RESUMEN
CCL18 is both a constitutively expressed and an inducible chemokine, whose role in the inflammatory reaction is poorly known. The aim of this study was to evaluate whether CCL18 has the capacity to attract human T cells with a regulatory function (regulatory T cells [Treg]). Results from chemotaxis assays performed on different types of Treg showed that CD4(+)CD25(+)CD127(low) cells, but neither T regulatory type 1 clones nor Treg differentiated in vitro with anti-CD3/CD46 mAbs, were recruited by CCL18 in a dose-dependent manner. CCL18-recruited memory CD4(+) T cells were enriched in CD25(high), CD25(+)CD127(low), latency-associated peptide/TGF-ß1, and CCR4-expressing T cells, whereas there was no enrichment in Foxp3(+) cells as compared with controls. Stimulated CCL18-recruited memory T cells produced significantly increased amounts of the regulatory cytokines IL-10 and TGF-ß1, as well as IL-4, but not IFN-γ and IL-17. Cell surface CCL18 binding was found predominantly on IL-10(+) (26.3 ± 5.8%) and on a few latency-associated peptide/TGF-ß1(+) (18.1 ± 1.9%) and IL-4(+) (14.5 ± 2.9%) memory T cells. In an in vivo model of SCID mice grafted with human skin and reconstituted with autologous PBMCs, the intradermal injection of CCL18 led to the cutaneous recruitment of CD4(+), CD25(+), and IL-10(+) cells, but not Foxp3(+) cells. Furthermore, CCL18-recruited memory T cells inhibited the proliferation of CD4(+)CD25(-) effector T cells through an IL-10-dependent mechanism. These data suggest that CCL18 may contribute to maintaining tolerance and/or suppressing deleterious inflammation by attracting memory Tregs into tissues, particularly in the lung, where it is highly and constitutively expressed.
Asunto(s)
Movimiento Celular/inmunología , Quimiocinas CC/fisiología , Pulmón/citología , Pulmón/inmunología , Linfocitos T Reguladores/inmunología , Animales , Células Cultivadas , Quimiotaxis de Leucocito/inmunología , Células Clonales , Humanos , Interleucina-10/biosíntesis , Pulmón/metabolismo , Ratones , Ratones SCID , Trasplante de Piel/inmunología , Trasplante de Piel/patología , Linfocitos T Reguladores/metabolismoRESUMEN
The aim of this study was to evaluate the nonchemotactic function of CCL18 on human dendritic cells (DCs). In different protocols of DC differentiation, CCL18 was highly produced, suggesting that it may constitute a mandatory mediator of the differentiation process. Differentiation of monocytes from healthy subjects in the presence of granulocyte-macrophage colony-stimulating factor and CCL18 led to the development of DCs with a semimature phenotype, with intermediate levels of costimulatory and MHC class II molecules, increased CCR7 expression, which induced, in coculture with allogenic naive T cells, an increase in IL-10 production. The generated T cells were able to suppress the proliferation of effector CD4(+)CD25(-) cells, through a cytokine-dependent mechanism, and exhibited characteristics of type 1 T regulatory cells. The generation of tolerogenic DCs by CCL18 was dependent on the production of indoleamine 2,3-dioxigenase through an interleukin-10-mediated mechanism. Surprisingly, when DCs originated from allergic patients, the tolerogenic effect of CCL18 was lost in relation with a decreased binding of CCL18 to its putative receptor. This study is the first to define a chemokine able to generate tolerogenic DCs. However, this function was absent in allergic donors and may participate to the decreased tolerance observed in allergic diseases.
