is associated with CAF pattern activation and Th2 infiltration. Therapeutic modulation of desmoplasia may be relevant in the metastatic phase and influence antitumor immune response.


Assuntos
Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal Pancreático/patologia , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Células Th2/patologia , Idoso , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células , Colágeno Tipo XI/genética , Colágeno Tipo XI/metabolismo , Matriz Extracelular/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/metabolismo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Pâncreas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Células Th2/metabolismo
8.
J Allergy Clin Immunol ; 143(1): 13-25, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30612664

RESUMO

Atopic dermatitis (AD) is characterized by severe pruritus and recurrent eczema with a chronic disease course. Impaired skin barrier function, hyperactivated TH2 cell-type inflammation, and pruritus-induced scratching contribute to the disease pathogenesis of AD. Skin microbial alterations complicate the pathogenesis of AD further. Mouse models are a powerful tool to analyze such intricate pathophysiology of AD, with a caution that anatomy and immunology of the skin differ between human subjects and mice. Here we review recent understanding of AD etiology obtained using mouse models, which address the epidermal barrier, skin microbiome, TH2 immune response, and pruritus.


Assuntos
Dermatite Atópica , Pele , Células Th2 , Animais , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Dermatite Atópica/fisiopatologia , Modelos Animais de Doenças , Humanos , Camundongos , Microbiota/imunologia , Prurido/genética , Prurido/imunologia , Prurido/patologia , Prurido/fisiopatologia , Pele/imunologia , Pele/microbiologia , Pele/patologia , Pele/fisiopatologia , Células Th2/imunologia , Células Th2/patologia
9.
J Allergy Clin Immunol ; 143(1): 245-257.e6, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30616774

RESUMO

BACKGROUND: GTPase of immunity-associated protein 5 (GIMAP5) is essential for lymphocyte homeostasis and survival. Recently, human GIMAP5 single nucleotide polymorphisms have been linked to an increased risk for asthma, whereas loss of Gimap5 in mice has been associated with severe CD4+ T cell-driven immune pathology. OBJECTIVE: We sought to identify the molecular and cellular mechanisms by which Gimap5 deficiency predisposes to allergic airway disease. METHODS: CD4+ T-cell polarization and development of pathogenic CD4+ T cells were assessed in Gimap5-deficient mice and a human patient with a GIMAP5 loss-of-function (LOF) mutation. House dust mite-induced airway inflammation was assessed by using a complete Gimap5 LOF (Gimap5sph/sph) and conditional Gimap5fl/flCd4Cre/ert2 mice. RESULTS: GIMAP5 LOF mutations in both mice and human subjects are associated with spontaneous polarization toward pathogenic TH17 and TH2 cells in vivo. Mechanistic studies in vitro reveal that impairment of Gimap5-deficient TH cell differentiation is associated with increased DNA damage, particularly during TH1-polarizing conditions. DNA damage in Gimap5-deficient CD4+ T cells could be controlled by TGF-ß, thereby promoting TH17 polarization. When challenged with house dust mite in vivo, Gimap5-deficient mice displayed an exacerbated asthma phenotype (inflammation and airway hyperresponsiveness), with increased development of TH2, TH17, and pathogenic TH17/TH2 cells. CONCLUSION: Activation of Gimap5-deficient CD4+ T cells is associated with increased DNA damage and reduced survival that can be overcome by TGF-ß. This leads to selective survival of pathogenic TH17 cells but also TH2 cells in human subjects and mice, ultimately promoting allergic airway disease.


Assuntos
Asma/imunologia , GTP Fosfo-Hidrolases/deficiência , Mutação com Perda de Função , Células Th17/imunologia , Células Th2/imunologia , Animais , Asma/genética , Asma/patologia , GTP Fosfo-Hidrolases/imunologia , Humanos , Camundongos , Camundongos Transgênicos , Células Th17/patologia , Células Th2/patologia , Fator de Crescimento Transformador beta/genética
10.
Int J Cancer ; 144(12): 3160-3173, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30536712

