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• Challenging the “hygiene hypothesis”
• IgE can mediate chronic allergic inflammation in skin
• Further evidence for long-term improvement with aspirin desensitization
• Maternal antibody responses: Predictors of immune responses or symptoms in the first 2 years?
• Bone mineral density and inhaled corticosteroids in postmenopausal women
• Id2 makes its debut as a player in the field of allergy
• Copyright

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Challenging the “hygiene hypothesis” 

The T_H1/T_H2 explanatory paradigm has in recent years emerged as the most plausible explanation for the rapid and sustained increase in atopic allergic conditions now being witnessed in many developed countries. Although the paradigm is biologically plausible, it is widely acknowledged that there remains a dearth of high-quality empiric research supporting this explanatory model. To investigate the relationship between T_H1- and T_H2-mediated disorders, Sheikh, Smeeth, and Hubbard (p 131) analyzed data from the nationally representative American National Health and Nutritional Examination Survey (NHANES III). In contrast to their original hypothesis, they found no evidence of an inverse relationship between objectively defined atopy and a history of T_H1-mediated autoimmune disease. Furthermore, they found a strong positive association between a history of T_H2-mediated atopic allergic disorders and T_H1-mediated autoimmune conditions. In what is by far the largest study conducted to date, these findings pose an important challenge to the T_H1/T_H2 paradigm as conventionally understood, and they will, argue Sheikh and colleagues, need to be accommodated in any reformulation of the thesis.

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IgE can mediate chronic allergic inflammation in skin 

It is well known that IgE mediates immediate hypersensitivity—so-called type I allergy. However, the pathologic role of IgE in chronic allergic inflammation observed in atopic diseases such as atopic dermatitis has not yet been elucidated. Sato et al (p 143) addressed this issue by using antigen-specific IgE-transgenic mice. A single administration of multivalent antigen, trinitrophenol-conjugated ovalbumin with a valency of >5, into the ear skin of trinitrophenol-specific IgE-transgenic mice induced not only immediate but also very delayed ear swelling, which started 2 to 3 days after the antigen challenge and lasted not less than 1 month when a high dose of the antigen was given. Massive infiltration of inflammatory cells was observed in the skin (see Figure).

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• Figure. Chronic inflammation with massive cellular infiltration in ear skin.

Cyclosporine A almost completely inhibited the ear swelling and cellular infiltration, whereas an antihistamine did not. Such mediation of chronic allergic inflammation by strong cross-linking of IgE on effector cells by multivalent antigen is atypical of type I to IV allergies. These findings thus present a novel pathologic role of IgE in chronic allergic inflammation and provide new insight into the etiology of atopic diseases, leading to the discovery of novel therapeutic targets.

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Further evidence for long-term improvement with aspirin desensitization 

Patients who have aspirin-exacerbated respiratory disease have been reported to experience improvement in both rhino/sinusitis and asthma after being desensitized to aspirin and placed on aspirin maintenance treatment. The most extensive experience with this treatment has been at the Scripps Clinic and Research Institute. This group has previously reported both double-blind trials and their long-term experience with this treatment. In this issue of the Journal, Berges-Gimeno, Simon, and Stevenson (p 180) report on a new cohort of patients, comparing the results at 6 months with those achieved over a longer term and analyzing how many patients improved, how many failed to improve, and how many had side effects from the aspirin treatment. Between July 1995 and July 2000, a total of 172 patients underwent single-blind oral aspirin desensitization in the General Clinical Research Center at Scripps Clinic. After desensitization, they were placed on 650 mg aspirin bid. Data on the outcome were collected prospectively for periods of up to 6 years. Fourteen percent of the patients discontinued aspirin during the first year because of known aspirin side effects, and another 11% discontinued who were considered treatment failures; 3% who responded clinically discontinued during the first year for other reasons. Of the remaining 126 patients who took aspirin daily and were followed for at least 1 year, 110 (87%) had improvement in their clinical course, whereas 16 (13%) were not improved. Among the responses noted were reductions in the number of sinus infections and improvements in the sense of smell and in global assessment of naso/sinus and asthma symptoms. Those patients who were treated with aspirin from 1 to 5 years after desensitization continued to show these same improvements; in addition, they reported significant reductions in emergency department visits and hospitalizations.

