Volume 125, Issue 3 , Pages 582-583, March 2010
The Editors' Choice
Article Outline
- Earlier identification of children at high risk of persistent asthma
- “Silenced” dendritic cells as tolerance inducers for allergy
- High burden of asthma in rural Mississippi
- A novel human tolerogenic dendritic cell subset re-establishes tolerance to allergen in vitro
- Higher doses of H1-antihistamines improve difficult-to-treat urticaria without increasing somnolence
- S100 proteins: Breaking down the barrier to understanding chronic rhinosinusitis
- Copyright
Earlier identification of children at high risk of persistent asthma
Sensitization to inhalants in preschoolers is recognized as a significant risk factor for subsequent development of persistent asthma, but Holt et al (p 653) have now demonstrated that potentially useful prognostic information on their atopy and asthma risk can be gleaned from IgE measurements of less than the conventional 0.35 kU/L IgE threshold. Notably, 86.1% of high-risk 2-year-olds who attained house dust mite–specific IgE titers of 0.2 kU/L or greater progressed to beyond the sensitization threshold by age 5 years. Moreover, their risk for subsequent asthma increased progressively from 11.3% to 59.2%, with specific IgE titers attained (see the left column of the Table), and, consistent with earlier studies, asthma risk appears markedly amplified if they also experienced early severe lower respiratory tract infections. This effect was again evident using the lower 0.2 kU/L cutoff (log −0.699), where asthma risk at 5 years increased from 20.5% in infection-free children to 92.4% in those experiencing multiple severe lower respiratory tract infections. These findings point to the potential value of quantitative information on early IgE status and infection history in prediction of risk for persistent asthma in children, and the development of a robust clinical tool for this purpose based on this approach might be an achievable aim for the midterm future.
Predicted probabilities of wheeze at 5 years.
“Silenced” dendritic cells as tolerance inducers for allergy
The potency and selectivity of gene silencing by small interfering RNA (siRNA) makes this technique idea for immunologic manipulation in conditions in which antibodies have drawbacks. A case in point is a recent article by Suzuki et al (p 737) in which the CD40-CD154 interaction was targeted by ex vivo siRNA silencing of dendritic cells (DCs) loaded with allergen. Although this interaction is known to be a potent switch for immune activation, antibody-mediated targeting has been limited by expression of CD154 on platelets. Generation of gene-silenced, antigen-pulsed DCs would allow for “tailor-made” immunomodulatory approaches for induction or suppression of tolerance. In this particular example, administration of CD40-silenced, allergen-loaded DCs before allergic sensitization reduced nasal allergic symptoms and local eosinophil accumulation in vivo, as well as allergen-specific T-cell and B-cell responses in vitro. The immunomodulatory effect appeared to be antigen specific and associated with generation of allergen-specific regulatory T cells. Immunomodulatory effects of the siRNA-manipulated DCs appeared to be dominant, inasmuch as suppression of allergic symptoms after onset of allergy was also reported. This study serves as a model for future antigen-specific immunomodulatory approaches that should be explored.
High burden of asthma in rural Mississippi
Roy et al (p 636) examined the role of race, sex, age, and income on asthma hospital discharges in 2 Mississippi regions, the urban Jackson Metropolitan Statistical Area (JMSA) and the rural Mississippi Delta, from 2003 to 2005. The monthly distribution of hospitalizations was similar in the JMSA and the Delta (see Figure). Black Mississippians have higher hospital discharge rates than white Mississippians; blacks in both regions had higher odds of having 3 or more hospitalizations during the study period than whites. In addition, rural Delta residents had higher odds of hospitalization for asthma than residents of the urban JMSA when race, age, sex, and income were controlled. This result differs from the large body of literature showing a higher burden of asthma hospitalizations in urban areas than in rural areas. The Delta residents had higher rates of emergency department visits and lower rates of outpatient visits for asthma than residents of the JMSA, suggesting that lack of preventive/acute outpatient care can contribute to the increased odds for hospitalization in the rural Delta. Studies regarding the influence of access to and quality of primary asthma care on asthma hospitalizations in rural populations are needed.
Distribution of monthly hospitalizations in urban and rural regions of Mississippi.
