RESUMEN
Background: Eosinophils have a double-edged role in the human body, being essential in important physiologic functions but whose presence is conspicuous in a variety of diseases characterized by a T2 inflammation phenotype. Eosinophils are exquisitely sensitive to corticosteroids, and the latter have, until recently, represented the cornerstone of treatment of eosinophilic diseases. However, most patients remain dependent on oral corticosteroids, with a notable adverse effect burden and experience a chronic relapsing disease that leads to high morbidity and mortality. Treatment prospects have changed with the advent of biologic drugs that target the eosinotropic cytokine interleukin (IL) 5 or its receptor. The success of the latter drugs in severe eosinophilic asthma has paved the way for their use in other, rarer, eosinophilic lung diseases. Recently, mepolizumab, a humanized monoclonal antibody that works against IL-5, was approved for the add-on treatment of relapsing-remitting or refractory eosinophilic granulomatosis with polyangiitis (EGPA) in patients ages ≥ 6 years. Benralizumab, a humanized antibody that binds to the α portion of the IL-5 receptor, is also being tested for its efficacy in EGPA in two clinical trials, after a growing number of case reports and case series supported its use as a steroid-sparing agent in the treatment of EGPA. Methods: In this review, we summarized the scientific literature evaluating the efficacy of benralizumab treatment in patients afflicted with rare primary eosinophilic lung diseases. Results: The literature we found, largely case reports, reported that the use of benralizumab in EGPA, chronic eosinophilic pneumonia (CEP) and allergic bronchopulmonary aspergillosis (ABPA) often led to a depletion of eosinophils, less exacerbations and a decreased systemic corticosteroid burden. No adverse effects were reported. Conclusion: Benralizumab has a prospective role in the treatment of rare eosinophilic lung diseases, which needs to be further elucidated in randomized controlled trials.
Asunto(s)
Asma , Síndrome de Churg-Strauss , Eosinofilia , Granulomatosis con Poliangitis , Humanos , Niño , Síndrome de Churg-Strauss/metabolismo , Granulomatosis con Poliangitis/metabolismo , Granulomatosis con Poliangitis/terapia , Eosinofilia/tratamiento farmacológico , Eosinófilos , Asma/tratamiento farmacológico , Corticoesteroides/uso terapéuticoRESUMEN
Galectin-10 is a member of the lectin family and one of the most abundant cytoplasmic proteins in human eosinophils. Except for some myeloid leukemia cells, basophils, and minor T cell populations, galectin-10 is exclusively present in eosinophils in the human body. Galectin-10 forms Charcot-Leyden crystals, which are observed in various eosinophilic diseases. Accumulating studies have indicated that galectin-10 acts as a new biomarker for disease activity, diagnosis, and treatment effectiveness in asthma, eosinophilic esophagitis, rhinitis, sinusitis, atopic dermatitis, and eosinophilic granulomatosis with polyangiitis. The extracellular release of galectin-10 is not mediated through conventional secretory processes (piecemeal degranulation or exocytosis), but rather by extracellular trap cell death (ETosis), which is an active cell death program. Eosinophils undergoing ETosis rapidly disintegrate their plasma membranes to release the majority of galectin-10. Therefore, elevated galectin-10 levels in serum and tissue suggest a high degree of eosinophil ETosis. To date, several studies have shown that galectin-10/Charcot-Leyden crystals are more than just markers for eosinophilic inflammation, but play functional roles in immunity. In this review, we focus on the close relationship between eosinophils and galectin-10, highlighting this protein as a potential new biomarker in eosinophilic diseases.
