IL-4 confers resistance to IL-27-mediated suppression on CD4+ T cells by impairing signal transducer and activator of transcription 1 signaling.

BACKGROUND: TH2 cells play a critical role in the pathogenesis of allergic asthma. Established TH2 cells have been shown to resist reprogramming into TH1 cells. The inherent stability of TH2 cells poses a significant barrier to treating allergic diseases. OBJECTIVE: We sought to understand the mechanisms by which CD4(+) T cells from asthmatic patients resist the IL-27-mediated inhibition. METHODS: We isolated and cultured CD4(+) T cells from both healthy subjects and allergic asthmatic patients to test whether IL-27 can inhibit IL-4 production by the cultured CD4(+) T cells using ELISA. Culturing conditions that resulted in resistance to IL-27 were determined by using both murine and human CD4(+) T-cell culture systems. Signal transducer and activator of transcription (STAT) 1 phosphorylation was analyzed by means of Western blotting and flow cytometry. Suppressor of cytokine signaling (Socs) mRNA expression was measured by using quantitative PCR. The small interfering RNA method was used to knockdown the expression of Socs3 mRNA. RESULTS: We demonstrated that CD4(+) T cells from asthmatic patients resisted the suppression of IL-4 production mediated by IL-27. We observed that repeated exposure to TH2-inducing conditions rendered healthy human CD4(+) T cells resistant to IL-27-mediated inhibition. Using an in vitro murine culture system, we further demonstrated that repeated or higher doses of IL-4 stimulation, but not IL-2 stimulation, upregulated Socs3 mRNA expression and impaired IL-27-induced STAT1 phosphorylation. The knockdown of Socs3 mRNA expression restored IL-27-induced STAT1 phosphorylation and IL-27-mediated inhibition of IL-4 production. CONCLUSIONS: Our findings demonstrate that differentiated TH2 cells can resist IL-27-induced reprogramming toward TH1 cells by downregulating STAT1 phosphorylation and likely explain why the CD4(+) T cells of asthmatic patients are resistant to IL-27-mediated inhibition.

Development of food allergies in patients with gastroesophageal reflux disease treated with gastric acid suppressive medications.

BACKGROUND: The prevalence of food allergy has steadily increased, especially in children. Reflux disease, a very common problem in children, is often treated with gastric acid suppressive (GAS) medications which may alter the processing of food allergens, thereby affecting oral mucosal tolerance. OBJECTIVE: The purpose of this study was to determine if use of GAS medications is associated with the occurrence of food allergies in children. METHODS: Using a large national commercial insurance database, we identified 4724 children aged 0-18 yrs who were diagnosed with Gastroesophageal Reflux Disease (GERD) and treated with GAS medications between January 1, 2008 and September 30, 2009. We then matched 4724 children with GERD not treated with GAS medications and 4724 children without GERD and not treated with GAS medications, at a 1:1 ratio, on age, gender and number of atopic risk factors. Patients were followed for 12 months. RESULTS: In comparison to the referent (children without GERD who received no GAS medications), children with GERD who were treated with GAS were more likely to be diagnosed with a food allergy (Hazard ratio (HR): 3.67, 95% CI 2.15-6.27), as were children with GERD diagnosis but who were not treated with GAS medications (HR: 2.15, 95% CI: 1.21-3.81). A direct comparison of the two GERD cohorts showed that children with GERD who were treated with GAS had a greater risk of food allergy than those with GERD who were untreated (HR, 1.68, 95%CI, 1.15-2.46). CONCLUSION: Treatment with GAS medications is associated with the occurrence of food allergy, an effect not apparently related to a diagnosis of GERD alone.

A comparison of specific IgE and skin prick test results to common environmental allergens using the HYTEC™ 288.

Although skin-prick testing (SPT) is commonly used by allergists in the evaluation of allergy, in-vitro testing for specific IgE (sIgE) is an attractive alternate because it can be performed remotely and is of utility when SPT is contraindicated, as in patients on anti-histamines, or with dermatitis or severe eczema. It is, however, necessary to determine the extent of correlation between the in-vitro and in-vivo methods. In this study, we examined the qualitative concordance between SPT and sIgE as measured on the HYTEC™288 platform for 10 commonly encountered inhalant allergens in 232 subjects, and analysed the performance characteristics for the HYTEC™288. Overall concordance between SPT and sIgE was >70% for all allergens tested. Sensitivity ranged from 25% to 95%, depending on the allergen, while specificity was significantly higher for all allergens (78-97%). NPV was >85% for all allergens tested, while PPV was more variable, ranging from 22% to 88%. These results are similar to findings in other studies comparing SPT with sIgE. Lack of concordance in a percentage of samples might be partly attributed to differences in allergen preparations for SPT and HYTEC™ 288. Follow-up studies utilizing identical allergen preparations for both in-vivo and in-vitro testing may address these discrepancies.

