Elevated Serum IgE Research Articles

Keratinocyte-specific deletion of STAT3 promotes elevated serum IgE in response to Staphylococcus aureus exposure: relevance to hyper-IgE syndrome

Abstract Autosomal dominant hyper-IgE syndrome is caused by STAT3 loss-of-function mutations, which results in a constellation of clinical features, including highly elevated serum IgE levels, a severe eczema-like skin eruption, and an increased susceptibility to Candida albicans and Staphylococcus aureus skin infections. However, the mechanism by which these individuals have elevated IgE levels is not well understood. To evaluate the role of defective STAT3 signaling in contributing to IgE production, we used a mouse model of atopic dermatitis-like skin inflammation induced by epicutaneous exposure to S. aureus in cre/lox mice with cell specific deletion of STAT3. Unexpectedly, STAT3 deletion in keratinocytes (K5-creERT2 × STAT3fl/fl mice) but not in T cells (CD4-creERT2 × STAT3fl/fl mice) resulted in a substantial elevation of serum IgE levels. The increase in serum IgE involved concomitant increase in IgG and IgA levels that were also significantly higher in the keratinocyte-specific STAT3-deficient mice compared with wildtype mice. CD4+ T cells were required for the IgE production, since CD4+ T cell depletion resulted in significantly reduced level of serum IgE in the K5-creERT2 × STAT3fl/fl mice. Taken together, these results indicate that keratinocytes can modulate serum antibody levels, especially in the absence of STAT3 signaling. These results provide an explanation of the increased serum IgE levels in autosomal dominant hyper-IgE syndrome and more broadly into the mechanisms that promote antibody production in response to epicutaneous exposure to microbes and inflammation.

Allergic Bronchopulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is an immunologic bronchopulmonary inflammation due to an immune response of the lower respiratory tract against Aspergillus fumigatus. The major clinical features of ABPA include asthma, recurrent pulmonary infiltrates, immediate wheal and flare skin reactivity to A. fumigatus, elevated total serum IgE levels, detectable serum precipitating antibodies to A. fumigatus, peripheral blood eosinophilia, elevated levels of Aspergillus-specific serum IgE and central bronchiectasis with normal distal structures. The diagnosis of ABPA should be considered in asthmatics of all ages. Evolution of the disease comprises five stages from the acute to the fibrotic stage including pulmonary fibrosis and respiratory insufficiency. The goals of ABPA treatment are to control patient's asthma and prevent exacerbations of ABPA. During the acute stage, prednisone should be administered. Antifungals agents (itraconazole) may be useful to prevent exacerbations of the disease.

TGFBR1M318R+/−: A monogenic presentation of eosinophilic esophagitis.

Abstract Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease characterized by esophageal dysfunction and accumulation of tissue eosinophils, T cells, and mast cells. The exact causes of EoE are not known. Sequence variants associated with increased EoE susceptibility have been identified, suggesting that there can be a genetic component to the disease. Several of the genes encode proteins involved in TGFβ signaling. Patients and mice heterozygous for a mutation in the kinase domain of TGFbR1 (TGFBR1M318R+/−) exhibit cardiovascular, skeletal, and immune manifestations of Loeys-Dietz syndrome (LDS). Immune symptoms include elevated serum IgE and a propensity to develop EoE. We used TGFBR1M318R+/− mice to determine which cells are responsible for the initiation and perpetuation of EoE. Current dogma posits that EoE occurs when Th2 cells are stimulated by inhaled or ingested antigens to secrete cytokines that then recruit and stimulate eosinophils and mast cells. Thus we were surprised to find that RAG2−/−R1 mice developed disease, illustrating that EoE associated with the TGFBR1M318R mutation was not lymphocyte-dependent. Bone marrow (BM) chimeras were made to confirm that altered TGFβ signaling in radio-resistant cells was sufficient to cause EoE. Lethally irradiated R1mice reconstituted with WT BM developed EoE. In contrast, eosinophils and IgE were not elevated in WT mice reconstituted with R1BM. We looked for other potential sources of type 2 cytokines and discovered that type 2 innate lymphoid cells (ILC2) were increased in the esophagus of R1 mice. We propose that altered TGFβ signaling in epithelial cells leads to EoE by stimulating ILC2 to proliferate and secrete cytokines that result in accumulation of eosinophils.