Asunto(s)
Síndrome de Churg-Strauss , Granulomatosis con Poliangitis , Humanos , Síndrome de Churg-Strauss/metabolismo , Granulomatosis con Poliangitis/metabolismo , Eosinófilos/metabolismo , Biomarcadores/metabolismo , Galectinas/metabolismoAsunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/metabolismo , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/fisiopatología , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Síndrome de Churg-Strauss/tratamiento farmacológico , Síndrome de Churg-Strauss/metabolismo , Síndrome de Churg-Strauss/fisiopatología , Femenino , Granulomatosis con Poliangitis/tratamiento farmacológico , Granulomatosis con Poliangitis/metabolismo , Granulomatosis con Poliangitis/fisiopatología , Humanos , Masculino , Poliangitis Microscópica/tratamiento farmacológico , Poliangitis Microscópica/metabolismo , Poliangitis Microscópica/fisiopatología , Persona de Mediana Edad , Proyectos Piloto , Resultado del Tratamiento , Adulto JovenRESUMEN
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but serious disease with poorly understood mechanisms. Here, we report that patients with EGPA have elevated levels of TSLP, IL-25, and soluble ST2, which are well-characterized cytokine "alarmins" that activate or modulate type 2 innate lymphoid cells (ILC2s). Patients with active EGPA have a concurrent reduction in circulating ILC2s, suggesting a role for ILC2s in the pathogenesis of this disease. To explore the mechanism of these findings in patients, we established a model of EGPA in which active vasculitis and pulmonary hemorrhage were induced by IL-33 administration in predisposed, hypereosinophilic mice. In this model, induction of pulmonary hemorrhage and vasculitis was dependent on ILC2s and signaling through IL4Rα. In the absence of IL4Rα or STAT6, IL-33-treated mice had less vascular leak and pulmonary edema, less endothelial activation, and reduced eotaxin production, cumulatively leading to a reduction of pathologic eosinophil migration into the lung parenchyma. These results offer a mouse model for use in future mechanistic studies of EGPA, and they suggest that IL-33, ILC2s, and IL4Rα signaling may be potential targets for further study and therapeutic targeting in patients with EGPA.
Asunto(s)
Síndrome de Churg-Strauss , Interleucina-33 , Linfocitos , Animales , Autoinmunidad/inmunología , Síndrome de Churg-Strauss/inmunología , Síndrome de Churg-Strauss/metabolismo , Síndrome de Churg-Strauss/patología , Modelos Animales de Enfermedad , Humanos , Inmunidad Innata/inmunología , Interleucina-33/inmunología , Interleucina-33/metabolismo , Pulmón/metabolismo , Pulmón/patología , Linfocitos/inmunología , Linfocitos/metabolismo , RatonesRESUMEN
Long-term observation of patients with ANCA-associated vasculitis (AAV) allows the identification of different longitudinal patterns of ANCA levels during follow-up. This study aimed to characterize these patterns and to determine their prognostic significance. All ANCA determinations performed in two university hospitals during a 2-year period were retrospectively reviewed. Patients were included in the analysis if they had high titers of anti-myeloperoxidase (anti-MPO) or anti-proteinase 3 (anti-PR3) antibodies at least once, ≥ 5 serial ANCA determinations and AAV diagnosed by biopsy or American College of Rheumatology (ACR) classification criteria. Patients' time-course ANCA patterns were classified as monophasic, remitting, recurrent or persistent. Associations between ANCA patterns and prognostic variables (relapse rate and renal outcome) were analysed by univariate and multivariate statistics. A total of 99 patients [55 with microscopic polyangiitis (MPA), 36 with granulomatosis with polyangiitis (GPA) and eight with eosinophilic granulomatosis with polyangiitis (EGPA)] were included. Median follow-up was 9 years. Among patients diagnosed with MPA or GPA, recurrent or persistent ANCA patterns were associated with a higher risk of clinical relapse [hazard ratio (HR) = 3·7, 95% confidence interval (CI) = 1·5-9·1 and HR = 2·9, 95% CI = 1·1-8·0, respectively], independently of clinical diagnosis or ANCA specificity. In patients with anti-MPO antibodies, the recurrent ANCA pattern was associated with worsening renal function [odds ratio (OR) = 5·7, 95% CI = 1·2-26·0]. Recurrent or persistent ANCA patterns are associated with a higher risk of clinical relapse. A recurrent ANCA pattern was associated with worsening renal function in anti-MPO-associated vasculitis.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/patología , Anticuerpos Anticitoplasma de Neutrófilos/metabolismo , Riñón/patología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/metabolismo , Biopsia , Enfermedad Crónica , Síndrome de Churg-Strauss/metabolismo , Síndrome de Churg-Strauss/patología , Femenino , Estudios de Seguimiento , Granulomatosis con Poliangitis/patología , Humanos , Riñón/metabolismo , Masculino , Poliangitis Microscópica/metabolismo , Poliangitis Microscópica/patología , Persona de Mediana Edad , Mieloblastina/metabolismo , Peroxidasa/metabolismo , Pronóstico , Recurrencia , Estudios RetrospectivosRESUMEN
