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Original Paper

Close Positive Correlation between the Lymphocyte Response to Hen Egg White and House Dust Mites in Infants with Atopic Dermatitis

Kimura M.a · Meguro T.a · Ito Y.a · Tokunaga F.a · Hashiguchi A.b · Seto S.a

Author affiliations

aDepartment of Allergy and Clinical Immunology, Shizuoka Children's Hospital, Shizuoka, and bBML Inc., Kawagoe City, Japan

Corresponding Author

Correspondence to: Dr. Mitsuaki Kimura

Department of Allergy and Clinical Immunology, Shizuoka Children's Hospital

Urushiyama 860, Aoi-ku

Shizuoka City, Shizuoka 420-0953 (Japan)

E-Mail mitsuaki-kimura@i.shizuoka-pho.jp

Related Articles for ""

Int Arch Allergy Immunol 2015;166:161-169

Abstract

Background: It was recently hypothesized that food allergens sensitize infants with atopic dermatitis (AD) via the skin. If this is the case, an intimate positive correlation should be observed between immune responses to both food and indoor allergens. Methods: One hundred and seven infants with AD and 32 controls were enrolled. The proliferation of lymphocytes stimulated with hen egg white (EW) or house dust mite (HDM) allergens was measured by means of an allergen-specific lymphocyte stimulation test (ALST). Cytokine production was measured in 13 patients and 4 controls. Results: ALST responses for EW (EW-ALST) were significantly higher in AD infants than in control subjects (stimulation index: 7.98 vs. 2.54, p < 0.0001). HDM-ALST responses were also significantly higher in AD infants than in controls (stimulation index: 5.09 vs. 1.44, p < 0.0001). A significant positive correlation was seen between HDM-ALST and EW-ALST responses in AD infants aged 5-6 months (rs = 0.77, p < 0.000001). Serum levels of EW-specific IgE (EW-IgE) were significantly correlated with both EW-ALST (rs = 0.43, p < 0.05) and HDM-ALST levels (rs = 0.47, p < 0.05) in AD patients aged 3-4 months. Serum EW-IgE levels in AD infants were significantly correlated with the ratio of IL-4/IFN-γ production from lymphocytes stimulated with EW (rs = 0.62, p < 0.01) and with HDM (rs = 0.67, p < 0.005). Conclusions: This study describes the close positive correlation between EW- and HDM-specific immune responses in infants with AD. These results may support the hypothesis that both food and indoor allergens concurrently sensitize infants via the skin.

© 2015 S. Karger AG, Basel


Introduction

Major allergic disorders in childhood, such as food allergies (FA), bronchial asthma (BA) and pollinosis develop one after another, referred to as the allergic march [1,2]. FA often develop in infants with atopic dermatitis (AD), and BA has a tendency to develop later in children who have or previously had FA and/or AD. Hen egg white (EW) is a major food allergen, while house dust mites (HDM) are major indoor allergens, thought to be the cause of BA. In children, serum levels of IgE specific to EW (EW-IgE) increase earlier than serum levels of HDM-IgE [3].

The earlier sensitization to EW is thought to progress through the intestine [4], while sensitization to HDM is assumed to develop via the skin [5]. However, it has recently been hypothesized that food allergens sensitize infants with AD through the skin, similar to HDM [6]. If this is the case, the immunological responses to EW and HDM should develop at roughly the same time. However, it is well known that HDM-IgE levels are undetectable or very low in infants with AD, while EW-IgE levels are already elevated [3]. This distinct difference in EW-IgE and HDM-IgE levels in infants with AD seems incompatible with the hypothesis that food allergens sensitize infants through the skin.

We have previously demonstrated that lymphocyte proliferations against EW are increased in infants with AD [7]. Moreover, although the serum level of HDM-IgE was undetectable in most infants with AD, lymphocyte proliferations against HDM were already elevated in these patients [8,9]. In this study, we further examined the correlations between EW- and HDM-specific cell-mediated immune responses by measuring lymphocyte proliferation and cytokine production.