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Maternal antibody responses: Predictors of immune responses or symptoms in the first 2 years? 

Platts-Mills et al (p 123) measured IgE and IgG antibodies to Fel d 1 and Der f 1 in sera from approximately 400 mothers and infants (cord bloods) as well as from 232 of the children at age 2 to 3 years. The results show that 12% of the mothers were making IgG (and IgG4) antibodies to Fel d 1 without IgE antibodies (a modified T_H2 response). As a result, one half of the infants who had circulating IgG antibodies to Fel d 1 at birth had received those antibodies from nonallergic mothers. By the age of 2 to 3 years, 41 of the 232 children studied had developed IgG antibodies to Fel d 1, and 15% of the total did not have IgE antibodies. The IgG antibody response without IgE antibodies was not a predictor of lung symptoms in the mothers or children but was associated with rhinitis in the mothers and eczema in the children. In both mothers and children, the strongest determinant of IgG antibodies to Fel d 1 was high domestic exposure. Taken together, the results strengthen the evidence that high exposure to cat allergens can give rise to a form of immunologic tolerance, which can develop in the first 2 years of life. The results also provide objective evidence about the ways in which the mother's immune response can influence the development of allergic disease in the child.

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Bone mineral density and inhaled corticosteroids in postmenopausal women 

Oral corticosteroids are a recognized cause of osteoporosis. However, reports on the risk of osteoporosis with inhaled steroids vary, perhaps because different inhaled steroids are used and perhaps because of confounding by previous use of oral steroids. In this issue of the Journal, Elmståhl and coworkers (p 91) report results from a subset of inhaled steroid–using postmenopausal women who were recruited from a prospective population-based study of diet and health. A total of 106 women who had used only inhaled corticosteroids for an average period of 8.2 years (average dose, 853 μg) were compared with 674 women who had not been exposed to corticosteroids and 49 women who had been exposed to oral and/or intra-articular injections in addition to inhaled corticosteroids. Eighty-eight percent of the women were using budesonide. The bone mineral density in those exposed only to inhaled corticosteroids (0.4334 g/cm²) was no different from that in the nonexposed group (0.429 g/cm²). This was also true when the corticosteroid users were stratified by cumulative dose, duration, or current dose above or below 1000 μg. On the other hand, the group that had been exposed to systemic corticosteroids had a significantly lower bone mineral density (0.408 g/cm²). The results of this study are quite reassuring regarding the risk for osteoporosis with the use of moderate doses of inhaled budesonide.

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Id2 makes its debut as a player in the field of allergy 

Although T_H1/T_H2 balance is important in allergy, the regulatory mechanism in vivo has not been well elucidated, and still-novel regulators might remain undiscovered. Kusunoki et al (p 136) reported that Id2, an inhibitor of the basic helix-loop-helix transcription factors, is one of them. Originally, their work with Id2-deficient mice showed that it is crucial for development of peripheral lymphoid organs and natural killer cells (Yokota et al. Nature 1999;397:702-6.). Totally unexpectedly, they also found that serum levels of IgE are markedly elevated and that T_H1/T_H2 balance is skewed to T_H2. They scrutinized the mechanism and found selective and remarkable reduction of the CD8a⁺ dendritic cell (DC) population, which is known to induce T_H1 differentiation. Thus, Id2 might control T_H1/T_H2 balance by regulating the development of the T_H1-inducible DC subset. Of course, it is not yet known whether the atopic status of the mice can be explained only by DC deficiency, and there might be additional mechanisms waiting to be revealed. However, the finding definitely shows the importance of Id2 as a negative regulator of atopy and indicates that a deficiency of this safeguard system leads to significant IgE production. Id2 thus deserves further investigation in the field of allergy.