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1.
HNO ; 67(11): 881-892, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31598772

RESUMO

Acute rhinosinusitis and chronic rhinosinusitis are inflammatory diseases of the mucosal membranes due to mislead immunological reactions to aeroallergens. T­cells are divided into different groups based on their cytokine secretion: T­helper type 1 (Th1) and type 2 (Th2) cells. The allergic immune response is caused by activation of specific Th2 cells. With specific immunotherapy, the mislead hyperactivated "allergic" immune response is reduced to a reaction within the normal range. The inflammatory forms of chronic rhinosinusitis are called endotypes, and, in the future, could enable a targeted, pathomechanistic therapy. These endotype-based treatment approaches target specific signaling pathways that have already shown good effects for chronic rhinosinusitis with nasal polyps using monoclonal antibodies. However, so far, only selected patients with non-rhinologic indications, off-label treatments, or in clinical trials have benefited from these treatments.


Assuntos
Rinite , Sinusite , Linfócitos T , Doença Crônica , Citocinas , Humanos , Mucosa Nasal/imunologia , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia
3.
Rhinology ; 57(5): 336-342, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31317972

RESUMO

BACKGROUND: Chronic rhinosinusitis (CRS) is a chronic inflammatory condition of the upper airways, often associated with the formation of nasal polyps (CRSwNP). It is well established that macroscopically normal (non-polypoidal) sinonasal mucosa in CRSwNP patients can undergo polypoidal change over time, turning into frank polyps. However, little is known about what drives this process. This study aimed to investigate potential drivers of nasal polyp formation or growth through comparison of the immunological profiles of nasal polyps with contiguous non-polypoidal sinonasal mucosa, from the same patients. METHODS: The immune profiles of three types of tissue were compared; nasal polyps and adjacent non-polypoidal sinonasal mucosa from 10 CRSwNP patients, and sinonasal mucosa from 10 control patients undergoing trans-sphenoidal pituitary surgery. Nasal polyp and control samples were also stimulated with Staphylococcus aureus enterotoxin B (SEB) using a nasal explant model, prior to cytokine analysis. Real time quantitative polymerase chain reaction (IL-5, T-bet, IL-17A, FoxP3, TLR-4, IL-8, IL-1beta and IL-6) and Luminex (IFNgamma, IL-5 and IL-17A) were used to quantify pro-inflammatory responses. RESULTS: Nasal polyps and contiguous non-polypoidal sinonasal mucosa from CRSwNP patients displayed a very similar pro-inflammatory profile. When stimulated with SEB, nasal polyps displayed a Th2/Th17 mediated response when compared to controls. CONCLUSIONS: In CRSwNP, nasal polyps and non-polypoidal sinonasal mucosa from the same patient displayed a similar pro-inflammatory profile skewed towards the Th2/Th17 pathway in nasal polyps following SEB stimulation, with evidence of disordered bacterial clearance. These factors may contribute to enhanced survival of bacteria and development of a chronic inflammatory milieu, potentially driving new polyp formation and recurrence following surgical removal.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Doença Crônica , Citocinas/metabolismo , Humanos , Membrana Mucosa , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia
4.
Nat Commun ; 10(1): 2162, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089134

RESUMO

Innate lymphoid cells (ILCs) are crucial for the immune surveillance at mucosal sites. ILCs coordinate early eradication of pathogens and contribute to tissue healing and remodeling, features that are dysfunctional in patients with cystic fibrosis (CF). The mechanisms by which ILCs contribute to CF-immunopathology are ill-defined. Here, we show that group 2 ILCs (ILC2s) transdifferentiated into IL-17-secreting cells in the presence of the epithelial-derived cytokines IL-1ß, IL-23 and TGF-ß. This conversion is abrogated by IL-4 or vitamin D3. IL-17 producing ILC2s induce IL-8 secretion by epithelial cells and their presence in nasal polyps of CF patients is associated with neutrophilia. Our data suggest that ILC2s undergo transdifferentiation in CF nasal polyps in response to local cytokines, which are induced by infectious agents.