Materials and Methods

Subjects

One hundred and sixty infants and young children who visited our institute for the treatment of AD from June 1, 2011 to January 31, 2014, were enrolled in the study (table 1). AD was diagnosed based on the criteria of Hanifin and Rajka [10], and cases complicated with BA were excluded. As controls, 61 children without any allergic disorders (AD, FA, BA or pollinosis) were also included in this study. Informed consent was obtained from parents before the examination, and the study was approved by the ethical committee of the Shizuoka Children's Hospital.

Table 1

Profiles of subjects

http://www.karger.com/WebMaterial/ShowPic/138832

Measurement of Lymphocyte Proliferation

Proliferation of lymphocytes stimulated with various allergens was examined using an allergen-specific lymphocyte stimulation test (ALST). The ALST was performed as described previously [9], with minor modifications. Briefly, peripheral blood mononuclear cells (PBMCs) were collected from heparinized peripheral blood, and suspended at a concentration of 1 × 106 cells/ml in RPMI 1640 medium, supplemented with 10% human AB serum and antibiotics (100 IU/ml penicillin and 100 μg/ml streptomycin). Quadruplicate aliquots of the PBMC suspensions (0.1 ml/well) for each allergen test were placed in a 96-well culture plate, along with octuplicate samples for unstimulated samples (negative control). After addition of the specific allergens, the PBMCs were cultured for 6 days at 37°C, in an atmosphere of 5% CO2 and 95% room air. Twenty-four hours before completion of the culture, 3H-thymidine (PerkinElmer Inc., Mass., USA) was added to each well (0.5 μCi/well). After completion of the culture, cells were collected on a glass fiber filter, and washed. The intensity of radiation emitted from the cells was measured using a liquid scintillation counter (Beta Plate 1205, PerkinElmer Inc.), and the result expressed as the stimulation index.

The volume of heparinized peripheral blood collected from each subject was 3 ml. The following allergens were used: EW (crude extract, Wako Pure Chemical Industries Ltd., Osaka, Japan), ovalbumin (OVA, Sigma-Aldrich Japan, Tokyo, Japan), ovomucoid (OM, Sigma-Aldrich), HDM (crude extract from feces of Der p, Wako), the Der f1 allergen (Wako) and the Der f2 allergen (recombinant, Wako). The concentrations of allergens necessary to induce the maximum proliferation of PBMCs were determined in preliminary experiments: 200 μg/ml for OVA and OM, 30 μg/ml for HDM and 1 μg/ml for Der f1 and Der f2. Endotoxin levels in the culture medium with each allergen were controlled to be <100 pg/ml.

Measurement of Cytokine Production

PBMCs were cultured under the same conditions as the ALST, with the same concentrations of allergens, but 3H-thymidine was not added. After the completion of the 6-day culture, the supernatants were collected, and the amounts of IL-4 and IFN-γ were measured. Since PBMC production of IL-4 is very low [7,8], ELISA kits with a high sensitivity were used (Quantikine HS IL-4, measurable range 250-16,000 fg/ml, R&D Systems Inc., Minneapolis, Minn., USA). IFN-γ was measured with an ordinary standard ELISA kit (Quantikine IFN-γ, measurable range 7.8-1,000 pg/ml, R&D Systems Inc.).

Measurement of Serum IgE Levels

Serum levels of allergen-specific IgE were measured using the ImmunoCAP system (ThermoFisher Scientific Inc., Tokyo, Japan).

Measurement of Serum Thymus and Activation-Regulated Chemokine

Serum levels of thymus and activation-regulated chemokine (TARC) are well correlated with the severity of AD in children and infants [11,12], and so serum TARC levels were measured as an indicator of the severity of AD, using an ELISA kit (Shionogi & Co. Ltd., Osaka, Japan).

Statistical Analysis

The significance of differences between allergens was estimated using the Mann-Whitney U test, and the significance of the correlation was analyzed using Spearman's rank correlation coefficient test. All analyses were performed with statistical software STATA 12 (LightStone Corp., Tokyo, Japan).

One coauthor (AH, employed by BML Inc.) contributed only to the measurement of ALST and cytokine levels, but did not take part in the selection of subjects or analysis of data.

Results

Profile of Subjects

There were 107 infants with AD with an age of <1 year, approximately three quarters of whom were male (table 1). The number of children aged 1 and 2-5 years was 31 and 22, respectively.