Asunto(s)
Presentación de Antígeno/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Quimiocinas CC/farmacología , Células Dendríticas/efectos de los fármacos , Tolerancia Inmunológica/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Presentación de Antígeno/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/fisiología , Diferenciación Celular/genética , Células Cultivadas , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Quimiocinas CC/fisiología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/fisiología , Factores de Transcripción Forkhead/metabolismo , Salud , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Interleucina-10/metabolismo , Cultivo Primario de Células , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
BACKGROUND: The predictive factors for treatment response in patients with severe chronic obstructive pulmonary disease (COPD) are unknown. We investigated predictive factors for response to fluticasone propionate/salmeterol (FSC) in severe COPD patients. METHODS: This prospective, open-label, non-comparative study included 921 adult patients with severe COPD (baseline forced expiratory volume in 1 s (FEV(1)) <50% of predicted), a history of repeated exacerbations, and symptoms despite bronchodilator treatment. FSC (500 µg/50 µg) was delivered via an inhaler, twice a day, for 12 weeks. The primary efficacy endpoint was the response rate for inspiratory capacity (IC), FEV(1), or quality of life (QoL), assessed with the Saint George's respiratory questionnaire, at week 6 and week 12. RESULTS: The overall response rate to FSC at 6 and 12 weeks was 79%. The corresponding rates for FEV(1), IC, and QoL were 38%, 55%, and 62%, respectively. More than 40% of patients showed a response for IC and/or QoL without being responders for FEV(1.) Overall lung function and QoL were improved. FSC was well tolerated with a safety profile consistent with that observed previously. CONCLUSION: Nearly 80% of patients responded to FSC treatment in this real-life study. Improvements in IC and QoL at 12 weeks revealed a clinically relevant response in patients with no improvement in FEV(1). IC reversibility to salbutamol before treatment might represent, better than FEV1, a prognostic factor of response to FSC in severe COPD. Moreover these tests are easy to perform routinely and in large numbers of patients.
Asunto(s)
Albuterol/análogos & derivados , Androstadienos/uso terapéutico , Broncodilatadores/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Anciano , Albuterol/uso terapéutico , Combinación de Medicamentos , Quimioterapia Combinada , Femenino , Combinación Fluticasona-Salmeterol , Volumen Espiratorio Forzado/efectos de los fármacos , Volumen Espiratorio Forzado/fisiología , Francia , Humanos , Masculino , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Calidad de Vida , Pruebas de Función Respiratoria , Resultado del TratamientoRESUMEN
Allergic bronchopulmonary aspergillosis (ABPA) results from a twofold mechanism: Th2-like hypersensitivity reaction and bronchial colonization by Aspergillus fumigatus. This relatively rare disease occurs in immunocompetent patients in two very different situations: refractory asthma and cystic fibrosis. Diagnosis in asthma patients is relatively easy; it is based on the association of several criteria: clinical (recurrent exacerbations despite adequate therapy and a positive A. fumigatus skin prick-test), laboratory (inconsistent blood eosinophilia, high serum levels of total IgE, presence of A. fumigatus-specific IgE and IgG) and radiological (mainly central bronchiectasis, sometimes transitory pulmonary infiltrates). Diagnosis is more difficult in patients with cystic fibrosis because of the similarity of their various criteria. Long-term prognosis is good in the early stages of the illness, although the natural history and course of the disease are not fully understood. Early diagnosis and active screening for exacerbations are recommended to prevent bronchiectasis and progression to end-stage lung disease. Two drugs have shown their efficacy in treating ABPA: corticosteroids and itraconazole. They are recommended in acute exacerbations and should not be used as long-term therapy, except in corticosteroid-dependent asthma and in some cases of cystic fibrosis.
Asunto(s)
Aspergilosis Broncopulmonar Alérgica/complicaciones , Aspergilosis Broncopulmonar Alérgica/diagnóstico , Asma/complicaciones , Aspergilosis Broncopulmonar Alérgica/tratamiento farmacológico , Asma/tratamiento farmacológico , Humanos , Insuficiencia del TratamientoRESUMEN
The development of the IgE-dependent inflammatory reaction is made of 3 successives phases. The initiation period is related to dendritic cells, present everywhere in peripheral tissues, able after maturation to migrate to the draining lymph-node and to present immunogenic peptides to the naïve T lymphocyte. After this first step of sensitization, in case of a new contact with allergens, the inflammatory phase is rapidly developing: mast cell activation, then massive influx of eosinophils, neutrophils and mononuclear phagocytes, all phenomenas under the control of different T-lymphocyte subpopulations: T-CD4+ cells with a pro-allergic Th2 profile but also newly identified T regulatory cells (Tr-1, T CD4+ CD25+). The third phase concerns the repair process or more often in case of repeated allergenic aggressions, a remodelling process such as observed in patients with severe allergic asthma. All these data have lead to reconsider our understanding of the allergic reaction. In fact allergy seems to result from an aberrant immune response to the environmental allergens, while the non-atopic subject, exposed to the same allergens will develop a natural tolerance.