Assuntos
Plasticidade Celular/imunologia , Fibrose Cística/imunologia , Inflamação/imunologia , Pólipos Nasais/imunologia , Células Th17/imunologia , Adulto , Animais , Linhagem Celular , Fibrose Cística/sangue , Fibrose Cística/patologia , Feminino , Humanos , Imunidade Inata , Inflamação/sangue , Inflamação/patologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-23/imunologia , Interleucina-23/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Mucosa Nasal/citologia , Mucosa Nasal/imunologia , Mucosa Nasal/patologia , Pólipos Nasais/sangue , Pólipos Nasais/patologia , Neutrófilos/imunologia , Adulto Jovem
5.
Mol Cells ; 42(4): 345-355, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31082802

RESUMO

Eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) is one of the most challenging problems in clinical rhinology. FZD5 is a receptor for Wnt5A, and its complex with Wnt5A contributes to activating inflammation and tissue modification. Nasal polyps and eosinophil/non-eosinophil counts are reported to be directly correlated. This study investigated the expression and distribution of FZD5, and the role of eosinophil infiltration and FZD5 in eosinophilic CRSwNP pathogenesis. The prognostic role of eosinophil levels was evaluated in seven patients with CRSwNP. Fifteen patients with CRS were classified based on the percentage of eosinophils in nasal polyp tissue. Methylated genes were detected using methyl-CpG-binding domain sequencing, and qRT-PCR and immunohistochemistry were used to detect FZD5 expression in nasal polyp tissue samples. The results showed that mRNA expression of FZD5 was upregulated in nasal polyps. FZD5 expression was significantly higher in nasal polyp samples from patients with eosinophilic CRSwNP than in those from patients with non-eosinophilic CRSwNP, as indicated by immunohistochemistry. Furthermore, inflammatory cytokine levels were higher in eosinophilic CRSwNP-derived epithelial cells than in normal tissues. In conclusion, FZD5 expression in nasal mucosal epithelial cells is correlated with inflammatory cells and might play a role in the pathogenesis of eosinophilic CRSwNP.


Assuntos
Metilação de DNA , Eosinófilos/metabolismo , Receptores Frizzled/genética , Pólipos Nasais/genética , Rinite/genética , Sinusite/genética , Adulto , Idoso , Citocinas/metabolismo , Epigênese Genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Receptores Frizzled/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/citologia , Mucosa Nasal/metabolismo , Pólipos Nasais/imunologia , Prognóstico , Regiões Promotoras Genéticas , Rinite/imunologia , Sinusite/imunologia , Regulação para Cima
6.
Int Arch Allergy Immunol ; 179(3): 209-214, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30970360

RESUMO

BACKGROUND: Nasal polyps are a common health problem that can significantly impact the quality of life. OBJECTIVE: To analyze the impact of allergy and peripheral eosinophils (EOS) on the morbidity of chronic rhinosinusitis with nasal polyps (CRSwNP) in Northwest China. METHODS: A retrospective cohort of 323 patients who underwent endoscopic sinus surgery (ESS) for chronic rhinosinusitis without nasal polyps (CRSsNP) and CRSwNP in Xijing Hospital was studied between January 5, 2011, and January 4, 2015. All of the patients underwent an allergen skin prick test and peripheral blood EOS inspection. Detailed information regarding the impact of allergy and EOS on the morbidity of CRSwNP was collected. Potential risk factors associated with nasal polyps were explored using logistic regression analysis. Multivariate logistic regression was performed to identify independent risk factors. RESULTS: The results revealed that EOS is an important risk factor for nasal polyps. In the univariate analysis, the adjusted OR was 2.01 (95% CI 1.08-3.72; p = 0.027). In the multivariate analysis, the adjusted OR was 2.02 (95% CI 1.08-3.76; p = 0.027). Compared to allergic rhinitis and normal EOS levels, nonallergic rhinitis and elevated EOS levels constituted a risk factor for CRSwNP (OR = 2.70; 95% CI 1.32-5.50). Compared to allergen-positive and EOS-normal status, allergen-negative and elevated-EOS status constituted a risk factor for CRSwNP (OR = 2.95; 95% CI 1.38-6.33). CONCLUSION: EOS is a significant factor related to the morbidity of CRSwNP in Northwest China. Elevated EOS levels occurring in the context of nonallergic rhinitis constitute a risk factor for CRSwNP. Similarly, elevated EOS levels occurring in the context of allergen-negative rhinitis are also an important risk factor for morbidity of CRSwNP.


