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The Editors' Choice
The Editors’ Choice Donald Y. M. Leung, MD, PhD Stanley J. Szefler, MD and the Associate Editors of the JACI
THE JOURNAL OF
Allergy Clinical Immunology AND
VOLUME 121
NUMBER 4
Not all proteins can become allergens In recent years, there has been an ongoing debate about whether allergens possess distinct features not present in nonallergenic proteins or whether allergic sensitization to certain proteins primarily depends on their abundance and other components present in the allergen source. In this context, the previous classification of food and pollen allergens into protein families provided some insights into possible common features of allergens. In this month’s article by Radauer et al (p 847), the authors used AllFam, a database of protein families of allergens, to establish a classification of all allergens by sequence, structure, and function (see Figure). The authors showed that only 2% of all protein families known to date contain allergens. In addition, most allergens can be grouped into a few functional classes, such as hydrolytic enzymes, metal-binding proteins, storage proteins, and cytoskeleton-associated proteins. These results suggest the existence of structural or functional features that make proteins allergenic. Knowledge of these features will provide new insights into the molecular mechanism of allergic sensitization and pave
The protein families containing the highest numbers of allergens.
the way for novel therapeutic concepts that target the patient’s immune system at the very beginning of the allergic sensitization process.
IL-13: Is RNA stability the Achilles’ heel? Since its discovery 15 years ago, IL-13, a product of TH2 cells and basophils, has rapidly emerged as a central cytokine in asthma and is increasingly appreciated as a participant in other conditions—eg, inflammatory bowel and scleroderma. IL-13 gene regulation is therefore a promising arena in the quest for molecular biomarkers and pharmacologic targets in human immune disease. Casolaro et al (p 853) present evidence that the IL-13 gene is subjected to at least 2 levels of regulation: in addition to the pathways that promote IL-13 gene transcription, the end product of these processes, IL-13 mRNA, is in turn targeted by intracellular molecules that regulate its stability and rate of translation. Specifically, the authors show that the RNA-binding protein HuR can interact with specific recognition sequences within the 39 untranslated region of the IL-13 mRNA—ie, the region located immediately downstream of the coding sequence—and prolong its half-life, hence contributing to increased production of this cytokine in mitogen-activated T cells (see Figure). Conversely, interfering with expression of this protein is sufficient to significantly affect IL-13 production in these cells. The authors conclude that
Novel genetic marker of exacerbations in childhood asthma Genome-wide association studies have added a new dimension in the search for genetic regulators of the asthma phenotype. Novel links between specific polymorphisms and clinical outcomes need to be replicated in different populations. In this issue, Tavendale et al (p 860) confirm that a common C/T single nucleotide polymorphism at a locus controlling the expression of the ORMDL3 gene is associated with both the presence (P ¼ 1.73 3 1012) and the severity of childhood asthma. In a study of more than 2000 children and young adults from Scotland, they have found that
J ALLERGY CLIN IMMUNOL
How HuR intracellular levels affect IL-13 mRNA generation.
HuR and RNA stability in general are suitable targets in the management of asthma and other IL-13–dependent conditions.
individuals with a single copy of the T allele were 50% more likely to have asthma and that homozygote individuals bearing 2 copies of the T allele were more than twice as likely to have asthma as individuals carrying only the C allele. The T allele was also associated (P ¼ .008) with an increased frequency of exacerbations of asthma, as determined by school absence, hospital admission, or use of oral steroids. This association with increased exacerbations was apparent in patients treated with all classes of asthma therapy. Robust confirmation of the association of this polymorphism with asthma and the finding that these individuals have poorer disease control has identified a novel therapeutic target, which, if successfully exploited, might provide an alternative approach to the management of asthma.
April 2008 Page 845
Leukotriene B4/BLT1 pathway contributes to corticosteroid-insensitive asthma by activating CD81 T cells CD4+ T cells and eosinophils play important roles in the pathogenesis of asthma, and the numbers of these cells in the airways are decreased by corticosteroid treatment. Recent studies have also revealed an important role for TH2 cytokineproducing effector memory CD8+ T cells (TEFF) in the development of airway hyperresponsiveness and allergic airway inflammation. Ligation of the leukotriene B4 (LTB4) receptor 1 (BLT1) on TEFF by LTB4 is essential to their recruitment into the airways. As reported in this issue of the Journal, Ohnishi et al (p 864) investigated the corticosteroid sensitivity of CD4+ T cells and CD8+ T cells and the effects on this LTB4/BLT1/CD8+ T-cell pathway. The authors found that corticosteroids upregulate BLT1 expression on these CD8+ TEFF, likely through increased IL-2 receptor expression, and potentiate CD8+ TEFF-mediated airway hyperresponsiveness, allergic airway inflammation, and goblet cell metaplasia (see Figure). They also showed that these CD8+ TEFF are resistant to corticosteroids. Inasmuch as LTB4 production is also resistant to corticosteroid treatment, these findings identify a novel pathway that can contribute to corticosteroid-insensitive asthma. Targeting of CD8+ T cells and the LTB4/BLT1 pathway may provide new therapeutic options for severe, corticosteroid-insensitive asthma. Dexamethasone-treated CD8+ TEFF lead to enhanced airway inflammation and goblet cell metaplasia.