421 Elevated serum IgE level, but not TARC and LDH, may reflect the impairment of stratum corneum barrier function in healthy individuals; Results of cross-sectional study of 1141 Japanese healthy individuals

421 Elevated serum IgE level, but not TARC and LDH, may reflect the impairment of stratum corneum barrier function in healthy individuals; Results of cross-sectional study of 1141 Japanese healthy individuals

Cynanchum atratum inhibits the development of atopic dermatitis in 2,4-dinitrochlorobenzene-induced mice

Cynanchum atratum Bunge (Apocynaceae) is a folk medicine to treat skin inflammatory diseases. However, the effects of C. atratum on atopic dermatitis have not been elucidated. In this study, we evaluate the effects of aqueous extract of C. atratum (CA) and its molecular mechanism on atopic dermatitis (AD).1 and 100mg/mL CA were topically applied to 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin lesions for 11 days. The number of scratching behavior was evaluated for 20min. AD-like symptoms including elevated serum IgE, skin hyperplasia and mast cell infiltration were investigated. The expressions of pro-inflammatory cytokines and mediators were analyzed in AD-like skin legions. In addition, pro-inflammatory cytokine production was confirmed in human mast cells (HMC)-1 stimulated with PMA plus A23187 (PMACI).Topical application of CA attenuated total serum IgE level and scratching behavior. Skin hyperplasia including epidermis and dermis was ameliorated in CA-treated skin legions. The number of infiltrated mast cells was significantly decreased by CA treatment. In addition, CA reduced pro-inflammatory cytokines, such as IL-6, IL-1β and TNF-α and Th2 cytokine, IL-4, in both of AD-like skin lesions and PMACI-sensitized HMC-1 cells. Furthermore, CA decreased the expressions of NF-κB, phospho-IκBα and MAP kinase.These results suggest the inhibitory effects of CA on the development of AD by regulating pro-inflammatory cytokines and mediators. CA could be an effective substance for the treatment of AD.

Ribosomal protein S3 gene silencing protects against experimental allergic asthma.

Ribosomal protein S3 (RPS3) is a 40S ribosomal protein of the S3P family essential for implementing protein translation. RPS3 has recently been found to interact with the p65 subunit of the NF-κB complex and promote p65 DNA-binding activity. Persistent activation of the NF-κB pathway is evident in allergic asthma. We hypothesized that gene silencing of lung RPS3 can ameliorate allergic airway inflammation. The gene silencing efficacy of RPS3 siRNA was screened in three different mouse cell lines by real-time PCR and immunoblotting. Protective effects of intratracheal RPS3 siRNA in a house dust mite (HDM) mouse asthma model were determined by measuring cell counts in lung lavage fluid and lung sections, lung cytokine profiles and airway hyperresponsiveness (AHR). RPS3 siRNA markedly knocked down RPS3 levels in all mouse cell lines tested, and in mouse lung tissues, blocked TNF-α- or HDM-induced release of mediators by the cultured cells and reduced eosinophil counts in lung lavage fluid from the HDM mouse asthma model. RPS3 siRNA lessened HDM-induced airway mucus hypersecretion, cytokine production and serum IgE elevation. Moreover, RPS3 knockdown significantly suppressed methacholine-induced AHR in experimental asthma. RPS3 siRNA disrupted TNF-α-induced NF-κB activation in a NF-κB reporter gene assay in vitro and prevented the nuclear accumulation of p65 subunit and p65 transcriptional activation in HDM-challenged lungs and cells. RPS3 gene silencing ameliorates experimental asthma, probably by disrupting NF-κB activity. RPS3 could be a novel therapeutic target for allergic airway inflammation.