Assuntos
Eosinófilos/imunologia , Hipersensibilidade/imunologia , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Adulto , China , Doença Crônica , Feminino , Humanos , Hipersensibilidade/epidemiologia , Masculino , Pessoa de Meia-Idade , Morbidade , Pólipos Nasais/epidemiologia , Estudos Retrospectivos , Rinite/epidemiologia , Fatores de Risco , Sinusite/epidemiologia , Adulto Jovem
7.
Laryngoscope ; 129(10): 2230-2235, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30973971

RESUMO

OBJECTIVE: In the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP), Aspergillus fumigatus (A. fumigatus) can upregulate IL-33 from human sinonasal epithelial cells (SNECs), which then activates innate lymphoid cells causing release of IL-13, an important driver of allergic inflammation. However, the mechanism by which A. fumigatus mediates the induction of IL-33 expression remains to be elucidated. The objectives of this study were to determine the specific fungal component(s) and the receptor responsible for mediating the A. fumigatus induced increase in IL-33 expression in SNECs from patients with CRSwNP. METHODS: SNECs from CRSwNP patients were cultured and stimulated with various fungal components in the absence or presence of 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride, an irreversible serine protease inhibitor, or GB83, a reversible protease activated receptor 2 (PAR2) inhibitor. IL-33 expression was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). PAR2 expression was examined in inflamed mucosa from nonatopic control and CRSwNP patients. RESULTS: Elevation of IL-33 expression in primary SNECs was found in response to fungal protease but not fungal cell wall components. PAR2 expression was elevated in inflamed mucosa from CRSwNP patients in comparison to controls. The A. fumigatus fungal protease-mediated elevation in IL-33 expression by human SNECs was serine protease- and PAR2-dependent. CONCLUSION: These data suggest that serine protease activity of A. fumigatus is capable of inducing IL-33 expression in CRSwNP SNECs via PAR2, a potential therapeutic target in the treatment of CRSwNP. LEVEL OF EVIDENCE: NA Laryngoscope, 129:2230-2235, 2019.


Assuntos
Aspergillus fumigatus/imunologia , Interleucina-33/metabolismo , Pólipos Nasais/microbiologia , Receptores Acoplados a Proteínas-G/imunologia , Rinite/microbiologia , Sinusite/microbiologia , Células Cultivadas , Doença Crônica , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Feminino , Humanos , Imunidade Inata , Linfócitos/imunologia , Linfócitos/microbiologia , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/imunologia , Mucosa Nasal/microbiologia , Pólipos Nasais/imunologia , Seios Paranasais/imunologia , Seios Paranasais/microbiologia , Rinite/imunologia , Sinusite/imunologia
8.
Int Arch Allergy Immunol ; 179(4): 304-319, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30982052