The median serum level of EW-IgE was 8.20 UA/ml in AD patients <1 year of age, 18.1 UA/ml in those who were 1 year old and 0.59 UA/ml in those aged 2-5 years. The median HDM-IgE level was <0.35 UA/ml in patients aged <1 year old, 0.75 UA/ml in those aged 1 year and >100 UA/ml in those aged 2-5 years. There was no significant positive correlation between EW-IgE and HDM-IgE in AD patients <1 year old, whereas a significant positive correlation was observed in the older age groups (table 2). The median TARC level in AD patients <1 year of age was 1,982 pg/ml, 1,211 pg/ml in the 1-year-old patients and 1,291 pg/ml in patients aged 2-5 years (table 1).

Table 2

Correlations between hen EW-specific and HDM-specific IgE

http://www.karger.com/WebMaterial/ShowPic/138831

Age-Dependent Changes in ALST

EW-ALST levels were significantly higher in infants with AD than in control subjects (fig. 1; table 3). In AD infants, the highest level of EW-ALST was reached in infants aged 3-4 months, persisting in infants aged 7-11 months and then subsequently decreasing with age.

Table 3

Age-dependent changes in ALST levels

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Fig. 1

Box and whisker plots of ALST levels for each allergen in AD patients (A, black box) and control subjects (C, open box) <1 year of age. The horizontal line in the box indicates the median, while the top and the bottom lines of the box indicate the upper and the lower quartile, respectively. The top and the bottom of the whisker line indicate the upper quartile + 1.5 × interquartile range and the lower quartile - 1.5 × interquartile range, respectively.

http://www.karger.com/WebMaterial/ShowPic/138826

The HDM-ALST level in AD infants was highest in those 5-6 months of age, and although it was slightly lower in patients 3-4 months of age, this difference was not significant. The HDM-ALST level in the age group of 7-11 months was equal to that in the age group of 5-6 months, and it subsequently decreased with age.

Regarding the component proteins, OVA-ALST levels were significantly higher than in the control subjects, and showed an age-dependent change similar to that of EW. On the other hand, the median ALST levels for Der f1 and Der f2 were not significantly different from those of the control subjects (table 3), although these levels were elevated in a subset of patients (fig. 1).

Correlation between HDM- and EW-ALST

Although there was no significant correlation between serum levels of EW-IgE and HDM-IgE (table 2) in AD patients <1 year of age, there was a significant positive correlation between EW- and HDM-ALST levels in this age group (table 4; fig. 2a). Significant positive correlations were also seen among allergens OVA, OM, Der f1 and Der f2 in the age groups of 5-6 and 7-11 months (table 4; fig. 2b).

Table 4

Correlations between ALST levels for various allergens

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Fig. 2

Correlations between ALST levels for EW and HDM (a) and for OVA and Der f2 (b) in AD infants aged 5-6 months. rs = Spearman's rank correlation coefficient.

http://www.karger.com/WebMaterial/ShowPic/138825

Correlation between ALST and IgE Levels

EW-ALST levels were significantly correlated with the serum levels of EW-IgE in patients who were 3-4 months of age (table 5; fig. 3a). Serum EW-IgE levels were also significantly correlated with HDM- and Der f1-ALST levels (fig. 3b, c). Although EW-ALST levels were not correlated with serum EW-IgE levels in AD patients aged 5-11 months, HDM-ALST levels were still significantly correlated with serum EW-IgE levels in these patients.

Table 5

Correlation between IgE and ALST levels

http://www.karger.com/WebMaterial/ShowPic/138828

Fig. 3

Correlations of serum EW-IgE levels with ALST levels for hen EW (a), HDM (b) and Der f1 (c) in AD patients. The age of subjects was 3-4 months (a) and 7-11 months (b, c). rs = Spearman's rank correlation coefficient.

http://www.karger.com/WebMaterial/ShowPic/138824

HDM-ALST levels showed no correlation or a weak positive correlation with serum levels of EW-IgE in AD patients aged 1 and 2-5 years, respectively. In contrast, they did show a significant positive correlation with serum HDM-IgE levels in patients >1 year of age, particularly in the age group of 2-5 years (table 5).