Asunto(s)
Hipersensibilidad Inmediata/inmunología , Inflamación/inmunología , Células Dendríticas/inmunología , Humanos , Hipersensibilidad Inmediata/metabolismo , Inflamación/metabolismo , Macrófagos/metabolismo , Mastocitos/metabolismo , Monocitos/metabolismo , Neutrófilos/metabolismoRESUMEN
INTRODUCTION: Pyoderma gangrenosum is an uncommon ulcerative cutaneous disorder. Extracutaneous localizations are rare. Respiratory system involvement has been described in a few cases, but the pulmonary features reported were highly variable. CASE: We report two cases of patients with Pyoderma gangrenosum combining cutaneous and pulmonary manifestations. One case presented multiple nodular lesions, some with cavitation. The underlying disease was varicella-zoster virus infection. The second presented pneumonitis with bronchiolar micronodules. DISCUSSION: Few cases have reported Pyoderma gangrenosum with pulmonary involvement, which appears to be manifested mainly as nodules or interstitial lung disease. The principal differential diagnosis is Wegener's granulomatosis.
Asunto(s)
Enfermedades Pulmonares/etiología , Piodermia Gangrenosa/complicaciones , Corticoesteroides/administración & dosificación , Corticoesteroides/uso terapéutico , Adulto , Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Biopsia , Diagnóstico Diferencial , Femenino , Granulomatosis con Poliangitis/diagnóstico , Humanos , Pulmón/patología , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/diagnóstico por imagen , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/patología , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/patología , Masculino , Neumonía/diagnóstico , Neumonía/diagnóstico por imagen , Neumonía/tratamiento farmacológico , Neumonía/etiología , Neumonía/patología , Prednisolona/administración & dosificación , Prednisolona/uso terapéutico , Fibrosis Pulmonar/diagnóstico , Fibrosis Pulmonar/diagnóstico por imagen , Fibrosis Pulmonar/etiología , Piodermia Gangrenosa/diagnóstico , Piodermia Gangrenosa/tratamiento farmacológico , Piodermia Gangrenosa/patología , Radiografía Torácica , Piel/patología , Nódulo Pulmonar Solitario/diagnóstico , Nódulo Pulmonar Solitario/diagnóstico por imagen , Nódulo Pulmonar Solitario/tratamiento farmacológico , Nódulo Pulmonar Solitario/etiología , Nódulo Pulmonar Solitario/patología , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Lactic acid bacteria (LAB) are Gram positive nonpathogenic commensal organisms present in human gastrointestinal tract. In vivo, LAB are separated from antigen-presenting cells such as dendritic cells (DC) by the intestinal epithelial barrier. In this study, the impact of one LAB strain (Lactobacillus casei ATCC393) on human monocyte-derived DC from allergic and healthy donors was assessed by using a polarized epithelium model. Confocal and flow cytometer analyses showed that immature DC efficiently captured FITC-labelled L. casei through the epithelial layer. After interaction with L. casei, DC acquired a partial maturation status (i.e., CD86 and CD54 increase) and increased their interleukin (IL)-10 and IL-12 production. Interestingly, after activation by L. casei in the presence of experimental epithelium, DC from allergic patients instructed autologous naïve CD4(+) T cells to produce more interferon-gamma than without the epithelium. Thus by modulating human DC reactivity, LAB and intestinal epithelium might modify T cell immune response and regulate the development of allergic reaction.