RESUMO

OBJECTIVES: To characterize the epithelial-mesenchymal transition (EMT) in chronic rhinosinusitis with nasal polyps (CRSwNP) and to investigate the mechanism by which microRNA-21 (miR-21) regulates EMT in CRSwNP. METHOD: (1) Tissue experiments: Mucosa tissues were collected from 13 patients with CRSwNP and 12 patients with CRS without nasal polyps (CRSsNP), as well as 11 patients without CRS (controls). Protein localization and quantification were achieved by immunofluorescence staining and Western blotting, involving the epithelial marker protein E-cadherin and the mesenchymal marker proteins α-smooth muscle actin (α-SMA), fibronectin, and vimentin. Quantitative RT-PCR was used to detect the relative expression levels of miR-21 and TGF-ß1 mRNAs. (2) Cellular experiments: Primary human nasal epithelial cells (PHNECs) treated with TGF-ß1, or TGF-ß1 with miR-21 inhibitor, or miR-21 mimics alone were observed for morphology changes under a phase-contrast microscope. The expression levels of epithelial/mesenchymal marker proteins were determined as aforementioned. PTEN and phosphorylated Akt were detected by Western blotting. RESULTS: (1) Tissue experiments: Compared with the CRSsNP and control groups, the expression of E-cadherin was downregulated in the CRSwNP group, whereas the expression of TGF-ß1, α-SMA, fibronectin, and vimentin was upregulated. The expression levels of miR-21 and TGF-ß1 mRNAs in CRSwNP were significantly higher than those in CRSsNP and controls. (2) Cellular experiments: TGF-ß1 induced EMT-like transformation in PHNECs, featured by changes in cell morphology and upregulation of mesenchymal proteins and miR-21. The miR-21 inhibitor, as well as the Akt-specific -inhibitor, suppressed TGF-ß1-induced EMT. Mechanically, downregulation of miR-21 resulted in increased PTEN and decreased Akt phosphorylation. Furthermore, overexpression of miR-21 had the opposite effects. CONCLUSIONS: Our findings suggest that the TGF-ß1-miR-21-PTEN-Akt axis may contribute to the pathogenesis of CRSwNP. miR-21 might be a reliable target for treating nasal polyp genesis through EMT suppression. Moreover, miR-21 inhibitors could be a novel class of antipolyp drug that modulates PTEN expression and Akt activation. In addition, further investigation regarding the reason underlying miR-21 overexpression in CRSwNP could provide a molecular target for novel treatment strategies for nasal polyposis.


Assuntos
Transição Epitelial-Mesenquimal , MicroRNAs/genética , Mucosa Nasal/fisiologia , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Fator de Crescimento Transformador beta1/genética , Adolescente , Adulto , Idoso , Células Cultivadas , Criança , Doença Crônica , Feminino , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Pólipos Nasais/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rinite/genética , Sinusite/genética , Fator de Crescimento Transformador beta1/metabolismo , Adulto Jovem
9.
Curr Allergy Asthma Rep ; 19(4): 21, 2019 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-30859336

RESUMO

PURPOSE OF REVIEW: Staphylococcus aureus (S. aureus) is correlated with the development of persistent severe inflammatory disease of the upper airway including chronic rhinosinusitis with nasal polyps (CRSwNP). The presence of S. aureus is associated with atopic disease including allergic rhinitis and atopic dermatitis and is associated with poor outcomes. RECENT FINDINGS: Several different strains of S. aureus generate different toxins and gene products that can account for organism pathogenicity. S. aureus bacteria and its antigens shape the bacterial and fungal microbiome and the mucosal niche which generates host responses that can account for inflammation. The multiple disease phenotypes and molecular endotypes seen in CRSwNP can be characterized by T-helper cell environment within the inflammatory milieu, the presence of epithelial barrier dysfunction, aberrant eicosanoid metabolism, poor wound healing, and dysfunctional host-bacteria interactions which lead to recalcitrant disease and worse surgical outcomes. Understanding the pathomechanisms that S. aureus utilizes to promote nasal polyp formation, prolonged tissue inflammation, and bacterial dysbiosis are essential in our efforts to identify new therapeutic approaches to resolve this chronic inflammatory process.


Assuntos
Pólipos Nasais/microbiologia , Rinite Alérgica/microbiologia , Sinusite/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/patogenicidade , Antígenos de Bactérias/imunologia , Doença Crônica , Enterotoxinas/imunologia , Humanos , Pólipos Nasais/diagnóstico , Pólipos Nasais/imunologia , Rinite Alérgica/diagnóstico , Rinite Alérgica/imunologia , Sinusite/diagnóstico , Sinusite/imunologia , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Superantígenos/imunologia
10.
Eur Arch Otorhinolaryngol ; 276(6): 1685-1691, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30888496