Correlation between Cytokine Production and EW-IgE

Cytokine production was examined in 13 AD infants [median (range): 8 (4-11) months)] and 4 control subjects (7.5 (6-10) months). The amount of IL-4 produced by EW-stimulated lymphocytes was 1,180 fg/ml, i.e. not significantly different from what was produced by HDM-stimulated lymphocytes (710 fg/ml; table 6). In contrast, the amount of IFN-γ production by EW-stimulated lymphocytes was significantly lower than that produced by HDM-stimulated lymphocytes (838 vs. 1,763 pg/ml, p = 0.006).

Table 6

Cytokine production for hen EW- and HDM-stimulated lymphocytes

http://www.karger.com/WebMaterial/ShowPic/138827

The ratio of IL-4/IFN-γ produced by EW-stimulated lymphocytes was significantly correlated with the serum level of EW-IgE (rs = 0.615, p = 0.009; fig. 4a). The ratio of IL-4/IFN-γ produced by HDM-stimulated lymphocytes was also significantly correlated with the serum level of EW-IgE (rs = 0.674, p = 0.003; fig. 4b).

Fig. 4

Correlations of serum EW-IgE levels with the ratio of IL-4/IFN-γ production by hen EW-stimulated lymphocytes (a) and HDM-stimulated lymphocytes (b). rs = Spearman's rank correlation coefficient. ⚫ = AD patients, ⚪ = control subjects.

http://www.karger.com/WebMaterial/ShowPic/138823

Discussion

Since serum HDM-IgE levels were very low, we were unable to find a significant correlation between EW- and HDM-IgE levels in AD infants (tables 1, 2). In contrast, a significant positive correlation was found between the EW-ALST and HDM-ALST levels (table 4). This correlation is not likely to be linked to the contamination of any component protein of EW into HDM, or vice versa, since ALST levels for purified EW components, OVA and OM were also significantly correlated with those for purified HDM components, Der f1 and Der f2.

In cases of oral allergy syndrome, close correlations between IgE levels for fruit and pollen allergens have been described [13]. This is attributed to the cross-reactivity of antibodies, as some components of fruit show a high degree of homology with similar components of pollen. In contrast, there are no significant homologies between the components of EW and HDM. Thus, our observed close correlation between EW-ALST and HDM-ALST levels cannot be explained by a hypothetical cross-reactivity of EW and HDM.

HDM is thought to sensitize the immune system via the skin [4], while it has been assumed that EW sensitizes subjects with AD through the intestine [3]. These mechanisms conveniently explain the delay between the initiation of EW-IgE synthesis, in comparison to that of HDM-IgE which occurs much later in AD patients. This delay may also suggest that sensitization via the intestine progresses more rapidly than that via the skin.

In contrast to IgE levels, a close positive correlation was observed between EW-ALST and HDM-ALST levels in this study (table 4). This might indicate the proximity of the pathways of sensitization between EW and HDM. Although it was originally thought that AD infants are sensitized to food allergens through the intestine, it is now hypothesized that sensitization may be via the skin, based on the etiologic analysis of peanut allergies [6]. This mechanism is supported by reports of the percutaneous sensitization to food allergens (e.g. EW or peanuts) in murine models [14,15,16]. Moreover, the presence of these major food allergens in house dust has already been described [17,18]. The results of this study are compatible with a sensitization mechanism whereby infants with AD are sensitized to both EW and HDM via the skin.

A recent report has described that HDM is found in breast milk at a concentration similar to that in EW [19]. Sensitization to HDM via the intestine has been demonstrated using a murine model, and therefore sensitization via the ingestion of breast milk is possible. If this were to occur, the mechanism of tolerance induction, an important property of the gastrointestinal immune system, may not be adequately activated by the very low levels of allergens in the breast milk. Thus, the intestine could be another route of simultaneous sensitization to HDM and EW, i.e. in addition to the skin. Our results are also compatible with concurrent sensitization to HDM and EW allergens via the intestine.