Filaggrin mutations, presistent eczema, and increased asthma risk Henderson et al (p 872) report the largest longitudinal and most detailed study on the effect of mutations in the skin barrier protein filaggrin on atopic diseases at a population level. Their findings replicate those of earlier studies showing a strong effect of filaggrin (FLG) mutations on eczema risk and associated asthma, but these longitudinal data additionally allowed analysis of the effect of FLG mutations on duration of eczema and on other atopic diseases. The key finding is that for children with eczema, FLG mutations predict a more prolonged course (see Figure) and a greater risk of asthma and allergic sensitization. In particular, FLG mutations appear to be particularly strongly associated with the complex ‘‘eczema plus asthma’’ phenotype. In keeping with previous work, mutations in FLG convey no risk of asthma in the absence of eczema; accordingly, these genetic findings may prompt exploration of classification of childhood asthma into ‘‘asthma occuring with eczema’’ and ‘‘asthma, no eczema’’ subtypes, among others.
Prematurity, chorioamnionitis, and the development of recurrent wheezing Previous studies on prematurity and asthma have yielded positive results in many, though not all, studies. A few studies have suggested that chorioamnionitis might contribute to the risk of asthma. The fact that most studies of prematurity and asthma have not accounted for chorioamnionitis may partly explain variability of the association between prematurity and asthma. Chorioamnionitis as a potential risk factor for wheezing illness or asthma becomes even more important for understanding asthma disparity, because prematurity and chorioamnionitis disproportionately affect African American births.
Page 846 April 2008
In children with eczema, FLG mutations predict significantly more persistent disease.
Overall, 46% of carriers of a single FLG mutation developed eczema by 42 months of age. Kumar et al (p 878) studied more than 1000 babies born in a Boston hospital as they sought to understand the relationship of prematurity and chorioamnionitis with recurrent wheezing in the child’s early life. They have confirmed that prematurity is associated with recurrent wheezing. Furthermore, they have demonstrated that very preterm birth and the presence of chorioamnionitis greatly increased the incidence of wheezing (odds ratio, 4.0; 95% CI, 2.0-8.0); this finding was even more pronounced in African American children (odds ratio, 5.4; 95% CI, 2.4-12.0). Neither prematurity nor chorioamnionitis was found to be associated with food allergy or eczema. Further study is warranted to evaluate whether these associations persist as children grow older and whether this translates to an increased risk of asthma.
J ALLERGY CLIN IMMUNOL
THE JOURNAL OF
Allergy Clinical Immunology AND
VOLUME 121
NUMBER 4
Not all proteins can become allergens In recent years, there has been an ongoing debate about whether allergens possess distinct features not present in nonallergenic proteins or whether allergic sensitization to certain proteins primarily depends on their abundance and other components present in the allergen source. In this context, the previous classification of food and pollen allergens into protein families provided some insights into possible common features of allergens. In this month’s article by Radauer et al (p 847), the authors used AllFam, a database of protein families of allergens, to establish a classification of all allergens by sequence, structure, and function (see Figure). The authors showed that only 2% of all protein families known to date contain allergens. In addition, most allergens can be grouped into a few functional classes, such as hydrolytic enzymes, metal-binding proteins, storage proteins, and cytoskeleton-associated proteins. These results suggest the existence of structural or functional features that make proteins allergenic. Knowledge of these features will provide new insights into the molecular mechanism of allergic sensitization and pave
The protein families containing the highest numbers of allergens.
the way for novel therapeutic concepts that target the patient’s immune system at the very beginning of the allergic sensitization process.
IL-13: Is RNA stability the Achilles’ heel? Since its discovery 15 years ago, IL-13, a product of TH2 cells and basophils, has rapidly emerged as a central cytokine in asthma and is increasingly appreciated as a participant in other conditions—eg, inflammatory bowel and scleroderma. IL-13 gene regulation is therefore a promising arena in the quest for molecular biomarkers and pharmacologic targets in human immune disease. Casolaro et al (p 853) present evidence that the IL-13 gene is subjected to at least 2 levels of regulation: in addition to the pathways that promote IL-13 gene transcription, the end product of these processes, IL-13 mRNA, is in turn targeted by intracellular molecules that regulate its stability and rate of translation. Specifically, the authors show that the RNA-binding protein HuR can interact with specific recognition sequences within the 39 untranslated region of the IL-13 mRNA—ie, the region located immediately downstream of the coding sequence—and prolong its half-life, hence contributing to increased production of this cytokine in mitogen-activated T cells (see Figure). Conversely, interfering with expression of this protein is sufficient to significantly affect IL-13 production in these cells. The authors conclude that
Novel genetic marker of exacerbations in childhood asthma Genome-wide association studies have added a new dimension in the search for genetic regulators of the asthma phenotype. Novel links between specific polymorphisms and clinical outcomes need to be replicated in different populations. In this issue, Tavendale et al (p 860) confirm that a common C/T single nucleotide polymorphism at a locus controlling the expression of the ORMDL3 gene is associated with both the presence (P ¼ 1.73 3 1012) and the severity of childhood asthma. In a study of more than 2000 children and young adults from Scotland, they have found that
J ALLERGY CLIN IMMUNOL
How HuR intracellular levels affect IL-13 mRNA generation.
