The Editors' Choice

Article Outline

• Cytokine regulation of IL-13Rα2 and IL-13 Rα1
• Animal sensitivity linked to HLA phenotype
• Changes in asthma pharmacotherapy over the past 3 decades
• Cysteine proteases can activate human eosinophils and cause degranulation
• Expression of profibrotic cytokines in acute and chronic skin lesions in atopic dermatitis
• Is early pet exposure really protective against sensitization?
• Copyright

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Cytokine regulation of IL-13Rα2 and IL-13 Rα1 

Many lines of evidence suggest that IL-13 is a key mediator of T_H2 inflammation that contributes significantly to the pathophysiology of asthma. IL-13 signals via a high-affinity receptor that includes IL-4Rα and IL-13Rα1. IL-13 also binds to the decoy receptor IL-13Rα2. To further understand the processes regulating IL-13 effector functions in the lung, Zheng et al (p 720) used in vivo and in vitro approaches to determine whether IL-13 and other cytokines regulated the expression of IL-13Rα1 and IL-13Rα2. They demonstrated that IL-13 is a potent stimulator of the expression and production of both receptor components in airway epithelial cells and macrophages. Interestingly, IL-4 had similar effects on both receptors. IL-10 and IFN-γ, while stimulating IL-13Rα2, did not alter and inhibited IL-13Rα1, respectively. These studies demonstrate that the components of the IL-13 receptor system are highly regulated in vivo and in vitro. In addition, these studies provide mechanisms by which IL-13 signaling can be fine-tuned at sites of inflammation to control the consequences of T_H2 tissue responses.

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• Arrows indicate localizations of IL-13Rα2 mRNA in macrophages (A) and small airway epithelial cells (B) .

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Animal sensitivity linked to HLA phenotype 

HLA genes are highly polymorphic, and particular HLA molecules might facilitate or protect against the development of an allergic reaction to a specific protein. Jeal et al (p 795) investigated HLA associations with specific IgE to rat urinary proteins (sensitization). They found an association with HLA-DR7 and sensitization (odds ratio [OR], 1.82; CI, 1.12-2.97), respiratory symptoms at work (OR, 2.96; CI, 1.64-5.37), and sensitization with symptoms (OR, 3.81; CI, 1.90-7.65). Conversely, HLA-DR3 protects against sensitization (OR, 0.55; CI, 0.31-0.97). Sequence analysis of HLA-DR7 and HLA-DR3 showed that HLA-DR7 is made up of hydrophobic residues, whereas HLA-DR3 is made up of hydrophilic residues at positions where these 2 molecules differ. The major rat allergen, Rat n 1, belongs to the lipocalin family, whose function is the transport of hydrophobic ligands. The authors suggest that Rat n 1 might bind with higher affinity to the hydrophobic amino acids in HLA-DR7 than to the hydrophilic amino acids in HLA-DR3. These findings indicate that HLA phenotype is an important determinant of individual susceptibility to sensitization and asthma among laboratory animal workers; the findings might have implications for other lipocalin allergens, as well as the mouse, cow, dog, and horse major allergens.

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Changes in asthma pharmacotherapy over the past 3 decades 

Although asthma is a serious global health problem and medication use is key in its care, research has been limited with respect to physicians' prescribing patterns, particularly in relation to clinical guidelines. In this issue of the Journal, Stafford et al (p 729) document changes in asthma office visits and prescribing practices by office-based US physicians from 1978 to 2002. Asthma office visits in the United States increased continuously from 1978 (9 million) to 1990 (18 million) and then remained relatively stable. The authors suggest that better application of asthma pharmacotherapy might have contributed to the recent lack of an increase in asthma visits. Most noticeably, the aggregate use of controller medications (83% of visits) superseded that of quick relievers (80%) for the first time in 2001—this after continued increases in controller use, particularly inhaled corticosteroids. By providing 25 years of data, the study demonstrates that asthma pharmacotherapy is increasingly consistent with evidence-based guidelines. However, underutilization of inhaled corticosteroids and some overreliance on short-acting inhaled β-agonists might still be present. In addition, the rapid growth of more recent drug entrants, including long-acting inhaled β-agonists and leukotriene modifiers, might warrant further investigation.