RESUMO

OBJECTIVE: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease. The surrogate indicating biomarkers in patients with CRSwNP need further evaluation. The aim of this study was to investigate the association of thymic stromal lymphopoietin (TSLP) and amphiregulin (AREG) cytokines in patients with CRSwNP. METHODS: Sinonasal tissue samples were collected from 33 patients with CRSwNP and 29 controls. Levels of AREG, IL-19, IL-21, IL-25, IL-33 and TSLP in nasal polyp and control sinonasal tissues were determined following the enzyme-linked immunosorbent assay method. RESULTS: We found that AREG, IL-19, IL-21, IL-25, IL-33 and TSLP levels were significantly higher in the CRSwNP group compared to the control group (p < 0.000; p < 0.000; p < 0.000; p < 0.000; p < 0.003; p < 0.021, respectively). CONCLUSIONS: Our findings indicated that AREG, IL-19, IL-21, IL-25, IL-33 and TSLP were significantly increased in tissue samples of CRSwNP patients and may be considered as molecular indicators and targets for therapeutic developments for patients with CRSwNP.


Assuntos
Anfirregulina/imunologia , Citocinas/imunologia , Interleucinas/imunologia , Rinite/imunologia , Sinusite/imunologia , Adulto , Idoso , Biomarcadores/sangue , Doença Crônica , Correlação de Dados , Feminino , Humanos , Interleucinas/classificação , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/diagnóstico , Pólipos Nasais/imunologia , Rinite/diagnóstico , Sinusite/diagnóstico
12.
Artigo em Chinês | MEDLINE | ID: mdl-30808151

RESUMO

Chronic rhinosinusitis with nasal polyps (CRSwNP) is one of the common diseases. Involving the nasal passages and nasal passages, it may affect 10% of the global population. Surgical intervention is usually required. Its pathogenesis is a multielement and multistep complex process. Current multi-factor hypothesisplays a dominant role in the etiology of nasal polyps (NP). Infectious factors always play an important role in the pathogenesis of CRSwNP. The lesions of nasal polyp have different inflammatory cell infiltration and can be divided into two types in immunophenotpe: the first is characterized by Th2 cell reaction and marked eosinophil infiltration,and the second is Th1/Th17 cell response and non-eosinophil infiltration are characteristic.NP, which is mainly infiltrated by neutrophils, is more and more common in China. B cell activation factor (BAFF) is a major inflammatory factor related to the regulation of B cell activation.Recent experiments have shown that BAFF is also high in nasal polyps.In this paper, the effects and interactions of BAFF and eosinophils and neutrophils in CRSwNP were reviewed.


Assuntos
Linfócitos B , Eosinófilos , Pólipos Nasais , Neutrófilos , Rinite , Sinusite , Linfócitos B/imunologia , China , Doença Crônica , Correlação de Dados , Humanos , Ativação Linfocitária , Pólipos Nasais/imunologia , Pólipos Nasais/patologia , Rinite/imunologia , Rinite/patologia , Sinusite/imunologia , Sinusite/patologia
13.
Acta Otolaryngol ; 139(1): 57-63, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30676835

RESUMO

BACKGROUND: Glucocorticoids (GC) therapeutic response in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) varies markedly. AIMS/OBJECTIVES: To compare the utility between subjective and objective assessment of GC sensitivity in reflecting the impact of GC on systemic and local eosinophilia in CRSwNP patients. MATERIAL AND METHODS: Twenty-six patients with CRSwNP were enrolled. All patients were given 30 mg of prednisone once daily for 7 days and subsequently classified into subjectively GC-sensitive and -insensitive subgroup or objectively GC-sensitive and -insensitive subgroup. The numbers of eosinophils and neutrophils in blood and polyp tissues were compared between GC-sensitive and GC-insensitive subgroup. RESULTS: 17/26 (65.4%) patients were subjectively and 8/26 (30.8%) patients objectively sensitive to GC treatment. The absolute number and percentage of eosinophils in blood were decreased both in GC-sensitive and -insensitive subjects after GC treatment. In addition, a significant reduction in tissue eosinophil percentage was only observed in objectively GC-sensitive subjects after GC treatment. Furthermore, the change of tissue eosinophil percentage in objectively GC-sensitive subjects was significantly higher than that in objectively GC-insensitive subjects. CONCLUSIONS AND SIGNIFICANCE: Objective assessment may better reflect oral GC response in tissue eosinophilic inflammation than subjective assessment in patients with CRSwNP.