A novel human tolerogenic dendritic cell subset re-establishes tolerance to allergen in vitro
Defects in the regulatory mechanisms mediated by adaptive type 1 regulatory T (TR1) cells are believed to be crucially involved in allergic reactions. A way to re-establish tolerance and therefore to cure allergic patients might be through induction, expansion, or both of allergen-specific TR1 cells. Dendritic cells (DCs), either at the immature stage or in specialized subsets, have been used to generate antigen-specific TR1 cells in vitro. As reported in this issue of the Journal, Pacciani et al (p 727) compared the in vitro ability of DCs incubated with IL-10 during the last 2 days of differentiation (IL-10–DCs) and DCs differentiated in the presence of IL-10 (DC-10s) to modulate allergen-specific T-cell responses and to prime T cells to become allergen-specific TR1 cells. Results demonstrated that despite the different phenotype and cytokine production, both DC subsets are powerful modulators of Dermatophagoides pteronyssinus allergen 2 (Der p 2)–specific TH2 responses in children with house dust mite allergy. However, only DC-10s pulsed with Der p 2 were able to induce anergic Der p 2–specific T cells, which were functionally equivalent to TR1 cells (see Figure). The use of tolerogenic DC-10s to modulate type 2 immune responses and induce allergen-specific TR1 cells opens up new therapeutic and prophylactic perspectives for allergic diseases.
Allergen-specific TR1 cells induced with DC-10s suppress TH2 cells of allergic patients, partially through IL-10 and TGF-β.
Higher doses of H1-antihistamines improve difficult-to-treat urticaria without increasing somnolence
Guidelines suggest increasing doses of second-generation H1-antihistamines up to 4-fold to improve symptom control of difficult-to-treat chronic urticaria before trying other therapeutic options. This recommendation is not evidence based, and concerns exist about excessive somnolence. Staevska et al (p 676) treated 80 patients with levocetirizine or desloratadine, increasing doses weekly from 5 through 10 to 20 mg in those not responding to the lower doses. Patients unresponsive to 20 mg of one drug were switched to the other. Wheal and pruritus scores, quality of life, patient discomfort, somnolence, and safety were assessed weekly. This dose-incremental approach improved symptoms in the majority of patients, but approximately 15% remained refractory to antihistamine therapy. Of the 28 patients remaining symptomatic on 20 mg of desloratadine, 7 became symptom free with 20 mg of levocetirizine. None of the 18 patients with a poor response to levocetirizine benefited with 20 mg of desloratadine. Increasing H1-antihistamine doses improved quality of life. Somnolence did not increase; in fact, levocetirizine decreased somnolence in parallel with symptom improvement indicative of reducing sleep deprivation in patients with chronic urticaria. In conclusion, increasing doses of second-generation H1-antihistamines improve symptoms of urticaria regardless of the drug used. The magnitude of the clinical benefit differs between antihistamines and appears to be related to their potency.
S100 proteins: Breaking down the barrier to understanding chronic rhinosinusitis
Chronic rhinosinusitis (CRS) is a persistent inflammatory disease of the nasal and paranasal sinus mucosae and is one of the most frequently reported chronic diseases in the United States. Allergens, fungi/bacteria, biofilms, and superantigens have been implicated in the development of CRS, but its cause remains poorly understood. More recently, studies have highlighted the importance of the epithelium and its barrier function in skin and airway diseases. In this issue Tieu et al (p 667) report significantly altered levels of the barrier and antimicrobial proteins psoriasin and calprotectin in the upper airways and sinuses of patients with CRS. Specifically, this study demonstrated a dramatic reduction in epithelial psoriasin and calprotectin levels at the epithelial interface in patients with CRS (see Figure). Thus reduced immune barrier function in patients with CRS might lead to increased susceptibility to bacterial and fungal colonization in the upper airways and sinuses, an event that cause play a causative role in CRS pathogenesis and susceptibility to infectious disease. Future studies aimed at understanding the molecular mechanism of the reduced immune barrier might point the way to strategies to increase or strengthen the immune barrier in patients with CRS.
Epithelial psoriasin (S100A7) levels are dramatically reduced in the sinonasal mucosae of patients with CRS.
PII: S0091-6749(10)00175-2
doi:10.1016/j.jaci.2010.01.042
© 2010 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Volume 125, Issue 3 , Pages 582-583, March 2010