RESUMEN
Mucosal immune response depends on the surveillance network established by dendritic cells (DC), APC localized within the epithelium. Bronchial epithelial cells (BEC) play a pivotal role both in the host defense and in the pathogenesis of inflammatory airway disorders. We previously showed that the outer membrane protein A from Klebsiella pneumoniae (KpOmpA), a pathogen-associated molecular pattern (PAMP) derived from Klebsiella pneumoniae, activates BEC. In this study, we evaluated the consequences of this activation on DC traffic and functions. KpOmpA significantly increased the production of CCL2, CCL5, CXCL10, and CCL20 by BEC. Stimulation of BEC increased their chemotactic activity for monocyte-derived DC (MDDC) precursors, through CCL5 and CXCL10 secretion. BEC/MDDC precursor coculture leads to an ICAM-1-dependent accelerated differentiation and enhanced maturation of MDDC. BEC/DC interactions did not affect the capacity of DC to induce T cell proliferation. However, DC preincubated with BEC increased significantly the IL-10 production by autologous T cells. Basolateral and intraepithelial DC differently enhance IL-4 and/or IL-10 synthesis according to the condition of stimulation. In vivo, intranasal injections of KpOmpA into BALB/c mice induced the recruitment of CD11c(+) and I-A(d+) myeloid DC associated with bronchial epithelium activation as evidenced by CCL20 expression. These data show that KpOmpA-exposed BEC participate in the homeostasis of myeloid DC network, and regulate the induction of local immune response.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/inmunología , Bronquios/inmunología , Células Dendríticas/inmunología , Administración Intranasal , Animales , Proteínas de la Membrana Bacteriana Externa/administración & dosificación , Bronquios/citología , Bronquios/efectos de los fármacos , Antígeno CD11c/análisis , Movimiento Celular , Quimiocinas/metabolismo , Técnicas de Cocultivo , Citocinas/metabolismo , Epitelio/efectos de los fármacos , Epitelio/inmunología , Antígenos de Histocompatibilidad Clase II/análisis , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Ratones , Ratones Endogámicos BALB C , Células Mieloides/inmunología , Linfocitos T/inmunologíaAsunto(s)
Antiasmáticos/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Asma/tratamiento farmacológico , Glucocorticoides/efectos adversos , Androstadienos/uso terapéutico , Antiasmáticos/uso terapéutico , Anticuerpos Antiidiotipos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Quimioterapia Combinada , Femenino , Fluticasona , Glucocorticoides/administración & dosificación , Humanos , Masculino , OmalizumabRESUMEN
PURPOSE: We evaluated the expression of endocan, a soluble lung- and kidney-selective endothelial cell-specific dermatan sulfate proteoglycan, in non-small cell lung tumors compared with normal lung and studied the significance of high levels of circulating endocan in patients with non-small cell lung cancer. MATERIAL AND METHODS: Endocan and vascular endothelial growth factor mRNA expression were evaluated by semiquantitative PCR in tumoral and nontumoral lung tissue samples from a first series of 24 patients submitted to curative surgery. Relationships between survival, time to tumor progression, and serum levels of endocan were evaluated in a second series of 30 previously untreated patients addressed for staging. RESULTS: In non-small cell lung cancers, endocan mRNA was overexpressed compared with control lung. Immunohistochemistry shows that endocan was expressed only by tumor endothelium in all cases, especially in the periphery of the tumors, with no differences between adenocarcinoma and squamous cell carcinoma. Endocan and vascular endothelial growth factor mRNA expression was positively correlated in lung tumors. Serum endocan levels, as well as tumor, node, and metastasis status, were correlated with both survival and time to tumor progression. However, endocan serum level was not an independent prognostic factor due to its correlation with the presence of metastasis. CONCLUSION: Endocan is overexpressed in non-small cell lung tumors compared with healthy lung and probably represents a response of tumoral endothelium to proangiogenic growth factor stimulation. Circulating levels of endocan might reflect tumor angiogenic stimulation and present prognostic significance.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Perfilación de la Expresión Génica , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Proteoglicanos/genética , Anciano , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Pronóstico , Proteoglicanos/biosíntesis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Tasa de Supervivencia , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
The polarized response of T helper-2 (Th2) lymphocytes to an allergen is considered to be the main cause of the pathogenesis of asthma. In this study, we asked a question whether M. bovis BCG mycobacteria which are known for the preferential stimulation of T helper-1 (Th1) immunity, diminish the effector functions of Th2 cells from allergic patients upon stimulation with a common house dust mite Der p-1 allergen. Our results allow a positive answer to this question. We demonstrate that BCG modulates the dendritic cell-dependent allergen presentation process and switches naive T lymphocytes towards an anti-allergic Th1 profile.
