The Editors' Choice
Authors: Donald Y.M. Leung, Stanley J. Szefler
Journal: Journal of Allergy and Clinical Immunology (2011)

Previous studies suggested a protective effect of farm exposures on allergic diseases, which could already be effective during pregnancy. However, this protective effect on atopic dermatitis remains inconsistent. In a prospective study, the Protection against Allergy Study in Rural Environments (PASTURE/EFRAIM), including 1063 children (508 born to farmers and 555 born to nonfarmers), Roduit et al (p 179) found that children with mothers having contact with farm animals and cats during their pregnancies had a significantly reduced risk of atopic dermatitis in the first 2 years of life (see Figure). Contact with 3 or more farm animal species during pregnancy reduced the risk of atopic dermatitis by more than half. Gene expression of innate immunity receptors, which reflects both genetic and environmental influences, was measured in the cord blood of these children; the authors found evidence that high expression of these genes at birth was associated with decreased physician’s diagnoses of atopic dermatitis. Moreover, a slight effect of gene-environment interaction with a polymorphism in the Toll-like receptor 2 gene (TLR2) was shown. These findings support that prenatal exposures, especially contact with animals, might prevent atopic dermatitis in young children and that the innate immune system plays a role in the development of this disease. There is increasing evidence of heterogeneity of asthma, with different phenotypes being identified. However, a consistent method for the classification of asthma phenotypes that combines clinical, cellular, and molecular information has not yet been defined. As reported in this issue of the Journal, Baines et al (p 153) investigated the presence of transcriptional asthma phenotypes (TAPs) using whole-genome gene expression of induced sputum samples. The authors demonstrate the use of unsupervised hierarchical clustering of sputum gene expression profiles to identify 3 TAPs relating to important differences in clinical asthma status, inflammatory cells, gene expression, and inflammatory pathways. They show that TAP1 was eosinophil enriched, had a higher fraction of exhaled nitric oxide level, and worsened airflow obstruction and asthma control. TAP2 was neutrophil enriched, and it had more severe airflow obstruction and upregulation of IL-1 and TNF-α/nuclear factor κB pathways. TAP3 had normal levels of sputum granulocytes, relatively normal lung function, and gene expression profiles similar to those of healthy control subjects. This study supports the molecular heterogeneity of asthma and has provided a further framework for exploration into the pathologic mechanisms of asthma phenotypes, which are important for the development of more effective treatments. Early studies have suggested that esophageal eosinophilia occurs in association with TH2 allergic responses, yet the local and systemic expression of relevant cytokines has not been well characterized. Blanchard et al (p 208) used a human inflammatory cytokine and receptor PCR array containing 84 genes followed by PCR validation and multiplex arrays to quantify cytokine mRNA in esophageal biopsy specimens and blood levels. Esophageal transcripts of numerous chemokines, cytokines, and cytokine receptors were induced at least 4-fold in patients with eosinophilic esophagitis (EE). Remarkably, analysis of 288 esophageal biopsy specimens revealed that eotaxin-3 mRNA levels alone had 89% sensitivity for distinguishing patients with EE from those without EE. The presence of allergy was associated with significantly increased esophageal expression of IL-4 and IL-5 mRNA in patients with active EE. A panel of 8 blood cytokine levels retrospectively distinguished subjects without EE from patients with EE with 100% specificity and 100% sensitivity; however, when applied to a blinded, prospectively recruited cohort, the cytokine panel scoring system had an average approximately 75% predictive value, sensitivity, and specificity. Taken together, these findings indicate that IL-13 and IL-5 associate with eosinophil and eotaxin-3 levels, indicating the key role of adaptive TH2 immunity in regulating eotaxin-3–driven esophageal eosinophilia in the absence of a consistent systemic change in cytokines. Furthermore, this study has determined that the single detection of esophageal eotaxin-3 mRNA levels has an excellent ability to diagnose EE. Excessive mucus production and mucus plugging are key pathologic features of asthma, yet the mechanisms responsible for mucus production remain largely unknown, and therapies to effectively target mucus hypersecretion are lacking. Expression of the serine protease inhibitors SerpinB3 and SerpinB4 is upregulated in patients with asthma, but their role in asthma has remained unclear. As reported in this issue, Sivaprasad et al (p 254) evaluated the role of the murine homolog of these genes using a murine model of asthma. They demonstrated that (1) Serpinb3a plays a nonredundant role in the development of airway hyperresponsiveness and mucus production in both house dust mite and IL-13–induced asthma models, (2) Serpinb3a expression lies downstream of IL-13, and (3) the induction of SPDEF, a transcription factor known to be required for goblet cell differentiation in the lung, is attenuated after allergen challenge in the absence of Serpinb3a (see Figure). The findings from this study describe a previously unrecognized role for Serpinb3a as a central regulator of mucus production in asthma and establish SerpinB3 and Serpinb4 as important new targets for therapeutic intervention to specifically target mucus production in asthma. In addition, the findings from these studies might have implications for other respiratory diseases characterized by mucus overproduction, including viral infection, chronic obstructive pulmonary disease, and cystic fibrosis. Regulatory T (Treg) cells play an important role during the establishment and maintenance of immunologic tolerance and prevent allergic and autoimmune disorders. Protocols to induce or generate Treg cells have thus gained increased attractiveness as therapeutic strategies during recent years. Transgenic overexpression of the transcription factor forkhead box protein 3 (FOXP3) in CD4+ T cells generates artificial Treg cells, which, however, constitute a polyclonal population of undefined antigen specificity. In this issue of the Journal, Schmetterer et al (p 238) combined transgenic overexpression of FOXP3 with a T-cell receptor specific for the major birch pollen allergen epitope Bet v 1142-153 expressed as a single translational unit from an internal ribosomal entry site (ie, green fluorescence protein) containing retroviral vector to engineer allergen-specific Treg cells. These engineered Treg cells suppress proliferation and both TH1 and TH2 effector cytokine production of Bet v 1–specific effector T cells in a dose-dependent manner. Importantly, the suppressive function is dependent on appropriate activation of transgenic Treg cells with the cognate allergenic peptide. In contrast, polyclonal FOXP3 transgenic T cells or CD4+CD25+ naturally occurring Treg cells showed only weak suppression on Bet v 1–specific activation. In summary, the authors have devised engineered customized Treg cells as a novel, highly specific tool for the immunomodulation of allergen-specific immune responses. Asthma and atopy are conditions in which both genetic and environmental factors play important roles, and interactions of both determinants have been described sporadically. Recent analyses on several thousand subjects have revealed a number of hot spots in the genome for susceptibility to asthma and atopy. Among environmental exposures, the farming environment has consistently been associated with protection from childhood asthma and atopy. As reported in this issue, Ege et al (p 138) performed a genome-wide interaction analysis for asthma and atopy using 500,000 genetic markers and farm-related exposures in 1708 children from rural regions of central Europe (see Figure). Despite sufficient statistical power, the study did not confirm previously described interactions. However, strong interactions for asthma and atopy in relation to farming, contact with cows and straw, and consumption of raw farm milk were found for 15 genes that have not yet been implicated in asthma or atopy pathogenesis. Remarkably, all interacting polymorphisms were rare. Hence the authors concluded that common genetic polymorphisms were unlikely to moderate the protective influence of the farming environment on childhood asthma and atopy. This raises the question of whether independent genetically or environmentally induced forms of asthma and atopy exist.