Since the proliferation of lymphocytes, measured by ALST, is closely correlated with serum EW-IgE levels, it is thought that activated helper T (Th) cells participate in the induction of IgE synthesis. We have previously shown that the amount of IL-4 produced by EW-stimulated lymphocytes is significantly correlated with the serum levels of EW-IgE in infants with AD [7]. Our results further confirm this (table 6). Interestingly, the serum level of EW-IgE was also significantly correlated with the ratio of IL-4/IFN-γ production in HDM-stimulated lymphocytes. This may suggest that HDM-specific Th cells also participate in the enhancement of EW-IgE synthesis. HDM-specific lymphocytes might play a more critical role in the regulation of EW-IgE synthesis, as a positive correlation between HDM-ALST levels and serum levels of EW-IgE was clear in the AD patients >5 months of age, in whom a positive correlation between the serum EW-IgE and EW-ALST levels no longer existed.

However, since the ratio of IL-4/IFN-γ produced by HDM-stimulated lymphocytes was significantly lower than that produced by EW-stimulated lymphocytes (0.44 vs. 1.24, p = 0.013; table 6), HDM-specific Th cells might not contribute significantly to the upregulation of EW-IgE synthesis. Much remains to be clarified regarding the influence of HDM-specific Th cells on EW-IgE synthesis. These findings might be a part of the genetic phenomenon of proatopic predisposition, which universally elevates all ALST levels, IL-4 production and IgE antibody formation against various major allergens. If this is the case, there is no need to discuss an exclusive collaboration between the EW and HDM-specific cellular immunity. However, the results may provide insight into how a proatopic predisposition affects the immune system during the very early stages of life.

In skin affected by AD, the integrity of the epidermis is damaged by inflammation, which results in a reduced barrier function [5]. Thus, various molecules can enter the skin tissue and sensitize the immune system. As the serum TARC level has been shown to be positively correlated with the severity of AD [11,12], it is expected to have a positive correlation with ALST and IgE levels. However, we did not observe any positive correlation with EW-IgE, EW-ALST or HDM-ALST levels (data not shown). AD patients with relatively low serum TARC levels often show high EW-IgE, EW-ALST and HDM-ALST levels. Thus, it is suggested that, although AD is indispensable for the progression of sensitization, even mild symptoms can induce sensitization. This raises a critical question regarding how the skin lesions of AD patients should be controlled to prevent percutaneous sensitization. A thorough treatment of AD, which does not permit any residual skin lesions, might be required.

Acknowledgements

This study was partly supported by the grants from the Shizuoka Prefectural Hospital Organization.