Clinical, endoscopic and histopathological features of eosinophilic gastroenteritis in 76 children

Objective To analyze the clinical, endoscopic and histopathological features of eosinophilic gastroenteritis (EG) in children. Methods A retrospective study of 76 children with EG was performed to analyze clinical symptoms, laboratory and imaging results, endoscopic and pathological features, status of Helicobacter pylori (H.pylori) infection, treatment and outcomes. Results The main clinical symptoms were abdominal pain in 55.3%(42/76) cases, vomiting in 39.5% (30/76) cases and hematochezia in 38.2% cases(29/76). The hemoglobin level decreased significantly in 34 cases (44.7%, 34/76). Peripheral blood eosinophil (EOS) count increased significantly in 9 cases (11.8%, 9/76) and EOS percentage increased significantly in 13 cases(17.1%, 13/76). Total serum IgE elevated in 32 cases (54.2%, 32/59). There were also 18 cases (36.7%, 18/49) positive in serum allergen-specific immunoglobulin E (sIgE) test and 25 cases (32.9%, 25/76) positive in fecal occult blood test. Among 51 cases of abdominal ultrasound examination, there were 7 cases of ascites, 4 cases of pelvis fluid and 3 cases of intestinal wall change. Endoscopic examination in 76 cases showed 63 cases (82.9%) of mucosal hyperemia/edema, 20 cases (26.3%) of ulceration, 17 cases (22.4%) of erosion, 11 cases (14.5%) of nodularity or hyperplasia and 9 cases (11.8%) of normal mucosa. The pathological examination showed mucosal inflammation with a large number of EOS infiltration(≥20 per HPF). There were 12 cases(15.8%, 12/76) of H. pylori infection. Among the 76 cases, clinical symptoms improved significantly in 74 patients after treatment with dietary allergen avoidance, anti-allergy medications, antacids, montelukast and corticosteroid, and the total efficacy was 97.4%. The efficacy of dietary allergen avoidance, anti-allergy medications, antacids and montelukast was 93.8%(61/65). The efficacy of corticosteroid was 86.7%(13/15). Conclusion The clinical manifestations and endoscopic characteristics of EG in children lack specificity. In terms of diagnosis, the elevated total serum IgE and the positive sIgE test may be taken as reference for the diagnosis of EG. The definite diagnosis is based on pathological examination(EOS infiltration≥20 per HPF). While in terms of treatment, dietary allergen exclusion, anti-allergy medications, antacids and montelukast are highly effective, which can be taken as the first option. There is no need of corticosteroid as routine therapy. Key words: Endoscopy; Histopathology; Child; Eosinophilic gastroenteritis

Group 2 Innate Lymphoid Cells Are Increased in Nasal Polyps in Patients with Eosinophilic Chronic Rhinosinusitis

ILC2s represent a critical innate cellular source of type 2 cytokines and may play important roles in various diseases. We examined the role of ILC2s in the pathogenesis of two subgroups of CRSwNP: ECRS and non-ECRS. We analyzed the prevalence of ILC2s in sinonasal tissues and in blood from patients with ECRS, non-ECRS, CRSsNP, and control. The prevalence of ILC2s in nasal tissues was higher in patients with ECRS as compared to those with non-ECRS or CRSsNP. The prevalence of blood ILC2s was not different between patients with ECRS and non-ECRS. The prevalence of blood ILC2s was higher in patients with allergic rhinitis and elevated serum IgE levels. Alternaria-induced IL-33 secretion was increased in nasal epithelial cells derived from patients with ECRS as compared to those from patients with non-ECRS or CRSsNP. ILC2s may be involved in the pathogenesis of CRSwNP, in particular in patients with tissue eosinophilia (i.e., ECRS).

Kimura's Disease without Peripheral Eosinophilia: An Unusual and Challenging Case Simulating Venous Malformation on Imaging Studies-Case Report and Review of literature.

Kimura's Disease (KD) is a rare chronic inflammatory disorder presenting as multiple painless solitary subcutaneous nodules, predominantly in the head and neck region and frequently associated with regional lymphadenopathy and/or salivary gland involvement. Because of painless nature and indolent course, there is usually a delay in the patient's presentation. KD may radiologically mimic other chronic inflammatory conditions like tuberculosis, vascular malformations and neoplasms. Clinical correlation and histological evaluation along with elevated peripheral eosinophil and serum IgE level are considered important for confirmatory diagnosis. We report a case of painless swelling over right submandibular region extending to the right superficial parotid. The haematological reports were within normal limits. Ultrasound (USG), Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiogram (MRA) favoured a diagnosis of venous malformation. However, histopathological examination of excised lesion confirmed a diagnosis of KD. This case proves the possibility of the KD even in the absence of peripheral eosinophilia and/ or elevated serum IgE level, and may mimic venous malformation on imaging studies. Therefore, KD must find a place in the differentials of solitary painless neck swelling even in the absence of peripheral eosinophilia and/or elevated IgE level.