RESUMO

Pulmonary fibrosis represents a leading cause of morbidity and mortality worldwide. Therapy induced lung fibrosis constitutes a pivotal dose-limiting side effect of radiotherapy and other anticancer agents. We aimed to develop objective criteria for assessment of fibrosis and discover pathophysiological and molecular correlates of lung fibrosis as a function of fractionated whole thoracic irradiation. Dose-response series of fractionated irradiation was utilized to develop a non-invasive and quantitative measure for the degree of fibrosis - the fibrosis index (FI). The correlation of FI with histopathology, blood-gas, transcriptome and proteome responses of the lung tissue was analyzed. Macrophages infiltration and polarization was assessed by immunohistochemistry. Fibrosis development followed a slow kinetic with maximum lung fibrosis levels detected at 24-week post radiation insult. FI favorably correlated with radiation dose and surrogates of lung fibrosis i.e., enhanced pro-inflammatory response, tissue remodeling and extracellular matrix deposition. The loss of lung architecture correlated with decreased epithelial marker, loss of microvascular integrity with decreased endothelial and elevated mesenchymal markers. Lung fibrosis was further attributed to a switch of the inflammatory state toward a macrophage/T-helper cell type 2-like (M2/Th2) polarized phenotype. Together, the multiscale characterization of FI in radiation-induced lung fibrosis (RILF) model identified pathophysiological, transcriptional and proteomic correlates of fibrosis. Pathological immune response and endothelial/epithelial to mesenchymal transition were discovered as critical events governing lung tissue remodeling. FI will be instrumental for deciphering the molecular mechanisms governing lung fibrosis and discovery of novel targets for treatment of this devastating disease with an unmet medical need.


Assuntos
Fibrose Pulmonar/diagnóstico por imagem , Lesões Experimentais por Radiação/diagnóstico por imagem , Algoritmos , Animais , Gasometria , Fracionamento da Dose de Radiação , Feminino , Estudos Longitudinais , Camundongos , Camundongos Endogâmicos C57BL , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Proteômica , Fibrose Pulmonar/sangue , Fibrose Pulmonar/fisiopatologia , Lesões Experimentais por Radiação/sangue , Lesões Experimentais por Radiação/fisiopatologia , Células Th2/imunologia , Células Th2/patologia , Transcriptoma
12.
J Allergy Clin Immunol ; 143(1): 46-55, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30458183

RESUMO

The atopic march recognizes the increased occurrence of asthma, allergic rhinitis, or both after atopic dermatitis (AD) onset. Mechanisms for developing atopic comorbidities after AD onset are poorly understood but can involve the impaired cutaneous barrier, which facilitates cutaneous sensitization. The association can also be driven or amplified in susceptible subjects by a systemic TH2-dominant immune response to cutaneous inflammation. However, these associations might merely involve shared genetic loci and environmental triggers, including microbiome dysregulation, with the temporal sequence reflecting tissue-specific peak time of occurrence of each disease, suggesting more of a clustering of disorders than a march. Prospective longitudinal cohort studies provide an opportunity to explore the relationships between postdermatitis development of atopic disorders and potential predictive phenotypic, genotypic, and environmental factors. Recent investigations implicate disease severity and persistence, age of onset, parental atopic history, filaggrin (FLG) mutations, polysensitization, and the nonrural environment among risk factors for development of multiple atopic comorbidities in young children with AD. Early intervention studies to repair the epidermal barrier or alter exposure to the microbiome or allergens might elucidate the relative roles of barrier defects, genetic locus alterations, and environmental exposures in the risk and sequence of occurrence of TH2 activation disorders.


Assuntos
Asma , Dermatite Atópica , Multimorbidade , Rinite Alérgica , Fatores Etários , Asma/genética , Asma/imunologia , Asma/patologia , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Exposição Ambiental , Genótipo , Humanos , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/imunologia , Mutação , Rinite Alérgica/genética , Rinite Alérgica/imunologia , Rinite Alérgica/patologia , Fatores de Risco , Pele/imunologia , Pele/patologia , Células Th2/imunologia , Células Th2/patologia
13.
Ann Allergy Asthma Immunol ; 122(5): 449-455, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30465859