References

  1. Gustafsson D, Sjoberg O, Foucard T: Development of allergies and asthma in infants and young children with atopic dermatitis - a prospective follow-up to 7 years of age. Allergy 2000;55:240-245.
  2. Carlsten C, Dimich-Ward H, Ferguson A, Watson W, Rousseau R, Dybuncio A, Becker A, Chan-Yeang M: Atopic dermatitis in a high-risk cohort: natural history, associated allergic outcomes, and risk factors. Ann Allergy Asthma Immunol 2013;110:24-28.
  3. Rowntree S, Cogswell JJ, Platts-Mills TAE, Mitchell EB: Development of IgE and IgG antibodies to food and inhalant allergens in children at risk of allergic disease. Arch Dis Child 1985;60:727-735.
  4. Friedman NJ, Zeiger RS: The role of breast-feeding in the development of allergies and asthma. J Allergy Clin Immunol 2005;115:1238-1248.
  5. Spergel JM: From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma Immunol 2010;105:99-106.
  6. Lack G: Epidemiologic risks for food allergy. J Allergy Clin Immunol 2008;121:1331-1336.
  7. Kimura M, Obi M: Ovalbumin-induced IL-4, IL-5 and IFN-γ production in infants with atopic dermatitis. Int Arch Allergy Immunol 2005;137:134-140.
  8. Kimura M, Yamaide A, Tsuruta S, Okafuji I, Yoshida T: Development of the capacity of peripheral blood mononuclear cells to produce IL-4, IL-5 and IFN-γ upon stimulation with house dust mite in children with atopic dermatitis. Int Arch Allergy Immunol 2002;127:191-197.
  9. Kimura M, Tsuruta S, Yoshida T: Correlation of house dust mite-specific lymphocyte proliferation with IL-5 production, eosinophilia, and the severity of symptoms in infants with atopic dermatitis. J Allergy Clin Immunol 1998;101:84-89.
  10. Hanifin JM, Rajka G: Diagnostic features of atopic dermatitis. Acta Derm Venereol 1980;92(suppl):44-47.
  11. Song TW, Sohn MH, Kim ES, Kim KW, Kim KE: Increased serum thymus and activation-regulated chemokine and cutaneous T cell-attracting chemokine levels in children with atopic dermatitis. Clin Exp Allergy 2006;36:346-351.
  12. Fujisawa T, Nagao M, Hiraguchi Y, Katsumata H, Nishimori H, Iguchi K, Kato Y, Higashiura M, Ogawauchi I, Tamaki K: Serum measurement of thymus and activation-regulated chemokine/CCL17 in children with atopic dermatitis: elevated normal levels in infancy and age-specific analysis in atopic dermatitis. Pediatr Allergy Immunol 2009;20:633-641.
  13. Webber CM, England RW: Oral allergy syndrome: a clinical, diagnostic, and therapeutic challenge. Ann Allergy Asthma Immunol 2010;104:101-108.
  14. Wong LF, Lin JY, Hsieh KH, Lin RW: Epicutaneous exposure of protein antigen induces a predominant Th2-like response with high IgE production in mice. J Immunol 1996;156:4079-4082.
    External Resources
  15. Strid J, Hourihane J, Kimber I, Callard R, Strobel S: Disruption of the stratum corneum allows potent epicutaneous immunization with protein antigens resulting in a dominant systemic Th2 response. Eur J Immunol 2004;34:2100-2109.
  16. Birmingham NP, Parvataneni S, Hassan HMA, Harkema J, Samineni S, Navuluri L, Kelly CJ, Gangur V: An adjuvant-free mouse model of tree nut allergy using hazelnut as a model tree nut. Int Arch Allergy Immunol 2007;144:203-210.
  17. Bertelsen RJ, Faeste CK, Granum B, Egaas E, London SJ, Carlsen KH, Lodrup Carlsen KC, Lovik M: Food allergens in mattress dust in Norwegian homes - a potentially important source of allergen exposure. Clin Exp Allergy 2014;44:142-149.
  18. Masuda S, Morishima T, Matsuyama A, Kagami M, Tokuda R, Urisu A, Fujita M, Miyazawa I, Okumura T, Matsumoto T, Takahata Y: Measurement of the amount of food allergens in house dust. Bulletin Yachiyo Hospital 2005;25:12-14 (Japanese).
  19. Macchiaverni P, Rekima A, Turfkruyer M, Mascarell L, Airouche S, Moingeon P, Adel-Patient K, Condino-Neto A, Annessi-Aaesano I, Prescott SL, Tulic MK, Verhasselt V: Respiratory allergen from house dust mite is present in human milk and primes for allergic sensitization in a mouse model of asthma. Allergy 2014;69:395-398.

Author Contacts

Correspondence to: Dr. Mitsuaki Kimura

Department of Allergy and Clinical Immunology, Shizuoka Children's Hospital

Urushiyama 860, Aoi-ku

Shizuoka City, Shizuoka 420-0953 (Japan)

E-Mail mitsuaki-kimura@i.shizuoka-pho.jp


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: August 11, 2014
Accepted: February 18, 2015
Published online: April 11, 2015
Issue release date: May 2015

Number of Print Pages: 9
Number of Figures: 4
Number of Tables: 6

ISSN: 1018-2438 (Print)
eISSN: 1423-0097 (Online)