Prospective open-label evaluation of long-term low-dose doxycycline for difficult-to-treat chronic rhinosinusitis with nasal polyps

This study aimed to assess clinical outcomes of long-term low-dose oral doxycycline therapy in difficult-to-treat chronic rhinosinusitis with polyps (CRSwNP). This was a prospective, open-label study of 60 patients with difficult-to-treat CRSwNP who had undergone endoscopic sinus surgery. Patients were divided into two groups: 28 received nasal steroids, saline irrigation, and doxycycline (200 mg on the first day, followed by 100 mg once daily) for 12 weeks, while 30 received only nasal steroids and saline irrigation. The main outcome measure was an adequate effect size of doxycycline treatment on clinically meaningful significant improvement of SNOT-20. Other outcome measures were the SNOT-20, NOSE, and Lund-Kennedy scores. The following parameters were also analyzed: asthma, rhinitis, non-steroidal-exacerbated respiratory disease (NERD), and baseline serum IgG, IgA, IgE, IgM, ANCA, and eosinophil count. There was an adequate effect size of doxycycline treatment on clinically meaningful significant improvement of SNOT-20. Patients who received doxycycline also had significantly better outcomes regarding SNOT-20, NOSE, and Lund-Kennedy scores. There was a negative association among a clinically significant improvement of SNOT-20 and presence of asthma, NERD, and elevated serum IgE levels before treatment. These findings suggest that doxycycline may have a beneficial role for CRSwNP patients, especially for patients without asthma, NERD or high levels of serum IgE before treatment.

Functional Defects in Type 3 Innate Lymphoid Cells and Classical Monocytes in a Patient with Hyper-IgE Syndrome

Hyper-IgE syndrome (HIES) is a very rare primary immune deficiency characterized by elevated serum IgE levels, recurrent bacterial infections, chronic dermatitis, and connective tissue abnormalities. Autosomal dominant (AD) HIES involves a mutation in signal transducer and activator of transcription 3 (STAT3) that leads to an impaired TH17 response. STAT3 signaling is also involved in the function of RORγt+ type 3 innate lymphoid cells (ILC3s) and RORγt+TH17 cells. The aim of this study was to investigate the role of innate immune cells such as innate lymphoid cells (ILCs), granulocytes, and monocytes in a patient with HIES. Peripheral blood mononuclear cells (PBMCs) from a patient with HIES and three age-matched healthy controls were obtained for the analysis of the innate and adaptive immune cells. The frequencies of ILCs in PBMCs were lower in the patient with HIES than in the controls. Moreover, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-17A produced by ILC3s in PBMCs were lower in the patient with HIES than the controls. Compared with the controls, classical monocytes (CD14+CD16low), which have a high antimicrobial capability, were also lower in the patient with HIES, while non-classical monocytes (CD14lowCD16+) as well as intermediate monocytes (CD14+CD16intermediate) were higher. Taken together, these results indicate that the impaired immune defense against pathogenic microbes in the patient with HIES might be partially explained by functional defects in ILC3s and inflammatory monocytes.

Патоморфологічні особливості ІgG4-пов’язаної склерозуючої хвороби шлунка: клінічний випадок

