News Beyond Our Pages

Even patients with severe asthma are often nonadherent 

Gamble et al (Am J Respir Crit Care Med 2009;180:817-22) used pharmacy records to assess adherence with inhaled corticosteroid/long-acting β-agonist combination therapy in 182 patients referred to a difficult asthma clinic in Northern Ireland. Over the previous 6 months, 35% of the patients were found to have filled less than 50% of the medication prescriptions. Women were more apt to be nonadherent than men (42% vs 23%). Those less than 50% adherent had clinically meaningfully lower Asthma Quality of Life scores and were significantly more apt to have been hospitalized 3 or more times in the last year. When adherence to oral corticosteroids was assessed based on measurement of plasma prednisone and cortisol levels, 45% of the 51 patients were found to be nonadherent. Therefore before prescribing expensive therapy for patients with severe refractory asthma, be certain they are taking their prescribed controller therapy.

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It's the little things 

MicroRNAs (miRNAs) have hit the immunologic research radar, and Mattes et al (Proc Natl Acad Sci U S A 2009;106:18704-9) targeted one that has big implications for asthma pathogenesis. The authors identified miR-126 as a critical link between innate and adaptive responses in allergic asthma. In a murine model of asthma induced by house dust mite allergens, they demonstrated that miR-126 expression and TH2-mediated allergic inflammation were dependent on the Toll-like receptor 4/MyD88 pathway. Mattes et al generated an antisense inhibitor, anti-miR-126, and administered it to murine airways. House dust mite–induced airway inflammation was abolished, as was mucus hypersecretion and eosinophil accumulation. The authors proposed that miRNA knockdown could hold promise as a potent anti-inflammatory treatment.

More awareness or more disease? 

Are food allergies on the rise, or has our awareness changed? Is it some of both? Branum and Lukacs (Pediatrics 2009, doi:10.1542/peds2009-1210) thought an epidemiologic analysis might provide some insight. Using the abundant health databases compiled by the National Center for Health Statistics, their analysis showed significant increases in rates of food allergy among all children from 1997-2007, as well as increased rates of skin allergy or eczema across the same time period. The authors also identified increasing trends in food allergy prevalence among non-Hispanic white, non-Hispanic black, and Hispanic children. They reported that the number of outpatient care visits with food allergy–related diagnoses almost tripled from 1993-1997 through 2003-2006. The authors commented that it was still unclear whether increased reports of food allergy in children were associated with increased diagnosis or increased awareness by health care providers and parents.

Lead author Amy Branum, MSPH, provided this comment: “Although the results are not as clinically based as we would like, the data from these large national surveys do provide some estimate of the food allergy experience among all children in the United States. This is important because it allows us to examine time trends and also to start to understand potential racial disparities in food allergy.”

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Treatment for the “septic system” 

Resolvins are recently identified lipid mediators from the omega-3 family that have been associated with inflammatory disease resolution. Spite et al (Nature 2009;461:1287-91) decided to look at resolvin D2 (RvD2) in patients with sepsis based on recent research that demonstrated that RvD2 was associated with the resolution phase of inflammation. Poor outcomes in patients with sepsis have been correlated strongly to the cytokine “storm” and impaired microbial clearance. Using a murine microbial peritonitis model, the authors reported that injected RvD2 dramatically diminished excessive neutrophil infiltration and cytokine production while enhancing mononuclear cell– and macrophage-mediated microbial clearance. They suggested that RvD2 might represent a new therapeutic intervention in septic inflammation that does not impair host immune responses.

Wandering receptors 

Conventional wisdom suggests that cross-linked high-affinity receptor–IgE complexes must be immobilized to initiate mast cell degranulation signaling. Andrews et al (Immunity 2009;31:469-79) have presented evidence that this just is not the case. Using quantum dot tracking, the authors demonstrated that small mobile clusters of FcεRI-IgE with a minimum of 3 receptors induce Syk kinase activation and high levels of secretion. They reported that receptor aggregates became immobile and were internalized as they increased in size and that this occurs in an antigen concentration–dependent manner. Andrews et al proposed that the size of cross-linked FcεRI-IgE complexes determined immobilization, which was a trigger for internalization only. Small cross-linked receptor complexes were sufficient to force kinase activation in the absence of immobilization.

Senior author Diane Lidke, PhD, had this to say about their findings: “Part of the excitement about this article is that we have captured the behavior of FcεRI in real time at the single-molecule level. We were able to observe small (cross-linked) FcεRI aggregates moving around on the cell surface under conditions that led to degranulation. This represents a paradigm shift because receptor immobilization has been proposed to be critical for FcεRI signaling. Instead, we show that immobilization is linked to larger aggregate size and a trigger for internalization. The fact that even modest doses of low-valency antigen can induce degranulation helps to explain the sensitivity of mast cells and basophils in the allergic response, where only a small subset of receptors needs to be engaged for the release of inflammatory mediators.”

