Medical Journal Review
Reviewed by Mark C. Glaum, MD, PhD and Gary Hellermann, PhD, WAO Guest Editors, Division of Allergy and Immunology, University of South Florida College of Medicine
1. RISKS OF INHALED CORTICOSTEROIDS IN COPD
Inhaled corticosteroids (ICS) are commonly used to treat COPD, although efficacy in this disease is less clear. A case-control study within a large cohort of Canadian patients with COPD was performed to determine whether ICS use is associated with increased risk of pneumonia. When normalized for COPD severity, ICS use is still associated with a 70% increased risk of hospitalization for pneumonia. With increased doses (fluticasone 1000 mcg per day or equivalent), the risk of hospitalization for pneumonia is 2-fold high than case control subjects. Editor’s comment: Risk for pneumonia should be considered when prescribing ICS in COPD. Ernst P, Gonzales AV, Brassard P, Suissa S. Am J Respir Crit Care Med 2007; 176:162-66.
2. POLYMORPHISMS IN IL-13 ARE ASSOCIATED WITH TOTAL IGE, EOSINOPHILIA AND ASTHMA EXACERBATIONS
Polymorphisms in the IL-13 gene were examined for association with total serum IgE, eosinophilia and asthma exacerbations in Costa Rican children and in children enrolled in the Childhood Asthma Management Program (CAMP). IL-13 polymorphisms are associated with elevated serum IgE, and eosinophilia, but these polymorphisms are associated with asthma exacerbations in subjects on inhaled corticosteroids only in the CAMP subjects. Editor’s comment: The IL-13 gene may be an important locus that predisposes for certain asthma phenotypes. Hunninghake GM, Soto-Quiros ME, Avila L, et al. J Allergy Clin Immunol 2007; 120: 84-90.
3. THE SEARCH FOR CHILDHOOD ASTHMA GENES
A genome-wide association scan was performed on DNA from 994 subjects with childhood-onset asthma and from 1243 non-asthmatics. More than one-third of children with asthma diagnosed at age 7 years or less show variations in the expression of the ORMDL3 gene on chromosome 17q21. Although the function of ORMDL3 gene product is not known, the gene codes for an evolutionarily ancient transmembrane protein also found in yeast and other primitive organisms. Editor’s comment: This study provides further evidence supporting the importance of genetic factors in childhood asthma. Moffatt MF, Kabesch M, Liang L, et al. Nature 2007; 448: 470-73.
4. ATTENTUATION OF ALLERGIC CONTACT DERMATITIS THROUGH THE ENDOCANNABINOID SYSTEM
The human cannabinoid receptors, CB1 and CB2, are G protein-coupled heterotrimers that bind endocannabinoids as well as exogenous agonists such as tetrahydrocannabinol. Triggers of contact dermatitis are small molecules that penetrate the skin and bind proteins to form haptens. The newly formed haptens are then presented to T lymphocytes by dendritic cells and cause an immune response leading to dermatitis. Mice deficient in CB1 and CB2 (Cnr1-/- and Cnr2-/-) develop an ulcerative dermatitis to nickel that is not seen in the wild type, suggesting that the cannabinoid receptors serve to control the immune response. To test this hypothesis, a model contact allergen, dinitrofluorobenzene (DNFB), which causes contact dermatitis, was applied to wild type mice and Cnr1-/- Cnr2-/- mice. DNFB causes a greater allergic response in cannabinoid receptor-deficient mice compared to normal mice. Stimulation of normal mice with tetrahydrocannabinol, an exogenous cannabinoid that binds to CB1/2, further reduces the DNFB-induced dermatitis. Editor’s comment: Human trials of cannabinoid receptor agonists may determine the efficacy of these compounds in reducing contact dermatitis. Karsak M et al. Science 2007; 316:1494.
5. A DISTINCT “ITCH” RECEPTOR IN THE CENTRAL NERVOUS SYSTEM
Chronic pruritus can be a debilitating condition for which there are few effective clinical remedies. Although the sensation of itch is mediated by unmyelinated C fibers, an itch-specific mediator in the central nervous system has yet to be identified – until now. Researchers at Washington University have identified a gastrin-releasing peptide (GRP) expressed in the dorsal horn of the spinal cord in mice that mediates itch sensation through its receptor (GRPR). Mice with a mutated GRPR gene demonstrate reduced scratching behavior in response to pruritic stimuli compared to wild type controls. In addition, direct injection of a GRPR antagonist into spinal CSF inhibits scratching but not pain perception. Editor’s comment: This CNS peptide receptor may represent a novel therapeutic target for the development of anti-pruritic agents. Sun Y, Chen Z Nature 2007;448: 700-03.