RATIONALE: Eosinophilic granulomatosis with polyangiitis (eGPA) is a small-vessel vasculitis where 40% of patients present with serum antineutrophil cytoplasmic antibodies (ANCAs). We examined the presence and clinical relevance of sputum ANCAs in the serum ANCA- patients with eGPA. METHODS: ANCA was investigated in matched sputum and blood samples collected from 23 patients with eGPA (n = 10, serum ANCA+), 19 patients with eosinophilic asthma (prednisone dependent), and 13 healthy volunteers. IgG reactivity to common target antigens and cytokine profiles in sputum samples were examined. Pathogenicity of detected sputum ANCA was assessed using in vitro degranulation assays. MEASUREMENTS AND MAIN RESULTS: Most patients with eGPA (17 of 23, 74%) showed significantly increased sputum ANCAs compared with patients with eosinophilic asthma (P = 0.002) and healthy controls (P < 0.0001), irrespective of their serum ANCA status. In addition, 16 of 17 (94%) of sputum ANCA+ patients had clinical manifestations of severe asthma compared with 3 of 6 (50%) in the sputum ANCA- subset (P = 0.04). Microarray analysis of 123 common antigens failed to reveal a specific target for the ANCA IgG. However, immunoprecipitated immunoglobulins from ANCA+ sputum allowed extensive extracellular trap formations from both neutrophils and eosinophils in vitro, indicating pathogenicity of detected IgG autoantibodies. Cytokine analysis showed lung-localized increases in CXCL8 (neutrophil/eosinophil chemotaxis), CCL24 (eosinophil recruitment), and CXCL12 (lymphocyte recruitment) in the sputa from ANCA+ patients (P < 0.01). CONCLUSIONS: We report a novel finding of ANCA reactivity in the sputa of patients with eGPA in whom disease severity is driven by respiratory complications. Investigating localized autoimmunity may lead to the discovery of novel pathomechanisms, therapeutic targets, and optimal biomarkers for diagnosing and managing eGPA.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/metabolismo , Síndrome de Churg-Strauss/metabolismo , Esputo/metabolismo , Adulto , Anciano , Biomarcadores/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a disease characterized by allergic granulomatosis, necrotizing vasculitis, and peripheral blood eosinophilia. Interleukin (IL)-33, thymic stromal lymphopoietin (TSLP), and type 2 innate lymphoid cells (ILC2) are involved in the innate and type 2 immune responses in EGPA. However, the relationships among these molecules and the mechanisms underlying the development of EGPA remain unknown. OBJECTIVE: We investigated the relationships among peripheral blood eosinophil count, serum IL-33 and TSLP concentration, and peripheral blood ILC2 count in patients with EGPA, chronic eosinophilic pneumonia (CEP), or bronchial asthma (BA). METHODS: We recruited 86 patients with EGPA in three groups (remission, relapse, and onset), 25 patients with CEP at active or inactive stages of disease, and 11 patients with BA. In patients with EGPA, CEP, or BA, serum IL-33, sST2, and TSLP concentrations were determined using ELISA and peripheral blood ILC2 counts (as Lin-1- CD127+ CRTH2+ cells) were determined using flow cytometry. RESULTS: Peripheral blood eosinophil count or ILC2 count, and serum sST2 or TSLP concentration were higher in patients with EGPA at onset than in those with EGPA at relapse or remission, or in those with BA or CEP. Serum IL-33 concentration was higher in patients with EGPA at relapse than in those with EGPA at onset or remission, or in those with BA or CEP. In a logistic regression model, EGPA disease activity was correlated with serum IL-33 concentration and peripheral blood ILC2 count, but not daily systemic and inhaled corticosteroid dose or immunosuppressant use. Eosinophil count was correlated with peripheral blood ILC2 count and serum TSLP concentration, but not serum IL-33 concentration. CONCLUSIONS: Increased peripheral blood ILC2 count and serum IL-33 concentration were associated with disease activity in EGPA. Increases in serum IL-33 concentration may indicate the presence of active vasculitis rather than peripheral or tissue eosinophilia.
