RESUMO
RATIONALE: Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation-prone asthma (EPA) remain incompletely defined. OBJECTIVES: To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA. METHODS: Baseline data from the NHLBI Severe Asthma Research Program (SARP)-3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), or exacerbation prone (≥3). Replication of a multivariable model was performed with data from the SARP-1 + 2 cohort. MEASUREMENTS AND MAIN RESULTS: Of 709 subjects in the SARP-3 cohort, 294 (41%) had no exacerbations and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP-3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP-3 multivariable model, blood eosinophils, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval], 1.6 [1.2-2.1] for every log unit of eosinophils, 1.3 [1.1-1.4] for every 10 body mass index units, and 1.2 [1.1-1.4] for every 10% increase in bronchodilatory responsiveness). Chronic sinusitis and gastroesophageal reflux were also associated with exacerbation frequency (1.7 [1.4-2.1] and 1.6 [1.3-2.0]), even after adjustment for multiple factors. These effects were replicated in the SARP-1 + 2 multivariable model. CONCLUSIONS: EPA may be a distinct susceptibility phenotype with implications for the targeting of exacerbation prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 01760915).
Assuntos
Albuterol/uso terapêutico , Asma/fisiopatologia , Broncodilatadores/uso terapêutico , Progressão da Doença , Resistência a Medicamentos/imunologia , Inflamação/etiologia , Adolescente , Adulto , Albuterol/administração & dosagem , Asma/tratamento farmacológico , Asma/epidemiologia , Asma/imunologia , Biomarcadores/análise , Índice de Massa Corporal , Testes Respiratórios , Broncodilatadores/administração & dosagem , Distribuição de Qui-Quadrado , Criança , Comorbidade , Suscetibilidade a Doenças , Eosinófilos/efeitos dos fármacos , Feminino , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/análise , Índice de Gravidade de Doença , Distribuição por Sexo , Escarro/químicaRESUMO
Vitamin D deficiency and asthma are common conditions that share risk factors such as African American ethnicity, inner-city residence, and obesity. This review provides a critical examination of current experimental and epidemiologic evidence of a causal association between vitamin D status and asthma or asthma morbidity, including potential protective mechanisms such as antiviral effects and enhanced steroid responsiveness. Because most published epidemiologic studies of vitamin D and asthma or asthma morbidity are observational, a recommendation for or against vitamin D supplementation as preventive or secondary treatment for asthma is not advisable and must await results of ongoing clinical trials. Should these trials confirm a beneficial effect of vitamin D, others will be needed to assess the role of vitamin D supplementation to prevent or treat asthma in different groups such as infants, children of school age, and ethnic minorities.
Assuntos
Asma/epidemiologia , Deficiência de Vitamina D/epidemiologia , Asma/tratamento farmacológico , Asma/etiologia , Conservadores da Densidade Óssea/uso terapêutico , Medicina Baseada em Evidências , Humanos , Fatores de Risco , Resultado do Tratamento , Estados Unidos/epidemiologia , Vitamina D/uso terapêutico , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológicoRESUMO
BACKGROUND: The chronic airway disease asthma causes significant burden to patients as well as the healthcare system with limited options for prevention or cure. Inadequate treatment strategies are most likely due to the complex heterogeneous nature of asthma. Furthermore, the severe asthma phenotype is characterized by the lack of a response to standard medication, namely, corticosteroids. SCOPE OF REVIEW: In the last several years it has been shown that the eosinophilic/atopic phenotype of asthma driven by T(H)2 mechanisms is not the only immunologic pathway contributing to disease. In fact, there has been evidence revealing that severe asthmatics in particular have neutrophilic inflammation, and this is associated with corticosteroid resistance. T(H)17 cells, a recently discovered lineage of T helper cells, play an important role in lung host defense against multiple pathogens via production of the cytokine IL-17. IL-17 promotes neutrophil production and chemotaxis via multiple factors. MAJOR CONCLUSIONS: Mouse and human studies provide robust evidence that T(H)17 cells and IL-17 play a role in severe asthma and may contribute to corticosteroid resistance. GENERAL SIGNIFICANCE: As we learn more about T(H)17 cells in severe asthma, the goal is to potentially target this pathway for treatment in the hope of significantly improving the quality of life for those children and adults affected with this disease. This article is part of a Special Issue entitled: Biochemistry of Asthma.
