News Beyond Our Pages

Article Outline

• Transplacental protection
• Transplacental pollution
• And developmental glitches
• Moving on, a new culprit from expression profiling
• Another one for the catalog

A lot of research is being published characterizing asthma pathogenesis in terms of genetic, morphogenetic, epigenetic, and/or in utero influences. In this month's News Beyond Our Pages we present overviews of a number of interesting reports published in the recent literature on different mechanisms that contribute to in utero and perinatal lung function.

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Transplacental protection 

As the mother goes, so goes the child. An article by Conrad et al (J Exp Med 2009;206: 2869-77), along with an excellent commentary by Holt and Strickland (J Exp Med 2009;206: 2861-4), has provided first-order evidence that the hygiene hypothesis should be revisited. Prenatal exposure might be already driving asthma. Holt and Strickland discussed the work of Conrad et al in the context of a secondary assumption of the hygiene hypothesis; children born to farming mothers who were exposed to nonpathogenic “cowshed” bacteria while pregnant had higher levels of regulatory T-cell activity and lower T_H2 responses at birth. Conrad et al investigated this observation using a murine model of experimental asthma involving the nonpathogenic bacteria Acinetobacter lwoffi. Pregnant mice were exposed intranasally to A lwoffi, and their neonates were challenged with A lwoffi. Not only did the F1 of A lwoffi–exposed mothers resist having asthma symptoms, but the offspring's T_H2 antibody titers were much lower than in the control F1. Conrad et al noted that the protective pathway begins as a local T_H1 response and then disseminates systemically, and they demonstrated that this protective effect was dependent on maternal Toll-like receptor signaling at the decidua/placental interface.

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Transplacental pollution 

Murdzoska et al (Am J Respir Crit Care Med 2010;181:64-71) looked at the effect of both maternal and infant detoxification pathways on neonatal airway function. Focusing on glutathione-S-transferase (GST) genes, they assessed the effect of 2 deletion mutations (GSTT1 and GSTM1) and 1 polymorphic gene (GSTP1, Ile105Val) on airway reactivity and lung function at 1, 6, and 12 months of age. Infant, maternal, or both non-null GSTT1 was associated with increased maximal flow at functional residual capacity at 6 months and decreased airway reactivity at 12 months. GSTT1 infants exposed to tobacco smoke in utero had reduced airway reactivity at 1 month and increased maximal flow at functional residual capacity throughout the first 12 months. Smoking mothers with the GSTP1 Ile/Val or Val/Val genotype conferred protection to their infant, regardless of the infant's genotype.

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• Jazminska Murdzoska

Lead author Jazminska Murdzoska, BSc, provided this statement: “This research highlights the effect of both maternal and fetal genetic variations in detoxification genes on infant lung health outcomes, particularly when investigating the effects of in utero smoke exposure. It further highlights the importance of both genetic and environmental factors on in utero lung development.”

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And developmental glitches 

Further complicating this very murky picture of asthma susceptibility is an article by Sharma et al (Am J Respir Crit Care Med 2009; published online as doi:10.1164/rccm.200907-1009OC) identifying polymorphisms in genes critical to lung morphogenesis that are strongly associated with clinical lung function values. Two genes from the Wnt-signaling pathway, WISP1 and WIF1, were strongly associated with lower FEV₁ and reduced forced vital capacity in a North American childhood asthma cohort and a Costa Rican childhood asthma cohort. The authors reported that Wnt-signaling proteins are known to orchestrate lung epithelial-mesenchymal interactions, and aberrations in Wnt gene expression have been correlated to submucosal gland dysfunction.

Lead author Sunita Sharma had this to say: “Using the gene expression signature of early human fetal lung development, we have identified genes in the Wnt-signaling pathway that are implicated in the pathogenesis of impaired lung function in patients with asthma. Our study provides further evidence of the developmental origins of adult disease by suggesting that genetic variants and environmental exposures that affect in utero gene expression appear to impact subsequent lung function in health and disease.”

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Moving on, a new culprit from expression profiling 

Hallstrand et al (PLoS ONE, doi:10.1371/journal.pone.0008583) found another novel gene associated with asthma and exercise-induced bronchoconstriction (EIB). The authors looked at genome-wide expression upregulation in 2 groups of subjects with asthma, one with comorbid EIB and one without, along with a group of healthy control subjects. After exercise challenge in both groups, genes involved in epithelial repair and mast cell activation had increased expression in the asthma plus EIB group compared with that seen in the asthma-only group. They reported an especially interesting finding that transglutaminase 2 (TGM2) was identified as the most differentially expressed gene at baseline across all 3 groups. TGM2 has not been previously linked to asthma pathogenesis; however, Hallstrand et al confirmed high expression levels in airway epithelium from subjects with asthma. TGM2 exerts its effects on secreted phospholipase A₂ enzymes, which are critical to the production of eicosanoids, such as the cysteinyl leukotrienes. They also pointed out that TGM2 is near a gene cluster associated with barrier function that has been linked to atopic dermatitis and asthma.

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• Teal Hallstrand

First author Teal Hallstrand, MD, MPSH, offered this comment: “Our findings provide another clue to the basis of dysregulated eicosanoid synthesis in asthma. We studied asthmatic patients with a phenotype of high leukotriene production, revealing that transglutaminase 2 (TGM2) was overexpressed in the airways of these patients and functions to activate a secreted phospholipase A₂ that serves as a key regulator of eicosanoid synthesis. More research is needed to understand whether epithelial injury in asthmatic patients amplifies eicosanoid synthesis through TGM2.”

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Another one for the catalog 

Sleiman and colleagues (N Engl J Med 2010;362:36-44) reported the discovery of another gene, DENND1B, linked to asthma susceptibility from a genome-wide association study across 4 cohorts, including one cohort of African ancestry. Sleiman et al confirmed a previous gene association on locus 17q21 and identified 8 single nucleotide polymorphisms on a new gene, 1q31, which codes for DENN/MADD, a TNF-α receptor–binding protein. The significant association was replicated in all noncontrol cohorts. Interestingly, the alternative allele at 1q31 was strongly associated with early onset of asthma in the African American cohort, whereas it was more protective and associated with delayed onset in the European American cohort. Editors' note: Readers interested in this topic might also want to read 3 genome-wide association studies reported in the February 2010 issue of the Journal of Allergy and Clinical Immunology (Wu et al, Mathias et al, and Li et al, with an accompanying editorial by Vercelli).

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