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Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/inmunología , Granulomatosis con Poliangitis/diagnóstico , Granulomatosis con Poliangitis/inmunología , Inmunidad Innata , Anciano , Asma/diagnóstico , Asma/inmunología , Asma/metabolismo , Biomarcadores , Síndrome de Churg-Strauss/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Granulomatosis con Poliangitis/metabolismo , Humanos , Inmunoglobulina E/inmunología , Recuento de Leucocitos , Linfocitos/inmunología , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Linfopoyetina del Estroma TímicoRESUMEN
OBJECTIVES: Given reports on the increased prevalence of thromboembolic incidents in patients with eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome), we investigated whether fibrin clot properties are unfavorably altered in EGPA. METHODS: Ex vivo plasma fibrin clot characteristics, including clot permeability, turbidimetry and efficiency of fibrinolysis using two assays, were investigated in 34 consecutive patients with remission in EGPA according to the Birmingham Vasculitis Activity Score version 3 (23 female, 11 male), aged 48 (range, 21-80) years. The control group comprised 34 age- and sex- matched volunteers. RESULTS: Compared with controls, patients with EGPA were characterized by denser fiber clots (estimated pore size, Ks, 7.30±0.93 vs 10.14±1.07 10-9 cm2), faster fibrin polymerization (lag phase in a turbidimetric curve, 41.8±3.6 vs 47.4±2.9 s), thicker fibrin fibers (maximum absorbance, ΔAbs, 0.87±0.09 vs 0.72±0.07), higher maximum levels of D-dimer released from clots (DDmax 4.10±0.46 vs 3.54±0.35 mg/L), and prolonged clot lysis time (t50%; 9.50±1.45 vs 7.56±0.87 min); all p<0.0001. Scanning electron microscopy images confirmed denser plasma fibrin networks composed of thinner fibers formed in EGPA. Antineutrophil cytoplasmic antibody status and C-reactive protein did not affect clot variables. Multivariate analysis adjusted for fibrinogen showed that Ks was predicted by eosinophil count, peak thrombin generation, factor VIII, and soluble CD40 ligand, whereas eosinophil count, peak thrombin generation and antiplasmin predicted t50%. CONCLUSION: This study is the first to show that EGPA is associated with prothrombotic plasma fibrin clot phenotype, which may contribute to thromboembolic manifestations reported in this disease.
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Coagulación Sanguínea/fisiología , Síndrome de Churg-Strauss/metabolismo , Eosinofilia/metabolismo , Fibrina/metabolismo , Granulomatosis con Poliangitis/metabolismo , Trombina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Femenino , Tiempo de Lisis del Coágulo de Fibrina/métodos , Fibrinógeno/metabolismo , Fibrinólisis/fisiología , Humanos , Masculino , Persona de Mediana Edad , Trombosis/metabolismo , Adulto JovenAsunto(s)
Asma/diagnóstico , Síndrome de Churg-Strauss/diagnóstico , Proteómica , Saliva/química , Calicreínas de Tejido/análisis , Anciano , Asma/metabolismo , Asma/fisiopatología , Biomarcadores/análisis , Estudios de Casos y Controles , Síndrome de Churg-Strauss/metabolismo , Síndrome de Churg-Strauss/fisiopatología , Electroforesis en Gel Bidimensional , Femenino , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Proteómica/métodos , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
OBJECTIVE: Churg-Strauss syndrome (CSS) is a rare systemic vasculitis associated with eosinophilia and asthma. We assessed the local immune response in airways of CSS patients with different activity of the disease. METHODS: Concentration of IL-5, CCL17, CCL22 and CCL26 (ELISA) together with cell expression of T-helper-related genes (real-time PCR array) were measured in bronchoalveolar lavage fluid (BALF) sampled from 11 patients with active CSS, 11 patients with CSS in remission and 9 control subjects with bronchial asthma. RESULTS: In active CSS, both BALF and blood eosinophil counts were increased (P<0.01). BALF cells in active disease were characterized by an increased expression of Th2 and regulatory-type transcripts: STAT6, STAT3, GATA3, IL4, IL5 and IL10 as compared with asthmatics, and STAT5A, CCR4, FOXP3, IL4, IL5 and IL10 when compared with inactive CSS. There was significant increase in BALF concentration of IL-5 and CCL26 in exacerbation of CSS. CCR4-active chemokines were detected more frequently in active disease. We found a strong positive correlation between clinical parameters of disease activity (BVAS, eosinophilia) and expression of IL4, IL5, IL10 and STAT5A. CONCLUSION: These results indicate that as compared with asthma, active-CSS patients have much stronger local Th2 response in the airways. Airway cells may contribute to lung eosinophilia in CSS by producing IL-5 and eosinophil active chemokines.