Assuntos
Asma/imunologia , Inflamação/imunologia , Células Th17/fisiologia , Animais , Asma/etiologia , Diferenciação Celular , Humanos , Interleucina-17/fisiologia , Interleucinas/fisiologia , Camundongos , Interleucina 22RESUMO
BACKGROUND: Asthma in children is a heterogeneous disorder with many phenotypes. Although unsupervised cluster analysis is a useful tool for identifying phenotypes, it has not been applied to school-age children with persistent asthma across a wide range of severities. OBJECTIVES: This study determined how children with severe asthma are distributed across a cluster analysis and how well these clusters conform to current definitions of asthma severity. METHODS: Cluster analysis was applied to 12 continuous and composite variables from 161 children at 5 centers enrolled in the Severe Asthma Research Program. RESULTS: Four clusters of asthma were identified. Children in cluster 1 (n = 48) had relatively normal lung function and less atopy. Children in cluster 2 (n = 52) had slightly lower lung function, more atopy, and increased symptoms and medication use. Cluster 3 (n = 32) had greater comorbidity, increased bronchial responsiveness, and lower lung function. Cluster 4 (n = 29) had the lowest lung function and the greatest symptoms and medication use. Predictors of cluster assignment were asthma duration, the number of asthma controller medications, and baseline lung function. Children with severe asthma were present in all clusters, and no cluster corresponded to definitions of asthma severity provided in asthma treatment guidelines. CONCLUSION: Severe asthma in children is highly heterogeneous. Unique phenotypic clusters previously identified in adults can also be identified in children, but with important differences. Larger validation and longitudinal studies are needed to determine the baseline and predictive validity of these phenotypic clusters in the larger clinical setting.
Assuntos
Asma/tratamento farmacológico , Adolescente , Asma/fisiopatologia , Criança , Análise por Conglomerados , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Masculino , National Institutes of Health (U.S.) , Estados UnidosRESUMO
BACKGROUND: Children with severe asthma have substantial morbidity and healthcare utilization. Pediatric severe asthma is a heterogeneous disease, and a multidisciplinary approach can improve the diagnosis and management of these children. METHODS: We reviewed the electronic health records for patients seen in the Severe Asthma Clinic (SAC) at UPMC Children's Hospital of Pittsburgh between August 2012 and October 2019. RESULTS: Of the 110 patients in whom we extracted data, 46% were female, 48% were Black/African American, and 41% had ≥1 admission to the pediatric intensive care unit (PICU) for asthma. Compared to patients without a PICU admission, those with ≥1 PICU admission were more likely to be non-White (64.4% vs. 41.5%, p = 0.031) and more atopic (eosinophil count geometric mean = 673 vs. 319 cells/mm3 , p = 0.002; total IgE geometric mean = 754 vs. 303 KU/L, p = 0.003), and to have lower pre-bronchodilator FEV1 (58.6% [±18.1%] vs. 69.9% [±18.7%], p = 0.002) and elevated FeNO (60% vs. 22%, p = 0.02). In this cohort, 84% of patients were prescribed high-dose ICS/LABA and 36% were on biologics. Following enrollment in the SAC, severe exacerbations decreased from 3.2/year to 2.2/year (p < 0.0001); compared to the year before joining the SAC, in the following year the group had 106 fewer severe exacerbations. CONCLUSIONS: This large cohort of children with severe asthma had a high level of morbidity and healthcare utilization. Patients with a history of PICU admissions for asthma were more likely to be nonwhite and highly atopic, and to have lower lung function. Our data support a positive impact of a multidisciplinary clinic on patients with severe childhood asthma.