For additional information: http://www.karger.com/IAA


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References

  1. Gustafsson D, Sjoberg O, Foucard T: Development of allergies and asthma in infants and young children with atopic dermatitis - a prospective follow-up to 7 years of age. Allergy 2000;55:240-245.
  2. Carlsten C, Dimich-Ward H, Ferguson A, Watson W, Rousseau R, Dybuncio A, Becker A, Chan-Yeang M: Atopic dermatitis in a high-risk cohort: natural history, associated allergic outcomes, and risk factors. Ann Allergy Asthma Immunol 2013;110:24-28.
  3. Rowntree S, Cogswell JJ, Platts-Mills TAE, Mitchell EB: Development of IgE and IgG antibodies to food and inhalant allergens in children at risk of allergic disease. Arch Dis Child 1985;60:727-735.
  4. Friedman NJ, Zeiger RS: The role of breast-feeding in the development of allergies and asthma. J Allergy Clin Immunol 2005;115:1238-1248.
  5. Spergel JM: From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma Immunol 2010;105:99-106.
  6. Lack G: Epidemiologic risks for food allergy. J Allergy Clin Immunol 2008;121:1331-1336.
  7. Kimura M, Obi M: Ovalbumin-induced IL-4, IL-5 and IFN-γ production in infants with atopic dermatitis. Int Arch Allergy Immunol 2005;137:134-140.
  8. Kimura M, Yamaide A, Tsuruta S, Okafuji I, Yoshida T: Development of the capacity of peripheral blood mononuclear cells to produce IL-4, IL-5 and IFN-γ upon stimulation with house dust mite in children with atopic dermatitis. Int Arch Allergy Immunol 2002;127:191-197.
  9. Kimura M, Tsuruta S, Yoshida T: Correlation of house dust mite-specific lymphocyte proliferation with IL-5 production, eosinophilia, and the severity of symptoms in infants with atopic dermatitis. J Allergy Clin Immunol 1998;101:84-89.
  10. Hanifin JM, Rajka G: Diagnostic features of atopic dermatitis. Acta Derm Venereol 1980;92(suppl):44-47.
  11. Song TW, Sohn MH, Kim ES, Kim KW, Kim KE: Increased serum thymus and activation-regulated chemokine and cutaneous T cell-attracting chemokine levels in children with atopic dermatitis. Clin Exp Allergy 2006;36:346-351.
  12. Fujisawa T, Nagao M, Hiraguchi Y, Katsumata H, Nishimori H, Iguchi K, Kato Y, Higashiura M, Ogawauchi I, Tamaki K: Serum measurement of thymus and activation-regulated chemokine/CCL17 in children with atopic dermatitis: elevated normal levels in infancy and age-specific analysis in atopic dermatitis. Pediatr Allergy Immunol 2009;20:633-641.
  13. Webber CM, England RW: Oral allergy syndrome: a clinical, diagnostic, and therapeutic challenge. Ann Allergy Asthma Immunol 2010;104:101-108.
  14. Wong LF, Lin JY, Hsieh KH, Lin RW: Epicutaneous exposure of protein antigen induces a predominant Th2-like response with high IgE production in mice. J Immunol 1996;156:4079-4082.
    External Resources
  15. Strid J, Hourihane J, Kimber I, Callard R, Strobel S: Disruption of the stratum corneum allows potent epicutaneous immunization with protein antigens resulting in a dominant systemic Th2 response. Eur J Immunol 2004;34:2100-2109.
  16. Birmingham NP, Parvataneni S, Hassan HMA, Harkema J, Samineni S, Navuluri L, Kelly CJ, Gangur V: An adjuvant-free mouse model of tree nut allergy using hazelnut as a model tree nut. Int Arch Allergy Immunol 2007;144:203-210.
  17. Bertelsen RJ, Faeste CK, Granum B, Egaas E, London SJ, Carlsen KH, Lodrup Carlsen KC, Lovik M: Food allergens in mattress dust in Norwegian homes - a potentially important source of allergen exposure. Clin Exp Allergy 2014;44:142-149.
  18. Masuda S, Morishima T, Matsuyama A, Kagami M, Tokuda R, Urisu A, Fujita M, Miyazawa I, Okumura T, Matsumoto T, Takahata Y: Measurement of the amount of food allergens in house dust. Bulletin Yachiyo Hospital 2005;25:12-14 (Japanese).
  19. Macchiaverni P, Rekima A, Turfkruyer M, Mascarell L, Airouche S, Moingeon P, Adel-Patient K, Condino-Neto A, Annessi-Aaesano I, Prescott SL, Tulic MK, Verhasselt V: Respiratory allergen from house dust mite is present in human milk and primes for allergic sensitization in a mouse model of asthma. Allergy 2014;69:395-398.
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