RESUMO

OBJECTIVE: To summarize studies investigating ethnical and racial differences in atopic dermatitis (AD) epidemiology, clinical features, and skin and blood phenotypes. DATA SOURCES: PubMed literature review (years 2000-2018). STUDY SELECTIONS: Articles discussing primarily human disease. RESULTS: Higher overall rates of AD were found in Africa and Oceania as opposed to India and Northern and Eastern Europe. In the United States, AD prevalence was found to be higher in African American (19.3%) compared with European American (16.1%) children. Although several studies have consistently found FLG loss-of-function mutations in up to 50% of European and 27% of Asian patients with AD, FLG mutations were 6 times less common in African American than in European American patients, even in patients with severe AD. Thus, FLG mutations seem to play less a pathogenic role in patients of African origin than in individuals of European or Asian ancestry. The immune phenotype of all ethnic groups was characterized by strong TH2 activation, but important differences in immune polarization exist among the different ethnicities. Asian patients with AD had stronger TH17/TH22 activation than African American and European American patients with AD, whereas African American patients had the highest serum IgE levels among all groups, while largely lacking TH1 and TH17 activation. CONCLUSION: AD is a heterogeneous disease that has differences among various ethnic and racial groups, which might be important for the development of future, targeted treatments and for personalized medicine approaches.


Assuntos
Dermatite Atópica/etnologia , Dermatite Atópica/genética , Predisposição Genética para Doença , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Grupo com Ancestrais do Continente Africano , Grupo com Ancestrais do Continente Asiático , Criança , Citocinas/genética , Citocinas/imunologia , Dermatite Atópica/epidemiologia , Dermatite Atópica/imunologia , Grupo com Ancestrais do Continente Europeu , Expressão Gênica , Hispano-Americanos , Humanos , Prevalência , Proteínas S100/genética , Proteínas S100/imunologia , Células Th1/patologia , Células Th17/patologia , Células Th2/patologia
14.
Am J Physiol Lung Cell Mol Physiol ; 316(1): L269-L279, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30407865

RESUMO

Histone deacetylase (HDAC)2 is expressed in airway epithelium and plays a pivotal role in inflammatory cells. However, the role of HDAC2 in allergic airway inflammation remains poorly understood. In the present study, we determined the role of HDAC2 in airway inflammation using in vivo models of house dust mite (HDM)-induced allergic inflammation and in vitro cultures of human bronchial epithelial (HBE) cells exposed to HDM, IL-17A, or both. We observed that HDM-challenged Hdac2+/- mice exhibited substantially enhanced infiltration of inflammatory cells. Higher levels of T helper 2 cytokines and IL-17A expression were found in lung tissues of HDM-challenged Hdac2+/- mice. Interestingly, IL-17A deletion or anti-IL-17A treatment reversed the enhanced airway inflammation induced by HDAC2 impairment. In vitro, HDM and IL-17A synergistically decreased HDAC2 expression in HBE cells. HDAC2 gene silencing further enhanced HDM- and/or IL-17A-induced inflammatory cytokines in HBE cells. HDAC2 overexpresion or blocking IL-17A gene expression restored the enhanced inflammatory cytokines. Collectively, these results support a protective role of HDAC2 in HDM-induced airway inflammation by suppressing IL-17A production and might suggest that activation of HDAC2 and/or inhibition of IL-17A production could prevent the development of allergic airway inflammation.


Assuntos
Asma/imunologia , Histona Desacetilase 2/imunologia , Interleucina-17/imunologia , Pyroglyphidae/imunologia , Animais , Asma/genética , Asma/patologia , Modelos Animais de Doenças , Feminino , Histona Desacetilase 2/genética , Interleucina-17/genética , Masculino , Camundongos , Camundongos Knockout , Células Th2/patologia
15.
Immunology ; 156(2): 199-212, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30418664