Assuntos
Antiasmáticos , Asma , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/terapia , Criança , Estudos de Coortes , Eosinófilos , Feminino , Humanos , Unidades de Terapia Intensiva Pediátrica , MasculinoRESUMO
BACKGROUND: Sjogren's syndrome (SS) is a rare chronic autoimmune disease involving exocrine glands presenting with sicca syndrome, recurrent parotitis and other extraglandular stigmata. SS is well characterized in the adult population with classification criteria; however, primary SS presenting in childhood is poorly defined and rare in males. Recurrent parotitis is the most common presenting symptom in children with primary SS; however, clinical phenotype in children appears more variable than in adults. The lungs are a common extraglandular location for manifestations of primary SS. However, interstitial lung disease (ILD) is rare in children with primary SS. There are only four published reports of ILD associated with primary SS in female children. Here, we present a very rare case of primary SS in a pediatric male with pulmonary manifestations and review of the literature on ILD in childhood-onset primary SS. CASE PRESENTATION: A 14-year-old White male with a history of chronic severe asthma, recurrent parotitis and idiopathic intracranial hypertension was referred to pediatric rheumatology for evaluation of a positive ANA. In early childhood, he was diagnosed with persistent asthma recalcitrant to therapy. At age 8, he developed recurrent episodes of bilateral parotitis despite multiple treatments with sialoendoscopy. At age 14, respiratory symptoms significantly worsened prompting reevaluation. Lab workup was notable for positive ANA and Sjogren's Syndrome A and B antibodies. Pulmonary function tests showed only a mild obstructive process. Computed tomography of chest was significant for small airway disease, and lung biopsy was positive for mild interstitial lymphocytic inflammation presenting a conflicting picture for ILD. The constellation of findings led to the diagnosis of primary SS with associated pulmonary manifestations. He was treated with hydroxychloroquine, mycophenolate mofetil and oral corticosteroids with resolution of symptoms. CONCLUSIONS: Primary SS is a rare disease in the pediatric population that is poorly characterized. This case is the very rare presentation of childhood-onset primary SS with pulmonary manifestations in a male patient. ILD associated with primary SS is also very rare with only four pediatric patients reported in the literature. Collaborative effort is needed to develop pediatric specific diagnostic and treatment guidelines in this rare condition.
Assuntos
Asma , Doenças Pulmonares Intersticiais , Parotidite , Síndrome de Sjogren , Masculino , Criança , Pré-Escolar , Feminino , Humanos , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico , Parotidite/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Pulmão/diagnóstico por imagem , Doenças RarasRESUMO
Th17 cells, a subset of T cells involved in autoimmunity and host defense against extracellular Gram-negative infection, express both IL-17A and IL-17F. Both IL-17A and IL-17F can signal via the IL-17RA; however, IL-17F does so at a 1- to 2-log higher concentration than IL-17A. In this study, we show that the IL-17F homodimer via IL-17RA is a negative regulator of IL-17 production in T cells and suggest a mechanism whereby IL-17RA on T cells serves as an autocrine/paracrine regulator of IL-17 synthesis in T cells.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Concanavalina A/toxicidade , Interleucina-17/imunologia , Mitógenos/toxicidade , Receptores de Interleucina-17/imunologia , Animais , Comunicação Autócrina/genética , Comunicação Autócrina/imunologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Infecções por Bactérias Gram-Negativas/genética , Infecções por Bactérias Gram-Negativas/imunologia , Interleucina-17/genética , Camundongos , Camundongos Knockout , Comunicação Parácrina/genética , Comunicação Parácrina/imunologia , Receptores de Interleucina-17/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
BACKGROUND: The effect of age on asthma severity is poorly understood. OBJECTIVES: The objective of this study was to compare the baseline features of severe and nonsevere asthma in the Severe Asthma Research Program (SARP) III cohort, and examine in cross section the effects of age on those features. METHODS: SARP III is a National Institutes of Health/National Heart Lung Blood Institute multisite 3-year cohort study conducted to investigate mechanisms of severe asthma. The sample included 188 children (111 severe, 77 nonsevere) and 526 adults (313 severe, 213 nonsevere) characterized for demographic features, symptoms, health care utilization, lung function, and inflammatory markers compared by age and severity. RESULTS: Compared with children with nonsevere asthma, children with severe asthma had more symptoms and more historical exacerbations, but no difference in body weight, post-bronchodilator lung function, or inflammatory markers. After childhood, and increasing with age, the cohort had a higher proportion of women, less allergen sensitization, and overall fewer blood eosinophils. Enrollment of participants with severe asthma was highest in middle-aged adults, who were older, more obese, with greater airflow limitation and higher blood eosinophils, but less allergen sensitization than adults with nonsevere asthma. CONCLUSIONS: The phenotypic features of asthma differ by severity and with advancing age. With advancing age, patients with severe asthma are more obese, have greater airflow limitation, less allergen sensitization, and variable type 2 inflammation. Novel mechanisms besides type 2 inflammatory pathways may inform the severe asthma phenotype with advancing age.