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Líquido del Lavado Bronquioalveolar/química , Síndrome de Churg-Strauss/inmunología , Expresión Génica/inmunología , Interleucina-5/análisis , Adulto , Líquido del Lavado Bronquioalveolar/inmunología , Quimiocina CCL17/análisis , Quimiocina CCL22/análisis , Quimiocina CCL26 , Quimiocinas CC/análisis , Síndrome de Churg-Strauss/metabolismo , Eosinófilos/inmunología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
RATIONALE: Churg-Strauss syndrome (CSS) and hypereosinophilic syndrome (HES) overlap considerably in clinical presentation. A reliable means of distinguishing between these groups of patients is needed, especially in the setting of glucocorticoid therapy. METHODS: A retrospective chart review of 276 adult subjects referred for evaluation of eosinophilia > 1500/µl was performed, and subjects with a documented secondary cause of eosinophilia or a PDGFR -positive myeloproliferative neoplasm were excluded. The remaining subjects were assessed for the presence of American College of Rheumatology (ACR) criteria. Laboratory and clinical parameters were compared between subjects with biopsy-proven vasculitis (CSS; n = 8), ≥4 ACR criteria (probable CSS; n = 21), HES with asthma and/or sinusitis without other CSS-defining criteria (HESwAS; n = 20), HES without asthma or sinusitis (HES; n = 18), and normal controls (n = 8). Serum biomarkers reported to be associated with CSS were measured using standard techniques. RESULTS: There were no differences between the subjects with definite or probable CSS or HES with respect to age, gender, or maintenance steroid dose. Serum CCL17, IL-8, and eotaxin levels were significantly increased in eosinophilic subjects as compared to normal controls, but were similar between the eosinophilic groups. Serum CCL17 correlated with eosinophil count (P < 0.0001, r = 0.73), but not with prednisone dose. CONCLUSIONS: In patients with a history of asthma and sinusitis, distinguishing between ANCA-negative CSS and PDGFR-negative HES is difficult because of significant overlap in clinical presentation and biomarker profiles.