Asunto(s)
Antígenos Dermatofagoides/inmunología , Vacuna BCG/inmunología , Pyroglyphidae/inmunología , Linfocitos T/inmunología , Animales , Proteínas de Artrópodos , Técnicas de Cocultivo/métodos , Cisteína Endopeptidasas , Células Dendríticas/inmunología , Humanos , Hipersensibilidad/inmunología , Interferón gamma/inmunología , Interleucina-4/inmunología , Interleucina-5/inmunología , Estadísticas no Paramétricas , Linfocitos T/metabolismo , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
BACKGROUND: The prevalence of allergic diseases has increased in the last 20 years, and a number of studies have shown that diesel exhaust particle-associated polyaromatic hydrocarbons can exacerbate the allergic reaction. Much less is known about their potential capacity to generate a T(H)2-type allergic reaction in nonatopic subjects. OBJECTIVE: The aim of this study was to test the hypothesis that diesel exhaust exposure might favor, in nonatopic donors, T(H)2-type cell recruitment, either through increased production of T(H)2-attracting chemokines or decreased production of T(H)1-attracting chemokines. METHODS: PBMCs from nonatopic donors were incubated with diesel exhaust particle-polyaromatic hydrocarbons, and the supernatants were evaluated for the presence of pro-T(H)1 chemokines (IFN-gamma-induced protein 10 and monokine Induced by IFN-gamma) and pro-T(H)2 chemokines (macrophage-derived chemokine, I-309, and pulmonary and activation-regulated chemokine) by means of ELISA. The functional effect was evaluated by using chemotaxis assays with polarized T(H)1 and T(H)2 cells. RESULTS: Diesel exhaust exposure of PBMCs from nonatopic donors induced a late increase after 48 hours in pulmonary and activation-regulated chemokine mediated by IL-13 and a decrease in IFN-gamma-induced protein 10 levels selectively at both the protein and mRNA levels. The functional effect of these chemokine variations resulted in an enhanced chemotaxis of T(H)2, but not T(H)1, cells. CONCLUSION: These findings show that diesel exhaust exposure might be involved in the genesis of allergic diseases by differentially regulating chemokines favoring the recruitment of T(H)2 cells in nonatopic subjects. CLINICAL IMPLICATIONS: Environmental factors, especially air pollution, might favor the genesis of allergic diseases.
Asunto(s)
Hipersensibilidad/etiología , Hidrocarburos Policíclicos Aromáticos/toxicidad , Células Th2/efectos de los fármacos , Emisiones de Vehículos/toxicidad , Adulto , Células Cultivadas , Quimiocinas/biosíntesis , Quimiotaxis de Leucocito/efectos de los fármacos , Humanos , Hipersensibilidad/inmunología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Persona de Mediana Edad , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th2/inmunologíaRESUMEN
CCR5 is one of the major inflammatory chemokine receptors with potential therapeutical applications in humans. However, the redundancy of chemokines and their receptors, and the species specificity of chemokine receptor antagonists pose challenges to understanding of the role they play in pharmacological situations. To address this question, we used a humanized severe combined immunodeficient mouse model grafted with human skin and autologous leukocytes, and evaluated the effect of a blocking antibody against human CCR5, on CCL5-induced cutaneous leukocyte recruitment in vivo. At baseline, CCL5 induced a significant recruitment of T cells mainly of the memory phenotype, of monocytes/macrophages, eosinophils, and IFN-gamma(+) but not IL-4(+) and IL-5(+) cells. In vivo, anti-CCR5 antibody was able to almost completely inhibit the recruitment of monocytes/macrophages and T-helper (Th)1-type cells to inhibit partially the attraction of memory T cells, but had no effect on eosinophil infiltration, although all these cell types express other CCL5 binding chemokine receptors than CCR5. These results indicate that the in vivo environment regulates target cell specificity of CCL5 leading to differential cell recruitment, suggesting that antagonizing CCR5 receptor may be of therapeutic value in diseases such as acquired immuno deficiency syndrome, where CCL5/CCR5, monocytes, and Th1-type cells play a predominant role.