Assuntos
Asma , Adolescente , Adulto , Fatores Etários , Idoso , Asma/tratamento farmacológico , Asma/imunologia , Asma/fisiopatologia , Broncodilatadores/uso terapêutico , Criança , Estudos de Coortes , Feminino , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/imunologia , Obesidade/fisiopatologia , Aceitação pelo Paciente de Cuidados de Saúde , Índice de Gravidade de Doença , Adulto JovemRESUMO
The presentation, evaluation, and management of chronic esophageal foreign bodies are not well described in pediatric patients. Many patients present with ill-defined respiratory symptoms, making diagnosis challenging. We report on a 2-year-old girl who presented with several months of worsening cough and wheezing unresponsive to medical management. She also had recent onset of feeding difficulty with certain consistencies. She underwent a joint bronchoscopy with the otolaryngology team. Bronchoscopy demonstrated severe tracheal narrowing and esophagoscopy showed severe inflammation. A chest computed tomography scan showed inflammation between the esophagus and trachea. Repeat esophagoscopy revealed an esophageal foreign body embedded into the anterior wall, which was removed via thoracotomy.
RESUMO
PURPOSE OF REVIEW: The review discusses what is known regarding airway molecular phenotypes in pediatric asthma, specifically biomarkers that have been studied and their relation to the various clinical phenotypes of asthma. RECENT FINDINGS: Pediatric asthma is a complex and heterogeneous disease that consists of several clinical phenotypes. There have been numerous studies investigating inflammatory markers that would increase our understanding of the underlying pathogenesis of asthma as well as facilitate the discovery of therapies for these patients. Some of these biomarkers, such as exhaled nitric oxide, exhaled breath condensate, urine leukotriene E4 and induced sputum are less invasive measures of inflammation than obtaining bronchoalveolar lavage fluid in children. Although recent data reveal that some of these measures may be helpful in classifying and managing pediatric asthma, further studies are critically needed before any of these biomarkers are able to be routinely used in clinical asthma care. SUMMARY: The search for noninvasive biomarkers to help elucidate specific underlying molecular phenotypes in pediatric asthma should be a continued priority as we work towards improved care and management of these children.
Assuntos
Asma/classificação , Mediadores da Inflamação , Inflamação/classificação , Pulmão/fisiopatologia , Adolescente , Asma/imunologia , Asma/fisiopatologia , Asma/terapia , Biomarcadores/sangue , Biomarcadores/metabolismo , Biomarcadores/urina , Criança , Pré-Escolar , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Inflamação/terapia , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/urina , Leucotrieno E4/urina , Pulmão/imunologia , Óxido Nítrico/metabolismo , Fenótipo , Escarro/imunologia , Escarro/metabolismoRESUMO
Allergic bronchopulmonary aspergillosis (ABPA) is caused by a dominant Th2 immune response to antigens derived from the opportunistic mold Aspergillus, most commonly Aspergillus fumigatus. It occurs in 4%-15% of patients with cystic fibrosis (CF); however, not all patients with CF infected with A. fumigatus develop ABPA. Therefore, we compared cohorts of A. fumigatus-colonized CF patients with and without ABPA to identify factors mediating tolerance versus sensitization. We found that the costimulatory molecule OX40 ligand (OX40L) was critical in driving Th2 responses to A. fumigatus in peripheral CD4+ T cells isolated from patients with ABPA. In contrast, CD4+ T cells from the non-ABPA cohort did not mount enhanced Th2 responses in vitro and contained a higher frequency of TGF-beta-expressing regulatory T cells. Heightened Th2 reactivity in the ABPA cohort correlated with lower mean serum vitamin D levels. Further, in vitro addition of 1,25 OH-vitamin D3 substantially reduced DC expression of OX40L and increased DC expression of TGF-beta. This in vitro treatment also resulted in increased Treg TGF-beta expression and reduced Th2 responses by CD4+ T cells from patients with ABPA. These data provide rationale for a therapeutic trial of vitamin D to prevent or treat ABPA in patients with CF.