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Cysteine proteases can activate human eosinophils and cause degranulation 

At inflammation sites in allergic diseases and asthma, the activation—and not the mere presence—of eosinophils is likely critical in the pathophysiology. However, the precise mechanisms of eosinophil activation are not well understood. Numerous allergens, such as house dust mite and fungal allergens, possess protease activity. A study by Miike and Kita (p 704) found that a cysteine protease, papain, and a natural cysteine protease from house dust mite allergen, Der f 1, induced eosinophil activation and degranulation. A cysteine protease inhibitor, E-64, abolished stimulation by papain, which suggests that protease activity of papain is necessary for eosinophil activation. The authors speculate on the presence of one or more novel receptors on eosinophils that are cleaved and activated by cysteine protease(s). Furthermore, a cytokine involved in allergic diseases, IL-5, markedly enhanced the eosinophil's responses to papain and Der f 1. Because both allergen proteases and eosinophils are localized at inflammation sites, pro-inflammatory, allergen-derived proteases might exacerbate allergic diseases.

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Expression of profibrotic cytokines in acute and chronic skin lesions in atopic dermatitis 

Atopic dermatitis (AD) is a chronic inflammatory skin disease with increased serum IgE levels and tissue eosinophilia. In AD, there is evidence of tissue fibrosis involving a number of structural changes, such as papillary dermal fibrosis and epidermal hyperplasia. Although several profibrotic cytokines, such as TGF-β1, IL-11, and IL-17, have been shown to be associated with fibrosis in diseases such as asthma, to date their expression has not been analyzed in AD. In this issue of the Journal, Toda et al (p 875) investigated the expression of TGF-β1, IL-11, and IL-17 and collagen deposition in skin biopsy specimens recovered from acute and chronic AD skin lesions, as well as in uninvolved skin from patients with AD and from normal healthy volunteers. The authors demonstrated an increase in IL-17 and IL-11 expression, which was polarized toward acute and chronic AD lesions, respectively; in contrast, TGF-β1 expression was increased in both acute and chronic skin lesions, though at higher levels in the chronic situation. Furthermore, though type III collagen deposition was not different among the groups, type I collagen deposition was significantly increased in chronic AD lesions. The findings in the study suggest that these mediators might be responsible for the characteristic lichenification and dermal fibrosis that accompany chronic AD skin lesions; they thus might serve as therapeutic targets.

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• Representative examples of total collagen deposition as detected by van Gieson staining in chronic (a) and acute (b) atopic dermatitis.

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Is early pet exposure really protective against sensitization? 

Several recent studies have concluded that pet ownership during the first year of a child's life reduces the risk of sensitization to the pet and sometimes the risk of sensitization to other inhalant allergens. The mechanism for this has been suggested to be an effect of high-dose exposure or the increase in endotoxin exposure associated with pet ownership. The finding that early pet ownership is protective has not been consistent, however. Others have concluded that early exposure is a risk for sensitization rather than a protection. In this setting of controversy, the findings reported by Almqvist and coworkers in this issue of the Journal (p 800) are intriguing. When they administered a questionnaire to 4089 parents of 2-month-old children, they found that cats were less frequently kept in families with parental asthma, rhinoconjunctivitis, or pet or pollen allergy. Dogs were less commonly kept with parental eczema. On the other hand, families in which the mother smoked and families with a low socioeconomic index kept cats and dogs more frequently. Even in families with cats, cat allergen levels were lower in homes with maternal pet allergy. Thus there seems to be a selection of pet exposure based on parental history of allergy, maternal smoking, and socioeconomic factors that must be taken into consideration when risk associations between pet exposure and allergic diseases in childhood are being evaluated.

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