RESUMO

Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in directing T-cell responses. Regulatory T (Treg) cells possess an immunosuppressive ability to inhibit effector T-cell responses, and Notch ligand Jagged1 (Jag1) is implicated in Treg cell differentiation. In this study, we evaluated whether bone marrow-derived DCs genetically engineered to express Jag1 (Jag1-DCs) would affect the maturation and function of DCs in vitro and further investigated the immunoregulatory ability of Jag1-DCs to manipulate T helper type 2 (Th2) -mediated allergic asthma in mice. We produced Jag1-DCs by adenoviral transduction. Overexpression of Jag1 by ovalbumin (OVA) -stimulated Jag1-DCs exhibited increased expression of programmed cell death ligand 1 (PD-L1) and OX40L molecules. Subsequently, co-culture of these OVA-pulsed Jag1-DCs with allogeneic or syngeneic CD4+ T cells promoted the generation of Foxp3+ Treg cells, and blocking PD-L1 using specific antibodies partially reduced Treg cell expansion. Furthermore, adoptive transfer of OVA-pulsed Jag1-DCs to mice with OVA-induced asthma reduced allergen-specific immunoglobulin E production, airway hyperresponsiveness, airway inflammation, and secretion of Th2-type cytokines (interleukin-4, interleukin-5, and interleukin-13). Notably, an increased number of Foxp3+ Treg cells associated with enhanced levels of transforming growth factor-ß production was observed in Jag1-DC-treated mice. These data indicate that transgenic expression of Jag1 by DCs promotes induction of Foxp3+ Treg cells, which ameliorated Th2-mediated allergic asthma in mice. Our study supports an attractive strategy to artificially generate immunoregulatory DCs and provides a novel approach for manipulating Th2 cell-driven deleterious immune diseases.


Assuntos
Adenoviridae , Asma/imunologia , Células Dendríticas/imunologia , Expressão Gênica , Proteína Jagged-1/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Animais , Asma/genética , Asma/terapia , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/patologia , Proteína Jagged-1/genética , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Reguladores/patologia , Células Th2/patologia , Transdução Genética
16.
Am J Physiol Lung Cell Mol Physiol ; 316(1): L187-L196, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30358441

RESUMO

High-molecular-weight kininogen is an important substrate of the kallikrein-kinin system. Activation of this system has been associated with aggravation of hallmark features in asthma. We aimed to determine the role of kininogen in enhanced pause (Penh) measurements and lung inflammation in a house dust mite (HDM)-induced murine asthma model. Normal wild-type mice and mice with a genetic deficiency of kininogen were subjected to repeated HDM exposure (sensitization on days 0, 1, and 2; challenge on days 14, 15, 18, and 19) via the airways to induce allergic lung inflammation. Alternatively, kininogen was depleted after HDM sensitization by twice-weekly injections of a specific antisense oligonucleotide (kininogen ASO) starting at day 3. In kininogen-deficient mice HDM induced in Penh was completely prevented. Remarkably, kininogen deficiency did not modify HDM-induced eosinophil/neutrophil influx, T helper 2 responses, mucus production, or lung pathology. kininogen ASO treatment started after HDM sensitization reduced plasma kininogen levels by 75% and reproduced the phenotype of kininogen deficiency: kininogen ASO administration prevented the HDM-induced increase in Penh without influencing leukocyte influx, Th2 responses, mucus production, or lung pathology. This study suggests that kininogen could contribute to HDM-induced rise in Penh independently of allergic lung inflammation. Further research is warranted to confirm these data using invasive measurements of airway responsiveness.


Assuntos
Asma/imunologia , Cininogênios/deficiência , Pulmão/imunologia , Pyroglyphidae/imunologia , Células Th2/imunologia , Animais , Asma/genética , Asma/patologia , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/patologia , Cininogênios/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Th2/patologia
17.
J Cell Physiol ; 234(3): 2204-2216, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30246383

RESUMO

Autoimmune thyroid disease (AITD) is one of the most common organ-specific autoimmune disorders. It mainly manifests as Hashimoto's thyroiditis (HT) and Graves' disease (GD). HT is characteristic of hypothyroidism resulting from the destruction of the thyroid while GD is characteristic of hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. T lymphocytes and their secretory cytokines play indispensable roles in modulating immune responses, but their roles are often complex and full of interactions among distinct components of the immune system. Dysfunction of these T cells or aberrant expressions of these cytokines can cause the breakdown of immune tolerance and result in aberrant immune responses during the development of AITDs. This review summarizes recently identified T subsets and related cytokines and their roles in the pathogenesis of AITDs with the hope to provide a better understanding of the precise roles of notably identified T subsets in AITDs and facilitate the discovery of functional molecules or novel immune therapeutic targets for AITDs.