Assuntos
Aspergilose Broncopulmonar Alérgica/imunologia , Aspergillus fumigatus/imunologia , Linfócitos T CD4-Positivos/imunologia , Colecalciferol/farmacologia , Fibrose Cística/imunologia , Células Th2/imunologia , Adulto , Aspergillus/imunologia , Feminino , Humanos , Masculino , Receptores OX40/metabolismo , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/imunologiaRESUMO
The innate immune functions of human airways include mucociliary clearance and antimicrobial peptide activity. Both functions may be affected by changes in epithelial ion transport. Interleukin-17A (IL-17A), which has a receptor at the basolateral membrane of airway epithelia, is a T cell cytokine that has been shown to increase mucus secretion and antimicrobial peptide production by human bronchial epithelial (HBE) cells. Furthermore, IL-17A levels are increased in sputum from patients during pulmonary exacerbations of cystic fibrosis. Therefore, we investigated the effects of IL-17A on basal, amiloride-sensitive, and forskolin-stimulated ion transport in mature, well-differentiated HBE cells. Exposure of HBE monolayers to IL-17A for 48 h induced a novel forskolin-stimulated bicarbonate secretion in addition to forskolin-stimulated chloride secretion and resulted in alkalinization of liquid on the mucosal surface of polarized cells. IL-17A-induced bicarbonate secretion was cystic fibrosis transmembrane conductance regulator (CFTR)-dependent, mucosal chloride-dependent, partially Na(+)-dependent, and sensitive to serosal, but not mucosal, stilbene inhibition. These data suggest that IL-17A modulates epithelial bicarbonate secretion and implicate a mechanism by which airway surface liquid pH changes may be abnormal in cystic fibrosis.
Assuntos
Bicarbonatos/metabolismo , Brônquios/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Interleucina-17/farmacologia , Amilorida/farmacologia , Transporte Biológico/efeitos dos fármacos , Brônquios/citologia , Brônquios/metabolismo , Células Cultivadas , Canais de Cloreto/antagonistas & inibidores , Canais de Cloreto/metabolismo , Cloretos/metabolismo , Colforsina/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Células Epiteliais/metabolismo , Bloqueadores do Canal de Sódio Epitelial , Canais Epiteliais de Sódio/metabolismo , Humanos , Microscopia de Fluorescência , Bloqueadores dos Canais de Sódio/farmacologiaRESUMO
Emerging evidence supports the concept that T helper type 17 (T(H)17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the T(H)17 lineage, and both were crucial for maintaining local control of the Gram-negative pulmonary pathogen, Klebsiella pneumoniae. Although both cytokines regulated CXC chemokines and granulocyte colony-stimulating factor production in the lung, only IL-22 increased lung epithelial cell proliferation and increased transepithelial resistance to injury. These data support the concept that the T(H)17 cell lineage and its effector molecules have evolved to effect host defense against extracellular pathogens at mucosal sites.