Since the first description in the middle of the 1990’s of last century, it has been steadily increasing the number of literary data concerning IgG4-related disease. The process involved more organs and tissues with predominance of pancreas, salivary glands, and lymph nodes affection. There are several documented cases arising in the gastrointestinal tract. The salient clinical features include a predisposition to affect middle-age men who present with the only symptoms referable to a mass lesion at one or more sites, without inflammation, hyperemia and other constitutional symptoms. Common laboratory features are elevated serum globulin, IgG, IgG4, and IgE subtypes and low titers of autoantibodies such as rheumatoid factor and ANA. Histological features vary depending on the affected organ. But there are some common features of extranodal sites: lymphoplasmacytic infiltration with lymphoid follicle formation, sclerosis, phlebitis, and significant tissue IgG4+ -plasmocytosis. The arteries usually are not involved in the inflammatory process. The most common features in the lymph nodes are follicular hyperplasia, interfollicular expansion and Castelman-like appearance. There are proposed by Cheuk and Chan criteria for the diagnosis such as >50 IgG4 plasma cells per HPF and IgG4+ / IgG+>40 % ratio. The calculation is based on the assessment of the 3 fields of view with the greatest color intensity and correlates with the area of 0.196 mm2 . The pancreas, salivary glands, hepatobiliary tract, orbit and lymph nodes are cites most frequently, although other sites such as the aorta, skin, central nervous system, breast, kidney, prostate, lung, and thyroid have also been occasionally reported. There are 6 cases reports of involving the GIT, 2 of them were described in the stomach, one case in esophagus, jejune, cecum and sigmoid colon. Most cases took the form of a circumscribed nodule, variably affecting the mucosa, submucosa, muscularis propria, and subserosa. Microscopically it was formed by paucicellular hyalinized fibrous tissue with patchy chronic inflammatory infiltrate compound with plasma cells and lymphocytes. The proposed by Cheuk and Chan criteria were present in 4 of these cases. In the case with involving the jejune there were diagnosed serum IgG4 elevation at 800 mg/dL, phlebitis and necrotizing mesenteric arteritis. IgG4+ plasma cells also were seen within the interfollicular region of mesenteric lymph nodes. In this report, we present the case of IgG4-related disease involving stomach, omentum and mesenteric lymph nodes. A previously well 29-year-old man presented with a 1-year history of intermittent epigastric pain, nausea and sometimes vomiting. Because of worsening and suspicion of cancer resection of stomach was made. Morphological investigation of stomach tissue revealed a chronic ulcer associated with transmural inflammatory infiltrate rich in IgG4-positiv plasma sells. Abundant IgG4+ interfollicular plasma cell were also identified in a lymph node in stomach serosa, lymph nodes of omentum and mesenteric lymph node. In view of sensitivity to steroids, this condition should be considered in the differential diagnosis of stomach ulcers and gastritis with severe plasma cell infiltration, especially in case of negative H. Pylori and absence of response to ordinary anti-inflammatory treatment. Our observation of IgG4-releated sclerosing disease of the stomach in 29-year-old male was carried out in context of modern information about IgG4-releated pathology of different organs. Data of clinical, laboratory, and pathomorphological studies which help to substantiate the diagnosis were presented.

Factors related to renal cortical atrophy development after glucocorticoid therapy in IgG4-related kidney disease: a retrospective multicenter study.

BackgroundIn immunoglobulin G4-related kidney disease (IgG4-RKD), focal or diffuse renal cortical atrophy is often observed in the clinical course after glucocorticoid therapy. This study aimed to clarify the factors related to renal atrophy after glucocorticoid therapy in IgG4-RKD.MethodsWe retrospectively evaluated clinical features including laboratory data and computed tomography (CT) findings before and after glucocorticoid therapy in 23 patients diagnosed with IgG4-RKD, all of whom were followed up for more than 24 months.ResultsSeventeen patients were men, and six were women (average age 62.0 years). Average follow-up period was 54.9 months. The average estimated glomerular filtration rate (eGFR) at diagnosis was 81.7 mL/min/1.73 m2. All patients had had multiple low-density lesions on contrast-enhanced CT before glucocorticoid therapy, and showed disappearance or reduction of these lesions after it. Pre-treatment eGFR and serum IgE level in 11 patients in whom renal cortical atrophy developed 24 months after the start of glucocorticoid therapy were significantly different from those in 12 patients in whom no obvious atrophy was found at that time (68.9 ± 30.1 vs 93.5 ± 14.1 mL/min/1.73 m2, P = 0.036, and 587 ± 254 vs 284 ± 263 IU/mL, P = 0.008, respectively). Pre-treatment eGFR and serum IgE level were also significant risk factors for renal atrophy development 24 months after the start of therapy with an odds ratio of 0.520 (per 10 mL/min/1.73 m2, 95% confidence interval (CI) 0.273–0.993, P = 0.048) and 1.090 (per 10 IU/mL, 95% CI: 1.013–1.174, P = 0.022), respectively, in age-adjusted, sex-adjusted, serum IgG4 level-adjusted logistic regression analysis. Receiver operating characteristic curve analysis showed that eGFR of less than 71.0 mL/min/1.73 m2 and serum IgE of more than 436.5 IU/mL were the most appropriate cutoffs and yielded sensitivity of 63.6% and specificity of 100%, and sensitivity of 90.9% and specificity of 75.0%, respectively, in predicting renal atrophy development.ConclusionsThis study suggests that pre-treatment renal insufficiency and serum IgE elevation predict renal atrophy development after glucocorticoid therapy in IgG4-RKD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1175-y) contains supplementary material, which is available to authorized users.