Angioedema with normal C1q and C1 inhibitor: an atypical presentation of Waldenström macroglobulinemia.

Angioedema is a recurrent, non-pitting, non-pruritic, transitory swelling due to transient increase of endothelial permeability in the capillaries of the deep cutaneous and mucosal layers. Angioedema is generally categorized based on etiology, and characteristic lab findings are associated with each category. Cases of acquired angioedema associated with myeloproliferative disorders have been described in the literature, but these have been associated with a characteristic low C1q, a defining laboratory finding in acquired angioedema. Here we present a case of 68-year-old female with acquired angioedema that was not associated with low C1q, but was found to have Waldenström disease. Her angioedema responded dramatically to combination therapy consisting of bortezomib, rituximab, and dexamethasone.

Benralizumab--a humanized mAb to IL-5Rα with enhanced antibody-dependent cell-mediated cytotoxicity--a novel approach for the treatment of asthma.

INTRODUCTION: Benralizumab is a monoclonal antibody that binds the α subunit of the receptor to IL-5. As IL-5 is implicated in disease states that are mediated by eosinophils, benralizumab is an attractive option for use in the management of asthma. As a result of enhanced antibody-directed cell cytotoxicity, it has enhanced eosinophil-depleting activity as compared with neutralizing monoclonal antibody directed against IL-5. AREAS COVERED: This review presents the available data on benralizumab, including pharmacodynamics, pharmacokinetics, preclinical data and relevant clinical studies. EXPERT OPINION: Our review indicates that although further investigation is necessary to demonstrate clinical benefit, benralizumab remains a promising treatment modality.

Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.-Canadian multicenter study.

BACKGROUND/AIMS: HIV-infected patients now live longer and often have complications of liver disease, especially with hepatitis B or C virus coinfection. Limited data are available on those with hepatocellular carcinoma (HCC). METHODS: A retrospective analysis from 1992 to 2005 in 6 centers identified 63 HIV-infected HCC patients. Controls were 226 consecutive HIV-negative HCC patients from four sites. RESULTS: HIV-positive patients were younger than controls (52 vs. 64 years, p<0.001), more commonly had chronic hepatitis B or C (97% vs. 73%, p<0.001), were more frequently symptomatic (51% vs. 38%, p=0.048), had a higher median alfa-fetoprotein level (227 vs. 51 ng/ml, p=0.005), but a similar mean Child-Turcotte-Pugh score (7.0 vs. 7.5, p=0.05) and HCC staging score (Barcelona-Clínic-Liver-Cancer stages C+D in 50% vs. 58%, p=0.24). HCC developed faster in HIV/HCV-coinfected than in HCV-monoinfected patients (mean, 26 vs. 34 years after HCV infection, p=0.002). HIV-positive patients received proven therapy more often (48% vs. 31%, p=0.017), but median survival was similar (6.9 vs. 7.5 months, p=0.44). Independent factors predicting survival were symptomatic presentation (hazard ratio [HR], 0.437; p<0.001), any proven therapy (HR, 2.19; p<0.001), diagnosis after 01-Jan-2002 (HR, 1.52; p=0.010), Barcelona-Clínic-Liver-Cancer stages C+D (HR, 0.491; p<0.001), AST/ALT >or= 2.00 (HR, 0.597; p=0.001), AFP >or= 400 ng/mL (HR, 0.55, p=0.003), and platelets >or= 100,000/mm3 (HR, 0.651; p=0.012), but not HIV-serostatus (p=0.19). In HIV-infected patients without HCC therapy (n=33), median survival was longer with undetectable HIV RNA (<400 copies/mL) than with HIV viremia (6.5 vs. 2.6 months, p=0.013). CONCLUSIONS: HIV-positive HCC patients are younger and more frequently symptomatic and infected with HCV or HBV than HIV-negative patients. Tumor staging and survival are similar. In untreated patients, undetectable HIV RNA independently predicts better survival.