Asunto(s)
Biomarcadores/sangre , Quimiocina CCL11/sangre , Quimiocina CCL17/sangre , Síndrome de Churg-Strauss/sangre , Síndrome Hipereosinofílico/sangre , Interleucina-8/sangre , Adulto , Anciano , Anciano de 80 o más Años , Síndrome de Churg-Strauss/metabolismo , Síndrome de Churg-Strauss/patología , Femenino , Humanos , Síndrome Hipereosinofílico/metabolismo , Síndrome Hipereosinofílico/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Churg-Strauss syndrome (CSS) shares similarities with asthma and hypereosinophilic syndrome (HES). Eicosanoids--important inflammatory and signaling molecules--are present in exhaled breath condensate (EBC) and broncho-alveolar lavage fluid (BALF). OBJECTIVES: To assess eicosanoid profile both in EBC and BALF of CSS subjects searching for a pattern characteristic of this syndrome. METHODS: EBCs from 23 CSS patients, 30 asthmatics, 12 HES patients and 54 healthy controls (HC) were assessed quantitatively for 19 eicosanoids by a high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS). In addition, in 21 of 23 CSS subjects and in nine asthmatics, eicosanoids were determined in BALF. RESULTS: EBC from CSS patients showed markedly elevated levels of 12-HETE as compared with other studied groups. BALF was characterized by a significant elevation of 12-HETE and its metabolite 12-tetranor HETE in CSS as compared with asthma. Clinical activity of CSS correlated with 12-HETE and its metabolites levels in BALF, but not in EBC. CONCLUSION AND CLINICAL RELEVANCE: CSS is clearly distinguished from bronchial asthma, and HES by a marked increase in 12-HETE concentration in both EBC and BALF. This points to a possible new pathogenic mechanism in CSS and may help in future in establishing the diagnosis of CSS.
Asunto(s)
Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/análisis , Biomarcadores/análisis , Síndrome de Churg-Strauss/diagnóstico , Adulto , Pruebas Respiratorias , Líquido del Lavado Bronquioalveolar/química , Cromatografía Líquida de Alta Presión , Síndrome de Churg-Strauss/metabolismo , Espiración , Femenino , Humanos , Masculino , Persona de Mediana Edad , Espectrometría de Masas en TándemRESUMEN
OBJECTIVES: The aim of this study was to analyse mPR3 expression on neutrophils in two Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), namely WG (localised vs. generalised) and Churg-Strauss syndrome (CSS) and other inflammatory disorders, in order to evaluate (i) whether the pattern of mPR3 expression is specific for AAV and (ii) to assess whether the mPR3high status is associated with clinically distinct disease stages of WG (localised vs. generalised). METHODS: Localised WG (n=15), generalised WG (n=55), Churg-Strauss Syndrome (CSS) (n=20), systemic lupus erythematosus (SLE) (n=15), Rheumatoid Arthritis (RA) (n=22) and healthy controls (n=30) were analysed. mPR3 and CD63 expression on surface of neutrophils were assessed by flow cytometric analysis on isolated neutrophils and whole blood. RESULTS: In patients with genWG and SLE, an increased percentage of mPR3+ neutrophils and an elevated level of mPR3 expression compared to healthy controls were found (percentage: p=0.001, p=0.000; MFI ratio: p=0.038, p=0.019, respectively). There was no increased frequency of mPR3+ neutrophils in CSS. Within the group of WG, an elevated level of mPR3 expression was significantly associated with disease stage (genWG and not locWG), and in genWG with disease activity and the presence of ANCA. CONCLUSIONS: The mPR3high status is associated with generalised WG and correlates with disease activity and ANCA status in generalised WG. An increased proportion of mPR3-positive neutrophils is not specific for AAV.
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Síndrome de Churg-Strauss/inmunología , Síndrome de Churg-Strauss/metabolismo , Granulomatosis con Poliangitis/inmunología , Granulomatosis con Poliangitis/metabolismo , Mieloblastina/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/inmunología , Antígenos CD/metabolismo , Autoantígenos/inmunología , Autoantígenos/metabolismo , Epítopos , Femenino , Citometría de Flujo , Humanos , Masculino , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Mieloblastina/inmunología , Neutrófilos/enzimología , Neutrófilos/inmunología , Glicoproteínas de Membrana Plaquetaria/inmunología , Glicoproteínas de Membrana Plaquetaria/metabolismo , Índice de Severidad de la Enfermedad , Tetraspanina 30 , Adulto JovenRESUMEN
BACKGROUND: Eosinophils develop from hematopoietic CD34(+) progenitor cells in the bone marrow (BM) under the influence of Interleukin-5 (IL-5). The primary source of IL-5 is T-lymphocytes, although other sources may exist. The aims of this study were to determine whether CD34(+) cells from human peripheral blood (PB) and BM have the capacity to produce IL-5 when stimulated in vitro, and secondly, whether an elevated number of IL-5-producing CD34(+) cells can be found in situ in ongoing eosinophilic disease. METHODS: CD34(+) cells from PB and BM were stimulated in vitro, and IL-5 production and release was assessed by ELISA, ELISPOT, flow cytometry and immunocytochemistry. Blood and BM from a patient with Churg-Strauss syndrome were analyzed by flow cytometry for CD34(+)/IL-5(+) cells, and immunohistochemical staining of CD34(+)/IL-5(+) cells in bronchial biopsies from an asthmatic patient was performed. RESULTS: Both PB and BM CD34(+) cells can produce and release IL-5 when stimulated in vitro. In the Churg-Strauss patient, IL-5-producing CD34(+) cells were found in PB and BM. Oral glucocorticoid treatment markedly decreased the number of IL-5-positive CD34 cells in the BM. CD34(+)/IL-5(+) cells were present in a patient with asthma. CONCLUSION: CD34(+) cells in blood and BM are capable of producing IL-5 both in vitro and in vivo in humans, arguing that these cells may have the capacity to contribute to eosinophilic inflammation. Consequently, targeting CD34(+) progenitor cells that produce and release IL-5 may be effective in reducing the mobilization of eosinophil lineage-committed cells in eosinophilic-driven diseases.