A novel microbe-based treatment that attenuates the inflammatory profile in a mouse model of allergic airway disease.

There is an unmet need for effective new and innovative treatments for asthma. It is becoming increasingly evident that bacterial stimulation can have beneficial effects at attenuating allergic airway disease through immune modulation. Our aim was to test the ability of a novel inactivated microbe-derived therapeutic based on Klebsiella (KB) in a model of allergic airway disease in mice. BALB/c mice were exposed intranasally to house dust mite (HDM) for two weeks. Mice were treated prophylactically via subcutaneous route with either KB or placebo for one week prior to HDM exposure and throughout the two week exposure period. 24 hours after the last exposure, lungs were analysed for inflammatory cell infiltrate, gene expression, cytokine levels, goblet cell metaplasia, and serum was analysed for allergen-specific serum IgE levels. HDM exposed mice developed goblet cell hyperplasia, elevated allergen-specific serum IgE, airway eosinophilia, and a concomitant increase in TH2 cytokines including IL-4, IL-13 and IL-5. Treatment with KB attenuated HDM-mediated airway eosinophilia, total bronchoalveolar lavage (BAL) cell numbers, BAL TH2 cytokine production, and goblet cell metaplasia. Our prophylactic intervention study illustrates the potential of subcutaneous treatment with bacterial derived biologics as a promising approach for allergic airway disease treatment.

Study of the clinical phenotype of symptomatic chronic airways disease by hierarchical cluster analysis and two-step cluster analyses

To study the distinct clinical phenotype of chronic airway diseases by hierarchical cluster analysis and two-step cluster analysis. A population sample of adult patients in Donghuamen community, Dongcheng district and Qinghe community, Haidian district, Beijing from April 2012 to January 2015, who had wheeze within the last 12 months, underwent detailed investigation, including a clinical questionnaire, pulmonary function tests, total serum IgE levels, blood eosinophil level and a peak flow diary. Nine variables were chosen as evaluating parameters, including pre-salbutamol forced expired volume in one second(FEV1)/forced vital capacity(FVC) ratio, pre-salbutamol FEV1, percentage of post-salbutamol change in FEV1, residual capacity, diffusing capacity of the lung for carbon monoxide/alveolar volume adjusted for haemoglobin level, peak expiratory flow(PEF) variability, serum IgE level, cumulative tobacco cigarette consumption (pack-years) and respiratory symptoms (cough and expectoration). Subjects' different clinical phenotype by hierarchical cluster analysis and two-step cluster analysis was identified. (1) Four clusters were identified by hierarchical cluster analysis. Cluster 1 was chronic bronchitis in smokers with normal pulmonary function. Cluster 2 was chronic bronchitis or mild chronic obstructive pulmonary disease (COPD) patients with mild airflow limitation. Cluster 3 included COPD patients with heavy smoking, poor quality of life and severe airflow limitation. Cluster 4 recognized atopic patients with mild airflow limitation, elevated serum IgE and clinical features of asthma. Significant differences were revealed regarding pre-salbutamol FEV1/FVC%, pre-salbutamol FEV1% pred, post-salbutamol change in FEV1%, maximal mid-expiratory flow curve(MMEF)% pred, carbon monoxide diffusing capacity per liter of alveolar(DLCO)/(VA)% pred, residual volume(RV)% pred, total serum IgE level, smoking history (pack-years), St.George's respiratory questionnaire(SGRQ) score, acute exacerbation in the past one year, PEF variability and allergic dermatitis (P<0.05). (2) Four clusters were also identified by two-step cluster analysis as followings, cluster 1, COPD patients with moderate to severe airflow limitation; cluster 2, asthma and COPD patients with heavy smoking, airflow limitation and increased airways reversibility; cluster 3, patients having less smoking and normal pulmonary function with wheezing but no chronic cough; cluster 4, chronic bronchitis patients with normal pulmonary function and chronic cough. Significant differences were revealed regarding gender distribution, respiratory symptoms, pre-salbutamol FEV1/FVC%, pre-salbutamol FEV1% pred, post-salbutamol change in FEV1%, MMEF% pred, DLCO/VA% pred, RV% pred, PEF variability, total serum IgE level, cumulative tobacco cigarette consumption (pack-years), and SGRQ score (P<0.05). By different cluster analyses, distinct clinical phenotypes of chronic airway diseases are identified. Thus, individualized treatments may guide doctors to provide based on different phenotypes.