HuR and RNA stability in general are suitable targets in the management of asthma and other IL-13–dependent conditions.
individuals with a single copy of the T allele were 50% more likely to have asthma and that homozygote individuals bearing 2 copies of the T allele were more than twice as likely to have asthma as individuals carrying only the C allele. The T allele was also associated (P ¼ .008) with an increased frequency of exacerbations of asthma, as determined by school absence, hospital admission, or use of oral steroids. This association with increased exacerbations was apparent in patients treated with all classes of asthma therapy. Robust confirmation of the association of this polymorphism with asthma and the finding that these individuals have poorer disease control has identified a novel therapeutic target, which, if successfully exploited, might provide an alternative approach to the management of asthma.
April 2008 Page 845
Leukotriene B4/BLT1 pathway contributes to corticosteroid-insensitive asthma by activating CD81 T cells CD4+ T cells and eosinophils play important roles in the pathogenesis of asthma, and the numbers of these cells in the airways are decreased by corticosteroid treatment. Recent studies have also revealed an important role for TH2 cytokineproducing effector memory CD8+ T cells (TEFF) in the development of airway hyperresponsiveness and allergic airway inflammation. Ligation of the leukotriene B4 (LTB4) receptor 1 (BLT1) on TEFF by LTB4 is essential to their recruitment into the airways. As reported in this issue of the Journal, Ohnishi et al (p 864) investigated the corticosteroid sensitivity of CD4+ T cells and CD8+ T cells and the effects on this LTB4/BLT1/CD8+ T-cell pathway. The authors found that corticosteroids upregulate BLT1 expression on these CD8+ TEFF, likely through increased IL-2 receptor expression, and potentiate CD8+ TEFF-mediated airway hyperresponsiveness, allergic airway inflammation, and goblet cell metaplasia (see Figure). They also showed that these CD8+ TEFF are resistant to corticosteroids. Inasmuch as LTB4 production is also resistant to corticosteroid treatment, these findings identify a novel pathway that can contribute to corticosteroid-insensitive asthma. Targeting of CD8+ T cells and the LTB4/BLT1 pathway may provide new therapeutic options for severe, corticosteroid-insensitive asthma. Dexamethasone-treated CD8+ TEFF lead to enhanced airway inflammation and goblet cell metaplasia.
Filaggrin mutations, presistent eczema, and increased asthma risk Henderson et al (p 872) report the largest longitudinal and most detailed study on the effect of mutations in the skin barrier protein filaggrin on atopic diseases at a population level. Their findings replicate those of earlier studies showing a strong effect of filaggrin (FLG) mutations on eczema risk and associated asthma, but these longitudinal data additionally allowed analysis of the effect of FLG mutations on duration of eczema and on other atopic diseases. The key finding is that for children with eczema, FLG mutations predict a more prolonged course (see Figure) and a greater risk of asthma and allergic sensitization. In particular, FLG mutations appear to be particularly strongly associated with the complex ‘‘eczema plus asthma’’ phenotype. In keeping with previous work, mutations in FLG convey no risk of asthma in the absence of eczema; accordingly, these genetic findings may prompt exploration of classification of childhood asthma into ‘‘asthma occuring with eczema’’ and ‘‘asthma, no eczema’’ subtypes, among others.
Prematurity, chorioamnionitis, and the development of recurrent wheezing Previous studies on prematurity and asthma have yielded positive results in many, though not all, studies. A few studies have suggested that chorioamnionitis might contribute to the risk of asthma. The fact that most studies of prematurity and asthma have not accounted for chorioamnionitis may partly explain variability of the association between prematurity and asthma. Chorioamnionitis as a potential risk factor for wheezing illness or asthma becomes even more important for understanding asthma disparity, because prematurity and chorioamnionitis disproportionately affect African American births.
Page 846 April 2008
In children with eczema, FLG mutations predict significantly more persistent disease.
Overall, 46% of carriers of a single FLG mutation developed eczema by 42 months of age. Kumar et al (p 878) studied more than 1000 babies born in a Boston hospital as they sought to understand the relationship of prematurity and chorioamnionitis with recurrent wheezing in the child’s early life. They have confirmed that prematurity is associated with recurrent wheezing. Furthermore, they have demonstrated that very preterm birth and the presence of chorioamnionitis greatly increased the incidence of wheezing (odds ratio, 4.0; 95% CI, 2.0-8.0); this finding was even more pronounced in African American children (odds ratio, 5.4; 95% CI, 2.4-12.0). Neither prematurity nor chorioamnionitis was found to be associated with food allergy or eczema. Further study is warranted to evaluate whether these associations persist as children grow older and whether this translates to an increased risk of asthma.
J ALLERGY CLIN IMMUNOL