Asunto(s)
Movimiento Celular/inmunología , Quimiocinas CC/inmunología , Inmunoterapia/métodos , Receptores CCR5/inmunología , Trasplante de Piel/inmunología , Células TH1/inmunología , Animales , Anticuerpos/farmacología , Quimiocina CCL5 , Modelos Animales de Enfermedad , Eosinófilos/citología , Eosinófilos/inmunología , Humanos , Memoria Inmunológica , Interferón gamma/metabolismo , Macrófagos/citología , Macrófagos/inmunología , Ratones , Ratones SCID , Monocitos/citología , Monocitos/inmunología , Mutación , Receptores CCR5/genética , Células TH1/citología , Células TH1/metabolismo , Células Th2/citología , Células Th2/inmunología , Trasplante Heterólogo/inmunologíaRESUMEN
Allergic asthma is associated with a pulmonary recruitment of Th type 2 cells, basophils, and eosinophils, mainly linked to chemokine production. CCL18 is a chemokine preferentially expressed in the lung, secreted by APCs, induced by Th2-type cytokines, and only present in humans. Therefore, CCL18 may be involved in allergic asthma. PBMC from asthmatics allergic to house dust mite cultured in the presence of Dermatophagoides pteronyssinus 1 (Der p 1) allergen secreted CCL18, 48 and 72 h after stimulation, whereas those from healthy donors did not. Part of CCL18 was directly derived from Der p 1-stimulated plasmacytoid dendritic cells, whereas the other part was linked to monocyte activation by IL-4 and IL-13 produced by Der p 1-stimulated T cells. In bronchoalveolar lavages from untreated asthmatic allergic patients, CCL18 was highly increased compared with controls. Functionally, CCL18 preferentially attracted in vitro-polarized Th2 cells and basophils, but not eosinophils and Th1 cells, and induced basophil histamine and intracellular calcium release. These data show a new function for CCL18, i.e., the recruitment of Th2 cells and basophils, and suggest that CCL18 may play a predominant role in allergic asthma.
Asunto(s)
Alérgenos/inmunología , Asma/inmunología , Asma/metabolismo , Quimiocinas CC/fisiología , Animales , Antígenos Dermatofagoides/inmunología , Proteínas de Artrópodos , Basófilos/metabolismo , Células Cultivadas , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Cisteína Endopeptidasas , Humanos , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Pyroglyphidae/inmunología , ARN Mensajero/biosíntesis , ARN Mensajero/metabolismo , Células Th2/metabolismo , Regulación hacia Arriba/inmunologíaRESUMEN
BACKGROUND: Diagnosis of pulmonary embolism (PE) is difficult in patients with chronic obstructive pulmonary disease (COPD) and exacerbation. OBJECTIVE: To evaluate PE in patients with COPD and exacerbation of unknown origin and explore factors associated with PE. DESIGN: Prospective cohort study. SETTING: University-affiliated hospital in France. PATIENTS: 211 consecutive patients, all current or former smokers with COPD, who were admitted to the hospital for severe exacerbation of unknown origin and did not require invasive mechanical ventilation. MEASUREMENTS: Spiral computed tomography angiography (CTA) and ultrasonography within 48 hours of admission and assessment of the Geneva score. Patients were classified as PE positive (positive results on CTA or negative results on CTA and positive results on ultrasonography) or PE negative (negative results on CTA and negative results on ultrasonography or negative results on CTA and no recurrence of PE at follow-up 3 months later). RESULTS: 49 of 197 patients (25% [95% CI, 19% to 32%]) met the diagnostic criteria for PE. Clinical factors associated with PE were previous thromboembolic disease (risk ratio, 2.43 [CI, 1.49 to 3.94]), malignant disease (risk ratio, 1.82 [CI, 1.13 to 2.92]), and decrease in PaCO2 of at least 5 mm Hg (risk ratio, 2.10 [CI, 1.23 to 3.58]). A total of 9.2% (CI, 4.7% to 15.9%) of patients with a low-probability Geneva score received a diagnosis of PE. An exploratory analysis suggested that substituting malignant disease for recent surgery in the Geneva score might improve its performance in excluding PE in this sample who were more likely to have malignant disease than to have had recent surgery. However, this improvement seems insufficient to exclude PE with enough certainty to withhold therapy for low-risk patients on the basis of the modified score. LIMITATIONS: This study was done in only 1 center. Patients with COPD requiring invasive mechanical ventilation in the intensive care unit were not included. The upper bound of the 95% CI for the low probability of PE according to the Geneva score is too high to rule out PE. The classification of COPD exacerbation of unknown origin was based on the clinician's assessment, not on a standard evaluation for all patients. CONCLUSION: This study showed a 25% prevalence of PE in patients with COPD hospitalized for severe exacerbation of unknown origin. Three clinical factors are associated with the increased risk for PE. The Geneva score and the modified Geneva score should be prospectively evaluated in patients with COPD.
Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Embolia Pulmonar/epidemiología , Anciano , Angiografía/métodos , Dióxido de Carbono/sangre , Humanos , Pierna/diagnóstico por imagen , Persona de Mediana Edad , Neoplasias/complicaciones , Prevalencia , Estudios Prospectivos , Embolia Pulmonar/diagnóstico por imagen , Factores de Riesgo , Tromboembolia/complicaciones , Tomografía Computarizada Espiral , Ultrasonografía Doppler en ColorRESUMEN
Epithelia represent a major portal of entry for pathogen microorganisms and allergens and are equipped with innate and adaptive immunity for their protection. Pattern recognition receptors (PRR), including Toll-Like Receptors (TLR), recognize pathogen-associated molecular patterns (PAMP) shared by numerous microorganisms. TLR engagement is involved in innate immunity but also participates in the control of the adaptive immune response, which may be involved in the pathophysiology of allergic diseases like asthma. Experimental studies have largely demonstrated the implication of TLR in both development and control of the allergic reaction. Dendritic cells (DC), which play a key role in these processes, are a privileged target for PAMP. During the allergic reaction, TLR engagement on DC directs the polarization of the T cell response and, while TLR2 and TLR4 may favour both Th1 and Th2 responses, TLR9 induces the development of regulatory T cells.
Asunto(s)
Asma/inmunología , Células Dendríticas/inmunología , Hipersensibilidad/inmunología , Receptores Toll-Like/inmunología , Asma/fisiopatología , Biomarcadores/análisis , Femenino , Humanos , Hipersensibilidad/fisiopatología , Masculino , Pronóstico , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Receptores Toll-Like/análisisRESUMEN
OBJECTIVES: a) To evaluate in septic patients the blood levels of endocan, a circulating proteoglycan, which regulates leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interactions in vitro; b) to determine whether endocan could be used as a diagnostic and prognostic marker in sepsis in the intensive care unit; and c) to study kinetics of endocan secretion by endothelial cells in vitro after stimulation by soluble mediators involved in sepsis. DESIGN: Prospective observational study. SETTING: Intensive care unit of the University Hospitals of Lille, France, and Geneva, Switzerland. PATIENTS: All patients admitted to the intensive care unit over a 6-month period with clinical evidence of severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In vitro, we showed a sustained endocan secretion by endothelial cells after stimulation by lipopolysaccharide and tumor necrosis factor-alpha. Circulating levels of endocan measured in 63 patients admitted to the intensive care unit with sepsis were significantly elevated compared with 20 healthy donors and seven patients with systemic inflammatory response syndrome: 2.71 +/- 4.88 ng/mL vs. 0.77 +/- 0.44 ng/mL vs. 0.68 +/- 1.03 ng/mL (median +/- interquartile range, p < .001). Endocan levels were higher in patients with septic shock (6.11 +/- 12.99 ng/mL, n = 22) than in patients with severe sepsis (1.97 +/- 7.8 ng/mL, n = 12) or sepsis (1.95 +/- 1.63 ng/mL, n = 29). Measurement of endocan at intensive care unit admission revealed higher levels in nonsurvivors (n = 12) than in patients still alive 10 days later (n = 51, 6.98 +/- 13.8 vs. 2.45 +/- 4.09, p < .01). CONCLUSIONS: These results suggest that in septic patients, endocan blood level is related to the severity of illness and the outcome of the patient and may represent a novel endothelial cell dysfunction marker.