Assuntos
Glucocorticoides/uso terapêutico , Pólipos Nasais/tratamento farmacológico , Prednisona/uso terapêutico , Índice de Gravidade de Doença , Adolescente , Adulto , Eosinofilia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/imunologia , Neutrófilos/efeitos dos fármacos , Projetos Piloto , Estudos Prospectivos , Adulto Jovem
14.
Acta Otolaryngol ; 139(1): 48-51, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30686139

RESUMO

BACKGROUND/OBJECTIVE: The pathophysiological and prognostic role of blood inflammatory cells in chronic rhinosinusitis with nasal polyps (CRSwNP) emerging from recent studies was investigated. MATERIAL AND METHODS: The main available evidence and largely-recent publications were critically analyzed. RESULTS: Several authors reported a direct association between blood eosinophilia and CRSwNP recurrence rates. In some large series, a direct association between recurrent CRSwNP and blood basophil values emerged too. CRSwNP patients' blood eosinophil and basophil values were strongly related. It was also found that preoperative neutrophil-to-lymphocyte, eosinophil-to-lymphocyte, and basophil-to-lymphocyte ratios were significantly higher in patients who experienced a disease relapse than in those who did not. In histologically-confirmed eosinophilic-type CRSwNP treated with endoscopic sinus surgery, mean blood eosinophil values dropped significantly from before to after the surgical procedure. CONCLUSIONS/SIGNIFICANCE: CRSwNP endotypes have different inflammatory profiles reflected in the relative proportions of different types of blood cells. The available data support the theory that blood eosinophil and basophil levels should be included in the routine preoperative work-up of CRSwNP patients in order to give patients accurate prognostic information, adopt rational follow-up protocols after surgery, and provide dedicated postoperative medical treatments.


Assuntos
Leucócitos , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Doença Crônica , Humanos , Contagem de Leucócitos , Pólipos Nasais/complicações , Pólipos Nasais/cirurgia , Rinite/complicações , Rinite/cirurgia , Sinusite/complicações , Sinusite/cirurgia
15.
Mucosal Immunol ; 12(2): 425-433, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30664707

RESUMO

The nasal cavity displays immune tolerance to commensal bacteria under homeostatic conditions, which is rapidly converted to a pro-inflammatory response upon infection. Yet, the factors that control this conversion are still largely unknown. Here, we provide evidence that Fc gamma receptor III (FcγRIII) stimulation breaks immune tolerance to bacteria in the human nasal cavity through activation of nasal epithelial cells, which are the first line of defense against invading microbes. While under steady-state conditions human nasal epithelial cells were completely non-responsive to Gram-negative bacteria P. aeruginosa or TLR4 ligand LPS, IgG opsonization of bacteria, as occurs upon infection, strongly induced production of pro-inflammatory agents such as IL-6 and IL-8. This breaking of tolerance to bacteria was completely dependent on FcγRIII, which amplified cytokine gene transcription through cross-talk with TLR4. In addition, we identified that epithelial cells from patients suffering from chronic rhinosinusitis with nasal polyps do not display LPS tolerance, thereby providing an explanation for the disturbed host defense responses of these patients. Taken together, these data are the first to identify FcγR expression on nasal epithelial cells, as well as to identify its important role in controlling the balance between tolerance and inflammation in the nasal cavity.


Assuntos
Células Epiteliais/imunologia , Cavidade Nasal/patologia , Pólipos Nasais/imunologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/fisiologia , Receptores de IgG/metabolismo , Rinite/imunologia , Sinusite/imunologia , Células Cultivadas , Doença Crônica , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Tolerância Imunológica , Lipopolissacarídeos/imunologia , Receptor Cross-Talk , Receptor 4 Toll-Like/metabolismo
16.
J Allergy Clin Immunol ; 143(2): 591-603.e3, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29935218