6-Shogaol, an active compound of ginger, alleviates allergic dermatitis-like skin lesions via cytokine inhibition by activating the Nrf2 pathway

Allergic dermatitis (AD) clinically presents with skin erythematous plaques, eruption, and elevated serum IgE, and T helper cell type 2 and 1 (Th2 and Th1) cytokine levels. 6-Shogaol [1-(4-hydroxy-methoxyphenyl)-4-decen-one], a pungent compound isolated from ginger, has shown anti-inflammatory effects, but its inhibitory effects on AD are unknown. The aim of this study was to examine whether 6-shogaol inhibits AD-like skin lesions and their underlying mechanism in vivo and in vitro. An AD-like response was induced by tumor necrosis factor-α (TNF-α)+IFN-γ in human keratinocytes or by 2,4-dinitrochlorobenzene (DNCB) in mice. In vivo, 6-shogaol inhibited the development of DNCB-induced AD-like skin lesions and scratching behavior, and showed significant reduction in Th2/1-mediated inflammatory cytokines, IgE, TNF-α, IFN-γ, thymus and activation-regulated chemokine, IL-1, 4, 12, and 13, cyclooxygenase-2, and nitric oxide synthase levels. In vitro, 6-shogaol inhibited reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs) signaling, and increased the levels of total glutathione, heme oxygenase-1, and quinone 1 via nuclear factor erythroid 2 related factor 2 (Nrf2) activation. 6-Shogaol can alleviate AD-like skin lesions by inhibiting immune mediators via regulating the ROS/MAPKs/Nrf2 signaling pathway, and may be an effective alternative therapy for AD.

Group 2 innate lymphoid cells are increased in nasal polyps in patients with eosinophilic chronic rhinosinusitis

ILC2s represent a critical innate cellular source of type 2 cytokines and may play important roles in various diseases. We examined the role of ILC2s in the pathogenesis of two subgroups of CRSwNP: ECRS and non-ECRS. We analyzed the prevalence of ILC2s in sinonasal tissues and in blood from patients with ECRS, non-ECRS, CRSsNP, and control. The prevalence of ILC2s in nasal tissues was higher in patients with ECRS as compared to those with non-ECRS or CRSsNP. The prevalence of blood ILC2s was not different between patients with ECRS and non-ECRS. The prevalence of blood ILC2s was higher in patients with allergic rhinitis and elevated serum IgE levels. Alternaria-induced IL-33 secretion was increased in nasal epithelial cells derived from patients with ECRS as compared to those from patients with non-ECRS or CRSsNP. ILC2s may be involved in the pathogenesis of CRSwNP, in particular in patients with tissue eosinophilia (i.e., ECRS).

Regulatory T Cells Control Th2-Dominant Murine Autoimmune Gastritis.

Pernicious anemia and gastric carcinoma are serious sequelae of autoimmune gastritis (AIG). Our study indicates that in adult C57BL/6-DEREG mice expressing a transgenic diphtheria toxin receptor under the Foxp3 promoter, transient regulatory T cell (Treg) depletion results in long-lasting AIG associated with both H(+)K(+)ATPase and intrinsic factor autoantibody responses. Although functional Tregs emerge over time during AIG occurrence, the effector T cells rapidly become less susceptible to Treg-mediated suppression. Whereas previous studies have implicated dysregulated Th1 cell responses in AIG pathogenesis, eosinophils have been detected in gastric biopsy specimens from patients with AIG. Indeed, AIG in DEREG mice is associated with strong Th2 cell responses, including dominant IgG1 autoantibodies, elevated serum IgE, increased Th2 cytokine production, and eosinophil infiltration in the stomach-draining lymph nodes. In addition, the stomachs exhibit severe mucosal and muscular hypertrophy, parietal cell loss, mucinous epithelial cell metaplasia, and massive eosinophilic inflammation. Notably, the Th2 responses and gastritis severity are significantly ameliorated in IL-4- or eosinophil-deficient mice. Furthermore, expansion of both Th2-promoting IFN regulatory factor 4(+) programmed death ligand 2(+) dendritic cells and ILT3(+) rebounded Tregs was detected after transient Treg depletion. Collectively, these data suggest that Tregs maintain physiological tolerance to clinically relevant gastric autoantigens, and Th2 responses can be a pathogenic mechanism in AIG.