Assuntos
Imunidade nas Mucosas/imunologia , Interleucinas/imunologia , Infecções por Klebsiella/imunologia , Klebsiella pneumoniae/imunologia , Animais , Células Cultivadas , Quimiocinas/metabolismo , Fibrose Cística/imunologia , Fibrose Cística/patologia , Células Epiteliais/metabolismo , Humanos , Interleucina-17/imunologia , Interleucina-23/imunologia , Interleucinas/metabolismo , Klebsiella pneumoniae/metabolismo , Pulmão/metabolismo , Pulmão/microbiologia , Linfonodos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testes de Neutralização , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Mucosa Respiratória/citologia , Baço/microbiologia , Linfócitos T/imunologia , Regulação para Cima , Interleucina 22RESUMO
Interleukin (IL)-17A and IL-17F are produced by a novel class of effector alphabeta T cells called Th17 cells as well as gammadelta T cells. alphabeta IL-17-producing T cells are controlled by the transcription factor RORgammat and develop independent of GATA-3, T-bet, Stat 4, and Stat 6. Effector molecules produced by these cells include IL-17A, IL-17F, and IL-22. IL-17A and IL-17F bind to IL-17 receptor (IL-17R) and receptor signaling is critical for host defense against extracellular bacteria by regulating chemokine gradients for neutrophil emigration into infected tissue sites as well as via regulation of host granulopoiesis. Furthermore, it has recently been shown that IL-17 and IL-22 regulate the production of antimicrobial proteins in epithelium. Although Th17 cells are important in mucosal host defense, in the setting of retained antigenic stimulation, such as in the setting of asthma or chronic infection, such as in cystic fibrosis, or in the setting of autoimmunity, these cells can mediate immunopathology.
Assuntos
Imunidade Inata/fisiologia , Interleucina-17/fisiologia , Pneumopatias/imunologia , Autoimunidade/fisiologia , Linfócitos T CD4-Positivos/imunologia , Humanos , Pneumopatias/fisiopatologia , Receptores de Interleucina-17/fisiologiaRESUMO
Th17 cells are a new lineage of T-cells that are controlled by the transcription factor RORgammat and develop independent of GATA-3, T-bet, Stat 4 and Stat 6. Novel effector molecules produced by these cells include IL-17A, IL-17F, IL-22, and IL-26. IL-17RA binds IL-17A and IL-17F and is critical for host defense against extracellular planktonic bacteria by regulating chemokine gradients for neutrophil emigration into infected tissue sites as well as host granulopoiesis. Moreover, IL-17 and IL-22 regulate the production of antimicrobial proteins in mucosal epithelium. Although TGF-beta1 and IL-6 have been shown to be critical for development of Th17 cells from naive precursors, IL-23 is also important in regulating IL-17 release in mucosal tissues in response to infectious stimuli. Compared to Th1 cells, IL-23 and IL-17 show limited roles in controlling host defense against primary infections with intracellular bacteria such as Mycobacterium tuberculosis suggesting a predominate role of the Th17 lineage in host defense against extracellular pathogens. However, in the setting of chronic biofilm infections, as that occurs with cystic fibrosis or bronchiectasis, Th17 cells may be key contributors of tissue injury.
Assuntos
Citocinas/metabolismo , Imunidade nas Mucosas , Interleucina-17/metabolismo , Receptores de Interleucina-17/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Autoimunidade , Vacinas Bacterianas/imunologia , Citocinas/imunologia , Humanos , Imunidade Inata , Interleucina-17/imunologia , Interleucinas/imunologia , Interleucinas/metabolismo , Mucosa/imunologia , Receptores de Interleucina-17/imunologia , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
The proinflammatory cytokines IL-17A and IL-17F have a high degree of sequence similarity and share many biological properties. Both have been implicated as factors contributing to the progression of inflammatory and autoimmune diseases. Moreover, reagents that neutralize IL-17A significantly ameliorate disease severity in several mouse models of human disease. IL-17A mediates its effects through interaction with its cognate receptor, the IL-17 receptor (IL-17RA). We report here that the IL-17RA-related molecule, IL-17RC is the receptor for IL-17F. Notably, both IL-17A and IL-17F bind to IL-17RC with high affinity, leading us to suggest that a soluble form of this molecule may serve as an effective therapeutic antagonist of IL-17A and IL-17F. We generated a soluble form of IL-17RC and demonstrate that it effectively blocks binding of both IL-17A and IL-17F, and that it inhibits signaling in response to these cytokines. Collectively, our work indicates that IL-17RC functions as a receptor for both IL-17A and IL-17F and that a soluble version of this protein should be an effective antagonist of IL-17A and IL-17F mediated inflammatory diseases.