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Diane Lidke

Resolving lung injury: A new role for regulatory T cells in controlling the innate immune response 

D'Alessio et al (J Clin Invest 2009;119:2898-913) have characterized elegantly a resolution mechanism in acute lung injury. Starting with observations that CD4+CD25+ forkhead box protein 3–positive regulatory T (Treg) cell numbers increase in the alveolar compartment as injury transitions to resolution, the authors demonstrated that adoptive transfer of Treg cells completely resolved acute lung injury in lymphocyte-deficient mice. This finding was correlated with Treg cell–enhanced TGF-β production by activated macrophages. Additionally, D'Alessio et al analyzed bronchoalveolar lavage samples from patients with acute lung injury, in which they found that Treg cells accumulated in the alveolar compartments in human subjects as well.

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Promiscuous proteins 

High-mobility group box (HMGB) proteins, which are present in the nucleus, cytosol, and extracellular fluid, have been identified as critical liaisons between nucleic acids associated with innate immune responses and transmembrane Toll-like receptors and cytosolic receptor activation pathways. Yanai et al (Nature 2009;462:99-103) discovered that HMGB proteins are the shuttles that make this system run. The authors reported that HMGB proteins bound to any available immunogenic nucleic acids and that affinity was strongly correlated to immunogenicity. Yanai et al demonstrated that nucleic acid–bound HMGBs were required for maximal activation of Toll-like receptors that sense nucleic acids.

More good news about fiber 

Just when you are bloated with all the astonishing medical benefits of fiber, Maslowski et al (Nature 2009;461:1282-6) add another soluble tablespoon. Maslowski et al reported that short-chain fatty acids (SCFAs), a product of fiber fermentation by gut microbes, bind G protein–coupled receptor 43 (GPR43), activating a crucial pathway in the normal immune response to inflammation. Alterations in healthy gut flora and reduced SCFA levels are associated with human colitic diseases. Because SCFAs are not confined to the gut but are absorbed efficiently and distributed systemically, the authors extended their findings to peripheral inflammatory diseases. They demonstrated that the inflammation-suppressive effect of coupled SCFA-GPR43 occurred in murine models of asthma and arthritis.

Charles Mackay, PhD, senior author, had this to say about the findings: “Our findings provide further support for a link between diet and immune and inflammatory responses. There is anecdotal evidence that the incidence of asthma in western countries might relate, at least in part, to Western diet, and therefore GPR43 binding to SCFAs provides a new molecular interaction that might be playing a role. . . . [W]e believe that manipulation of gut microbiota holds considerable promise for the treatment of inflammatory diseases.”

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Or . . . not so much, really 

Does the single nucleotide polymorphism Gly→Arg in the β-adrenergic receptor diminish the treatment benefit of long-acting β2-agonists in asthmatic patients who are homozygous for the substitution? Wechsler et al, of the Asthma Clinical Research Network, put it to the test. The Asthma Clinical Research Network multicenter LARGE study was a randomized, double-blind, placebo-controlled, crossover study comparing salmeterol and placebo in subjects receiving inhaled corticosteroid therapy. The treatment groups were divided into asthmatic subjects homozygous for glycine and homozygous for arginine. The article in the Lancet (2009;374:1754-64) reported no significant difference in morning peak expiratory flow when each group was randomized to add salmeterol to inhaled corticosteroids, although airway hyperresponsiveness was greater in the Arg/Arg group. A subanalysis did reveal an interesting and important finding: 8 African American subjects with the Arg/Arg single nucleotide polymorphism did not benefit from the addition of salmeterol to inhaled corticosteroid therapy. The authors noted that this was consistent with recent findings by the US Food and Drug Administration that long-acting β2-agonists are associated with greater risk of serious side effects in African American asthmatic patients.

In concluding their article, the authors, led by Michael Wechsler, MD, and Elliot Israel, MD, observed: “We need to further investigate the importance of the genotype-differentiated response in airway reactivity favoring Gly/Gly participants, as well as the finding that African Americans with the Arg/Arg genotype might not benefit from treatment with salmeterol.”

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Michael Wechsler and Elliot Israel

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Jean Bousquet

The Journal of Allergy and Clinical Immunology is pleased to announce that Jean Bousquet, MD, PhD, has joined our editorial team as coeditor of the News Beyond Our Pages section, beginning with this issue. Marc Rothenberg, MD, PhD, will continue in his role as section coeditor with Dr Bousquet. We extend our gratitude to Harold Nelson, MD, who has served as Dr Rothenberg's coeditor since 2007.

Most news items are written by Sherri Gabbert, PhD.