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Antígenos CD34/metabolismo , Asma/metabolismo , Síndrome de Churg-Strauss/metabolismo , Células Madre Hematopoyéticas/metabolismo , Interleucina-5/metabolismo , Antígenos CD34/inmunología , Asma/inmunología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Separación Celular , Síndrome de Churg-Strauss/inmunología , Eosinofilia/etiología , Eosinofilia/inmunología , Femenino , Citometría de Flujo , Células Madre Hematopoyéticas/inmunología , Humanos , Inmunohistoquímica , Interleucina-5/inmunología , Persona de Mediana EdadRESUMEN
OBJECTIVE: Churg-Strauss Syndrome (CSS) is characterized by excessive eosinophil accumulation in peripheral blood and affected tissues with development of granulomatous vasculitic organ damage. The contribution of eosinophil-chemotactic cytokines (eotaxin family) to eosinophilia and disease activity in CSS is unknown. Thus, we compared serum levels of the eotaxin family members in CSS patients with healthy and disease controls. METHODS: Forty patients with CSS diagnosed according to ACR 1990 criteria, 30 healthy controls (HC) and 57 disease controls (28 asthma, 20 small vessel vasculitis, 9 hypereosinophilic syndrome) were studied. Clinical data were collected and serum levels of eotaxin-1, -2 and -3 were determined by ELISA. Further, immunohistochemistry was applied to identify eotaxin-3 expression in tissue biopsies from patients with CSS. RESULTS: In contrast to eotaxin-1 and -2, eotaxin-3 was highly elevated in serum samples of active CSS patients and correlated highly significantly with eosinophil counts, total immunoglobulin E (IgE) levels and acute-phase parameters. Moreover, eotaxin-3 was not elevated in other eosinophilic and vasculitic diseases. Immunohistochemical analysis revealed strong expression of eotaxin-3 in endothelial and inflammatory cells in affected tissues of active CSS patients. CONCLUSIONS: This study reveals the specific association of elevated eotaxin-3 expression with high disease activity and eosinophilia in CSS patients. Eotaxin-3 might thus be a pathogenic player, biomarker and potential therapeutic target in CSS.
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Quimiocinas CC/sangre , Síndrome de Churg-Strauss/sangre , Adulto , Biomarcadores/sangre , Biomarcadores/metabolismo , Biopsia , Quimiocina CCL11/sangre , Quimiocina CCL24/sangre , Quimiocina CCL26 , Quimiocinas CC/metabolismo , Síndrome de Churg-Strauss/metabolismo , Síndrome de Churg-Strauss/patología , Eosinofilia/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vasculitis/sangreRESUMEN
Churg-Strauss syndrome (CSS) is characterized by asthma and/or a history of allergy, eosinophilia and an often life-threatening systemic necrotizing vasculitis. We describe a patient with CSS and hypoxemia with a high alveolar-arterial oxygen gradient (AaDO2), but no pulmonary parenchymal involvement. The patient also had a low diffusion capacity with normal lung volume and a high level of serum thrombomodulin, a marker of endothelial cell injury. Treatment for CSS, such as corticosteroid, improved both hypoxemia and AaDO2 consistent with amelioration of diffusion capacity and serum thrombomodulin level, suggesting that this pathosis involves microangiopathy with endothelial cell damage induced by vasculitis in pulmonary blood vessels.