Assuntos
Doenças Autoimunes/imunologia , Doença de Graves/imunologia , Doença de Hashimoto/imunologia , Doenças da Glândula Tireoide/imunologia , Doenças Autoimunes/patologia , Citocinas/imunologia , Doença de Graves/patologia , Doença de Hashimoto/patologia , Humanos , Linfócitos T/imunologia , Linfócitos T/patologia , Células Th1/imunologia , Células Th1/patologia , Células Th2/imunologia , Células Th2/patologia , Doenças da Glândula Tireoide/patologia , Glândula Tireoide/imunologia , Glândula Tireoide/patologia
19.
Am J Pathol ; 189(1): 82-93, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30558726

RESUMO

Advances in the past two decades have resulted in the recognition of several tumefactive pancreatic lesions that, on histologic evaluation, show a varying combination of inflammation and fibrosis. Autoimmune pancreatitis, the prototypic tumefactive pancreatic fibroinflammatory lesion, is composed of two distinct diseases, type 1 autoimmune pancreatitis and the less common type 2 autoimmune pancreatitis. Although designated as autoimmune pancreatitis, the two diseases show little morphologic or pathogenic overlap. In type 1 disease, subsets of T lymphocytes (type 2 helper T cells, regulatory T cells, and T follicular helper 2 cells) are hypothesized to drive the inflammatory reaction. The B-cell response is characterized by an oligoclonal expansion of plasmablasts, with dominant clones that vary among patients and distinct clones that emerge at the time of relapse. Although the precise role of IgG4 in this condition remains uncertain, recent studies suggest that other IgG subclasses (eg, IgG1) may mediate the immune reactions, whereas IgG4 represents a response to dampen excessive inflammation. A recent study of type 2 autoimmune pancreatitis highlights the role of CXCL8 (alias IL-8), with duct epithelium and infiltrating T lymphocytes expressing this chemokine; the latter may contribute to the distinct form of neutrophilic inflammation in this disease. The review also highlights other forms of mass-forming chronic pancreatitis: follicular pancreatitis, groove pancreatitis, and those associated with rheumatologic diseases.


Assuntos
Doenças Autoimunes , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Pancreatite Crônica , Anticorpos Antineoplásicos/sangue , Anticorpos Antineoplásicos/imunologia , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Fibrose , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Inflamação/sangue , Inflamação/imunologia , Inflamação/patologia , Interleucina-8/sangue , Interleucina-8/imunologia , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/imunologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Pancreatite Crônica/sangue , Pancreatite Crônica/imunologia , Pancreatite Crônica/patologia , Plasmócitos/imunologia , Plasmócitos/metabolismo , Plasmócitos/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/patologia
20.
J Allergy Clin Immunol ; 143(1): 142-154, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30121291

RESUMO

BACKGROUND: IL-22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL-22 antagonism have not been defined in human subjects. OBJECTIVE: We sought to evaluate the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD. METHODS: We assessed lesional and nonlesional skin from 59 patients with moderate-to-severe AD treated with anti-IL-22 (fezakinumab) versus placebo (2:1) using transcriptomic and immunohistochemistry analyses. RESULTS: Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 × 10-5) and 65.5% versus 13.9% at 12 weeks (P = 9.5 × 10-19), respectively. Because IL-22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL-22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL-22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22-high drug-treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL-22-high placebo-treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL-22-low groups. Significant downregulations of multiple immune pathways, including TH1/CXCL9, TH2/CCL18/CCL22, TH17/CCL20/DEFB4A, and TH22/IL22/S100A's, were restricted to the IL-22-high drug group (P < .05). Consistently, tissue predictors of clinical response were mostly genes involved in T-cell and dendritic cell activation and differentiation. CONCLUSIONS: This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucinas/biossíntese , Pele/metabolismo , Adulto , Anticorpos Monoclonais Humanizados , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Pele/imunologia , Pele/patologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/patologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/patologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/patologia
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