Coexisting atopic conditions influence the likelihood of allergic bronchopulmonary aspergillosis in asthma

BackgroundThe diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in asthma is often made in patients with total serum IgE levels greater than 1,000 IU/mL in conjunction with evidence of Aspergillus sensitization. The specificity of total serum IgE for the diagnosis of ABPA is low even when combined with serum Aspergillus specific IgE. ObjectiveTo determine the prevalence of ABPA and to identify alternative clinical predictors for ABPA among asthmatic patients with a total serum IgE level greater than 1,000 IU/ml. MethodsThis study was conducted in a tertiary hospital in Melbourne, Australia, with a large asthma and allergy service. Patients with asthma and total serum IgE levels greater than 1,000 IU/ml from January 1, 2005, through December 31, 2014, were included. Patients were considered to have concomitant allergic conditions if they had atopic eczema, allergic rhinitis, or both. The diagnosis of ABPA was based on the managing physician's documented diagnosis and referenced to criteria proposed by the International Society for Human and Fungal Mycology. ResultsThe prevalence of ABPA in our cohort was 15.8%. Older age, elevated total serum IgE level, reduced lung function, and the absence of other concomitant allergic conditions increased the risk of ABPA. After multivariate logistic regression, patients without concomitant allergic conditions had an odds ratio of 4.4 (95% confidence interval, 1.9–10.1; P = .001) for ABPA when compared with patients with allergic conditions. ConclusionThe absence of atopic eczema and allergic rhinitis in these patients increases the likelihood of ABPA. Eliciting an accurate allergy history may be a useful bedside clinical tool when considering the diagnosis of ABPA.

Adeno-associated viral vector-mediated anti-inflammasome gene transfer alleviates asthmatic airway inflammation in OVA-sensitized mice model

Abstract Bronchial asthma is a chronic inflammatory disorder of the airway characterized by airway hyperresponsiveness (AHR), pulmonary eosinophilia, elevated serum IgE, and dysregulated T helper (Th) 2 cytokines. It is becoming urgent to identify target molecules for the preventive and therapeutic purpose. ATP accumulation in bronchoalveolar lavage fluid (BALF) of asthmatic subjects indicates that extracellular ATP and the downstream responses are involved. ATP is an activator of NLRP3 inflammasomes and tightly regulated by CD39, a nucleoside triphosphate diphosphohydrolase encoded by entpd1. Upregulated BALF ATP levels and decreased CD39 RNA were accompanied with asthmatic cardinal features in ovalbumin (OVA)-sensitized mice. Recombinant adeno-associated virus (rAAV) has been developed to carry exogenous genes with safe and low toxic therapeutic potential. The different serotypes and tropisms of AAVs benefit tissue specific gene targeting. This study aims for determining whether lung-targeting rAAV carrying CD39 (AAV/CD39) is able to reduce extracellular ATP in BALF and inhibit the OVA-induced allergic inflammation in an asthmatic murine model. The mice were sensitized and challenged with OVA. rAAV vectors were administrated into the lungs of mice 3 days before the first OVA exposure. The data indicated that ATP levels in BALF were downregulated accompanied with rescued CD39 expression. The administration of AAV/CD39 was able to suppress AHR, pulmonary eosinophilia, and the production of IL-5 from OVA-activated mediastinal lymph nodes (MLNs) cells. The treatment of AAV/CD39 attenuated the asthmatic airway inflammation and AHR. Collectively, ATP could be a potential target for gene therapy on asthma.