Asunto(s)
Proteínas de Neoplasias/sangre , Proteoglicanos/sangre , Sepsis/sangre , Choque Séptico/sangre , Biomarcadores , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Sepsis/clasificación , Sepsis/mortalidad , Índice de Severidad de la Enfermedad , Choque Séptico/clasificación , Choque Séptico/mortalidadRESUMEN
BACKGROUND: Lactic acid bacteria (LAB) are suggested to play a regulatory role in the development of allergic reactions. However, their potential effects on dendritic cells (DCs) directing the immune polarization remain unclear. OBJECTIVE: The immunologic effect of Lactobacillus plantarum NCIMB 8826 (LAB1) on monocyte-derived dendritic cells (MD-DCs) from patients allergic to house dust mite was evaluated. METHODS: MD-DCs were stimulated for 24 hours with the related allergen Der p 1 in the presence or absence of LAB1. Cell-surface markers were assessed by means of FACS analysis, and the key polarizing cytokines IL-12 and IL-10 were quantified. The subsequent regulatory effect of pulsed MD-DCs on naive or memory T cells was evaluated by determining the T-cell cytokine profile. RESULTS: LAB1 induced the maturation of MD-DCs, even if pulsed with Der p 1. Interestingly, after incubation with LAB1 and Der p 1, MD-DCs produced higher amounts of IL-12 than Der p 1-pulsed DCs. Indeed, the T H 2 cytokine (IL-4 and IL-5) production observed when naive or memory autologous T cells were cocultured with Der p 1-pulsed MD-DCs was highly reduced in the presence of LAB1. Finally, in contrast to naive or memory T cells exposed once to Der p 1-pulsed DCs, T cells stimulated by MD-DCs pulsed with Der p 1 and LAB1 failed to produce T H 2 cytokines in response to a new stimulation with Der p 1-pulsed DCs. CONCLUSION: Thus in the presence of LAB1, MD-DCs from allergic patients tend to reorientate the T-cell response toward a beneficial T H 1 profile.
Asunto(s)
Antígenos Dermatofagoides/inmunología , Diferenciación Celular/inmunología , Células Dendríticas/inmunología , Células Dendríticas/microbiología , Lactobacillus plantarum/inmunología , Animales , Proteínas de Artrópodos , Cisteína Endopeptidasas , Citometría de Flujo , Humanos , Interleucina-10/biosíntesis , Interleucina-12/biosíntesis , Ácido Láctico , Activación de Linfocitos , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Airway dendritic cells (DCs) are crucial for allergen-induced sensitization and inflammation in allergic asthma. After allergen challenge, an increased number of DCs is observed in airway epithelium from patients with allergy. OBJECTIVE: Because Der p 1, a cysteine protease allergen from Dermatophagoides pteronyssinus , induces chemokine production by bronchial epithelial cells (BECs), the purpose of this investigation was to evaluate the capacity of BEC exposed to Der p 1 to recruit DCs. METHODS: Chemotactic activity of BEAS-2B, a bronchial epithelial cell line, and BECs from nonatopic controls and patients with allergic asthma was evaluated on the migration of precursors, immature and mature monocyte-derived DCs (MDDCs), and CD34 + -derived Langerhans cells (LCs). RESULTS: C-C chemokine ligand (CCL)-2, CCL5, and C-X-C chemokine ligand 10 production by BEAS-2B and BEC was increased after Der p 1 exposure, whereas the proenzyme proDer p 1 devoid of enzymatic activity had no effect. Der p 1 stimulation of BEAS-2B and BEC from both groups increased significantly the recruitment of MDDC precursors, depending on CCL2, CCL5, and C-X-C chemokine ligand 10 production. In a reconstituted polarized epithelium, apical application of Der p 1 enhanced MDDC precursor migration into the epithelial layer. Moreover, Der p 1 stimulation of BEC from patients with asthma but not from controls increased the migration of LC precursors, mainly dependent on CCL20 secretion. No migration of immature and mature DCs was observed. CONCLUSION: These data confirmed that BECs participate in the homeostasis of the DC network present within the bronchial epithelium through the secretion of chemokines. In allergic asthma, upregulation of CCL20 production induced LC recruitment, the role of which remains to be determined.