6. RELATIONSHIP BETWEEN AIRWAY NARROWING, PATCHY VENTILATION AND LUNG MECHANICS IN ASTHMATICS
Defects in asthmatic lung ventilation can be localized to heterogeneous areas (Vdefs) which, if numerous or extensive, may have a serious effect on breathing in asthmatics. In this report, 10 mild to moderate asthmatics are tested before and after bronchoconstriction with methacholine. Positron emission tomography (PET) is used to map the regional defects, while lung function (dynamic resistance and elastance) is measured by oscillatory mechanics. The results are mapped into a 3-dimensional lung model to verify that the location and extent of Vdefs, as determined by PET scans, correspond to changes in airflow. A heterogeneous constriction of the airways outside the major bronchioles was found to be necessary to account for the observed changes in lung function and gas exchange upon methacholine challenge. This high degree of specificity in measuring lung mechanics is brought about through an ingenious combination of PET scanning, oscillatory dynamics and computer modeling. Editor’s comment: This paper points out the importance of continued improvement in technology in the understanding of asthma pathology. Tgavalekos NT et al. Eur Resp J 2007; 29:1174.
7. IRRITANT SKIN TEST REACTIONS TO COMMON VACCINES
Concern over potential reactions to a vaccine is a common cause for allergy consultation. Skin testing against vaccines may be indicated in certain individuals; however interpretation of test results is complicated by irritant skin reactions. Twenty healthy volunteers with no history of allergy to foods or drugs and without a history of adverse reactions to vaccines were skin tested to 10 common vaccines. Results demonstrate that skin prick testing with vaccines does not cause irritant reactions even at full strength. Intradermal testing is more likely to induce irritant reactions with certain vaccines (influenza, MMR, varicella), particularly when used at full strength. Editor’s comment: This work provides clinicians with useful guidelines for choosing appropriate concentrations for vaccine skin testing. Wood RA, Setse R, Halsey N. J Allergy Clin Immunol 2007; 120: 478-81.
8. ASSOCIATION OF SELENIUM SUPPLEMENTATION WITH DIABETES TYPE 2
Vitamin supplements are commonly used by patients to treat a variety of medical conditions. Observational epidemiological studies suggest a protective role for antioxidants, including selenium, against the development of diabetes type 2 (DM2). The role of selenium supplementation on the risk of new onset DM2 was examined utilizing data generated from a randomized double-blinded placebo-controlled study designed to study the effect of selenium supplementation on cancer prevention (Nutritional Prevention of Cancer Trial). Supplementation with selenium 200 mcg daily was associated with an incidence of 12.6 cases of DM2 per 1000 person years vs. 8.4 cases per 1000 person years with placebo, hazzard ratio, 1.55 [95% CI, 1.03 to 2.33], despite normalization for age, sex, BMI and tobacco use during an average follow-up period of 7.7 years. Editor’s comment: Prolonged administration of selenium is not protective against DM2 and may even increase risk for this disease. Stranges S, Marshall J, Natarajan J, et al. Ann Intern Med 2007; 147:217-23.
9. TH17 CELLS CONTRIBUT TO UVEITIS AND SCLERITIS AND ARE EXPANDED BY IL-2 AND INHIBITED BY IL-27/STAT1
The possible role of Th17 cells in the generation of uveitis and scleritis in humans was investigated in a mouse model of experimental autoimmune uveitis (EAU). Scleritis and uveitis are chronic inflammatory ocular diseases that can lead to blindness. The number of Th17 cells and level of IL-17 is elevated in peripheral blood from human uveitis and scleritis patients and this causes an increase in TNF-alpha which could account for the pathology. The authors found that humans have Th17 cells in peripheral blood while mice do not. Blocking IL-17 with IL-17 antibody reduces EAU in mice. IL-27, a member of the IL-12 family of proteins that is expressed in retina, inhibits the expansion of Th17 cells and is upregulated by IFN-gamma. In EAU in mice, the disease increases in severity as the IL-17 level goes up and vice versa. As EAU resolves, IL-17 is reduced while the Th-17 phenotype is replaced by Th1. Editor’s comment: Intervention to reduce the number of Th17 cells in patients with chronic uveitis may ameliorate the pathology. Amadi-Obi A, et al. Nature Medicine 2007; 13:711.
10. FLAVONOIDS AND RELATED COMPOUNDS AS ANTI-ALLERGIC SUBSTANCES
The role of diet in the etiology of asthma and other diseases with an inflammatory component is highly controversial. Plant-derived flavonoids and polyphenols are among the best-studied groups of dietary compounds shown in various model systems and in some clinical studies to reduce inflammation and allergic responses. This comprehensive review evaluates the extensive literature on flavonoids and the immune response especially with regard to the mechanism of action (e.g., inhibition of IL-4 synthesis) and the structure-function relationships. Numerous examples of the clinical effects of flavonoids on allergic disease, both positive and negative are given. Editor’s comment: The evidence seems to demonstrate a protective anti-inflammatory effect of plant flavonoids that are commonly found in fruits, vegetables and beverages. More extensive clinical studies are needed before specific dietary recommendations can be implemented. Kawai M et al. Allergology Internatl 2007; 56:113.