RESUMO

BACKGROUND: The effect of Staphylococcus aureus on nasal epithelial repair has never been assessed in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVE: This study aimed to determine whether (1) nasal epithelial cell cultures from patients with CRSwNP and control subjects repair differently; (2) S aureus exoproducts compromise nasal epithelial repair; (3) S aureus alters lamellipodial dynamics; and (4) deleterious effects could be counteracted by the Rho-associated coiled-coil kinase inhibitor Y-27632. METHODS: Primary nasal epithelial cells (pNECs) collected during surgeries were cultured and injured under 3 conditions: (1) basal conditions, (2) exposed to S aureus exoproducts, and (3) exposed to S aureus exoproducts and Y-27632. Epithelial repair, lamellipodial dynamics, and cytoskeletal organization were assessed. RESULTS: Under basal conditions, pNEC cultures from patients with CRSwNP presented significantly lower repair rates and reduced lamellipodial protrusion length and velocity than those from control subjects. S aureus exoproducts significantly decreased repair rates and protrusion dynamics in both control subjects and patients with CRSwNP; however, the effect of S aureus on cell protrusions was more sustained over time in patients with CRSwNP. Under basal conditions, immunofluorescence assays showed significantly reduced percentages of cells with lamellipodia at the wound edge in patients with CRSwNP compared with control subjects. S aureus altered cell polarity and decreased the percentage of cells with lamellipodia in both groups. Finally, Y-27632 prevented the deleterious effects of S aureus exoproducts on CRSwNP repair rates, as well as on lamellipodial dynamics and formation. CONCLUSIONS: S aureus exoproducts significantly alter epithelial repair and lamellipodial dynamics on pNECs, and this impairment was more pronounced in patients with CRSwNP. Importantly, Y-27632 restored epithelial repair and lamellipodial dynamics in the presence of S aureus exoproducts.


Assuntos
Pólipos Nasais/imunologia , Seios Paranasais/patologia , Mucosa Respiratória/fisiologia , Rinite/imunologia , Sinusite/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Adulto , Idoso , Amidas/farmacologia , Células Cultivadas , Doença Crônica , Citoesqueleto/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Seios Paranasais/microbiologia , Piridinas/farmacologia , Mucosa Respiratória/patologia , Cicatrização , Quinases Associadas a rho/metabolismo
17.
HNO ; 67(1): 15-26, 2019 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-30167718

RESUMO

BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial inflammation of the nasal and paranasal mucosa. Until now, no internationally standardized classification could be developed. In most cases, CRS is phenotypically classified according to chronic rhinosinusitis with (CRScNP) and without nasal polyps (CRSsNP). However, recent studies could show that there are numerous endotypes within these phenotypes based on different inflammatory mechanisms. This review describes the important immunological mechanisms of CRScNP and highlights modern treatment options with biologicals directly addressing particular immunological processes. METHODS: Current knowledge on immunological and molecular processes of CRS, particularly CRScNP, was extracted from Medline, PubMed, national and international study- and guideline-registers, and the Cochrane library by a systematic review of the literature. RESULTS: Based on current literature, various immunological mechanisms for CRS and CRScNP could be identified. Relevant studies for the treatment of eosinophilic conditions such as asthma or CRScNP are presented and, if available, results of these studies are discussed. CONCLUSION: The growing insight into the underlying immunological mechanisms of CRScNP could pave the way for new personalized treatment options such as biologicals in the future.


Assuntos
Produtos Biológicos , Pólipos Nasais/imunologia , Pólipos Nasais/terapia , Rinite/imunologia , Rinite/terapia , Doença Crônica , Humanos , Sinusite
18.
Auris Nasus Larynx ; 46(3): 374-383, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30243753