Asunto(s)
Síndrome de Churg-Strauss/complicaciones , Hipoxia/etiología , Oxígeno/metabolismo , Alveolos Pulmonares/metabolismo , Intercambio Gaseoso Pulmonar , Adulto , Arterias , Síndrome de Churg-Strauss/tratamiento farmacológico , Síndrome de Churg-Strauss/metabolismo , Femenino , HumanosRESUMEN
DNA diagnostics are useful but are hampered by difficult ethical issues. Moreover, it cannot provide enough information on the environmental factors that are important for pathogenesis of certain diseases. However, this is not a problem for RNA diagnostics, which evaluate the expression of the gene in question. We here report a novel RNA diagnostics tool that can be employed with peripheral blood mononuclear cells (PBMCs). To establish this tool, we identified 290 genes that are highly expressed in normal PBMCs but not in TIG-1, a normal human fibroblast cell. These genes were entitled PREP after predominantly expressed in PBMC and included 50 uncharacterized genes. We then conducted PREP gene-focused microarray analysis on PBMCs from seven cases of Churg-Strauss syndrome (CSS), which is a small-vessel necrotizing vasculitis. We found that PREP135 (coactosin-like protein), PREP77 (prosaposin), PREP191 (cathepsin D), PREP234 (c-fgr), and PREP136 (lysozyme) were very highly up-regulated in all seven CSS patients. Another 28 genes were also up-regulated, albeit more moderately, and three were down-regulated in all CSS patients. The nature of these up- and down-regulated genes suggest that the immune systems of the patients are activated in response to invading microorganisms. These observations indicate that focused microarray analysis of PBMCs may be a practical, useful, and low-cost bedside diagnostics tool.
Asunto(s)
Síndrome de Churg-Strauss/diagnóstico , Perfilación de la Expresión Génica , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Proteínas/metabolismo , Síndrome de Churg-Strauss/inmunología , Síndrome de Churg-Strauss/metabolismo , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Humanos , Proteínas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
OBJECTIVE: Prolonged survival of eosinophils plays an important role in the pathogenesis of Churg-Strauss syndrome (CSS); however, its detailed molecular mechanism is still unclear. TRAIL and its receptors are expressed on a variety of cells, including eosinophils. In this study, we examined the expression of TRAIL receptors on eosinophils from patients with CSS. METHODS: TRAIL receptor expression was assessed on eosinophils from healthy volunteers, patients with CSS, patients with asthma, and patients with hypereosinophilia due to parasitic infection. TRAIL-induced apoptosis of eosinophils was compared between the patients with CSS and patients with asthma. RNA interference was used to assess the effects of suppression of TRAIL receptor 3. RESULTS: Expression of TRAIL receptor 3, a decoy receptor that acts as an antiapoptotic receptor, on eosinophils from patients with CSS was significantly higher than that in the other subjects. Moreover, in CSS, serum TRAIL receptor 3 levels showed a significant positive correlation with peripheral eosinophil counts, tissue-infiltrating eosinophils stained positive for this receptor, and peripheral T cells expressed TRAIL on their surface. Compared with asthma patients, eosinophils from CSS patients showed a significantly lower percentage of recombinant TRAIL, less autologous T cell-induced apoptosis, and decreased level of active caspase 3. Suppression of TRAIL receptor 3 through RNA interference significantly increased the recombinant TRAIL-induced apoptosis of eosinophils from CSS patients. CONCLUSION: Increased expression of TRAIL receptor 3 on eosinophils from patients with CSS was observed. These alterations in TRAIL receptor 3 expression might be involved in the molecular pathogenesis of CSS eosinophilia.