RESUMO

OBJECTIVE: Recently, JESREC score and mucosal eosinophil count have been used to diagnose eosinophilic chronic rhinosinusitis (ECRS) in Japan. However, it remains unknown whether the subtypes of CRS diagnosed by these criteria have different endotypes. In the present study, we investigated whether JESREC score and mucosal eosinophil count were appropriate for classification of CRS subgroups into endotypes. METHODS: A cross-sectional study involving 71 consecutive patients with CRS with nasal polyps (CRSwNP) and 13 control patients was performed. Nasal polyp tissues from CRSwNP patients and uncinate process tissues from control patients were collected for analysis of inflammatory cells by immunohistochemistry and measurement of cytokines and chemokines by ELISA and quantitative real-time PCR. We compared the differences between subtypes according to JESREC score and mucosal eosinophil count and investigated the subgroups with different endotypes by cluster analysis and principal component analysis. RESULTS: In the 71 CRSwNP patients, 9 patients had JESREC score <11 and mucosal eosinophil count <70/HPF (Group A), 20 patients had JESREC score ≥11 and mucosal eosinophil count <70/HPF (Group C), and 42 patients had JESREC score ≥11 and mucosal eosinophil count ≥70/high-power field (HPF) (Group D). Semiquantitative analysis of inflammatory cells showed that eosinophils, neutrophils, macrophages, mast cells, and basophils differed significantly between the subgroups. At the mRNA level, CLC, IL5, IL13, CCL11, CCL24, CCL26, POSTN, CSF3, and IL8 showed significant differences. At the protein level, eotaxin-2/CCL24, eotaxin-3/CCL26, and G-CSF had significant differences. Cluster analysis using gene expression levels in 55 CRS patients and 11 control patients revealed that the patients could be classified into five clusters. Cluster 1 (n=27) contained all patients with Group D. Cluster 2 (n=11) comprised all control patients. Cluster 3 (n=4) included mixed subtypes: one with Group A and three with Group D. Cluster 4 (n=7) and Cluster 5 (n=17) contained all patients with Groups A and C, respectively. Furthermore, the principal component analysis revealed that the subtypes had different characteristics. CONCLUSION: CRS subtypes based on JESREC score and mucosal eosinophil count showed different inflammatory patterns, and unsupervised statistical analyses supported the classification that can predict endotypes. From these results, we concluded that the classification based on JESREC score and mucosal eosinophil count was useful for predicting CRS endotypes.


Assuntos
Citocinas/imunologia , Eosinofilia/imunologia , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Adulto , Doença Crônica , Citocinas/genética , Eosinofilia/genética , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/citologia , Pólipos Nasais/genética , Análise de Componente Principal , RNA Mensageiro/metabolismo , Rinite/genética , Sinusite/genética
20.
Allergol Int ; 68(2): 216-224, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30316748

RESUMO

BACKGROUND: IgG4 production is regulated by type 2 (IL-4 and IL-13) and regulatory (IL-10) cytokines involved in the pathophysiology of chronic rhinosinusitis (CRS). We sought to determine the pathophysiological characteristics of IgG4-positive cells in sinonasal tissues in CRS, especially eosinophilic CRS (ECRS). METHODS: IgG4-positive cells in uncinate tissues (UT) and nasal polyps (NP) were examined by immunohistochemistry. Associations between the number of IgG4-positive cells and clinicopathological factors were analyzed. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of IgG4-positive cells in tissue that can predict the post-operative course. RESULTS: IgG4 was mainly expressed in infiltrating plasma and plasmacytoid cells, and the number of IgG4-positive cells was significantly higher in NP, especially those from severe ECRS patients, than in UT. In CRS patients, the number of IgG4-positive cells significantly and positively correlated with blood and tissue eosinophilia, radiological severity, and serum level of total IgE. The number of infiltrating IgG4-positive cells was significantly higher in patients with a poor post-operative course (sustained sinus shadow 6 months after surgery) than in those with a good one. The number of IgG4-positive cells in NP could discriminate patients with a good or a poor post-operative course (area under the curve: 0.769). Also, 73.3% sensitivity and 82.5% specificity were achieved when the cut-off value was set at 17 cells/high-power field. CONCLUSIONS: Our results suggest that the local expression of IgG4 on cells may be used as a biomarker that reflects the pathophysiology of CRS, including the post-operative course.


Assuntos
Eosinófilos/imunologia , Imunoglobulina G/imunologia , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/imunologia , Doença Crônica , Eosinofilia/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/imunologia , Pólipos Nasais/sangue , Rinite/sangue , Sinusite/sangue
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