Cutaneous exposure to agglomerates of silica nanoparticles and allergen results in IgE-biased immune response and increased sensitivity to anaphylaxis in mice
- Toshiro Hirai1,
- Yasuo Yoshioka1, 2, 3Email author,
- Hideki Takahashi1, 2,
- Ko-ichi Ichihashi1,
- Asako Udaka1,
- Takahide Mori4,
- Nobuo Nishijima1,
- Tokuyuki Yoshida1,
- Kazuya Nagano5,
- Haruhiko Kamada5, 6,
- Shin-ichi Tsunoda5, 6,
- Tatsuya Takagi7, 8,
- Ken J. Ishii9, 10,
- Hiromi Nabeshi11,
- Tomoaki Yoshikawa1,
- Kazuma Higashisaka1, 5 and
- Yasuo Tsutsumi1, 4, 6Email author
© Hirai et al. 2015
Received: 18 April 2015
Accepted: 16 June 2015
Published: 26 June 2015
The skin is a key route of human exposure to nanomaterials, which typically occurs simultaneously with exposure to other chemical and environmental allergen. However, little is known about the hazards of nanomaterial exposure via the skin, particularly when accompanied by exposure to other substances.
Repeated topical treatment of both ears and the shaved upper back of NC/Nga mice, which are models for human atopic dermatitis (AD), with a mixture of mite extract and silica nanoparticles induced AD-like skin lesions. Measurements of ear thickness and histologic analyses revealed that cutaneous exposure to silica nanoparticles did not aggravate AD-like skin lesions. Instead, concurrent cutaneous exposure to mite allergens and silica nanoparticles resulted in the low-level production of allergen-specific IgGs, including both the Th2-related IgG1 and Th1-related IgG2a subtypes, with few changes in allergen-specific IgE concentrations and in Th1 and Th2 immune responses. In addition, these changes in immune responses increased the sensitivity to anaphylaxis. Low-level IgG production was induced when the mice were exposed to allergen–silica nanoparticle agglomerates but not when the mice exposed to nanoparticles applied separately from the allergen or to well-dispersed nanoparticles.
Our data suggest that silica nanoparticles themselves do not directly affect the allergen-specific immune response after concurrent topical application of nanoparticles and allergen. However, when present in allergen-adsorbed agglomerates, silica nanoparticles led to a low IgG/IgE ratio, a key risk factor of human atopic allergies. We suggest that minimizing interactions between nanomaterials and allergens will increase the safety of nanomaterials applied to skin.
Because of their unique features and physicochemical properties [1, 2], nanomaterials are increasingly being used to add value to new and existing goods, such as cosmetics, foods, medicines, and industrial products [3–5]. However, these same novel features of nanomaterials make them hazardous under some conditions [6, 7]. To take full advantage of the potential benefits of nanomaterials, we must learn more about their hazards so that safer nanomaterials can be designed.
Numerous epidemiologic studies have prompted concerns regarding the health risks associated with exposure to nanomaterials; in particular, such studies have revealed that exposure to particulate matter (PM), including PM2.5 and Asian dust, induces many adverse effects, including facilitating the onset and severity of allergic diseases [8–11]. Because inhalational exposure to PM has been considered to be the main inducer of these adverse effects, this route has received the most attention regarding exposure to nanomaterials . However, the skin is a major route of both intentional (from clothing, cosmetics, and other skin care products) and unintentional (from the environment) exposure to nanomaterials [13–15]. Furthermore, exposure to nanomaterials often occurs simultaneously with exposure to other chemical compounds and environmental allergens , but little is known about the hazards of cutaneous exposure to nanomaterials, particularly in combination with other substances.
In the current study, we investigated the effects of concurrent topical application of mite extract and amorphous silica nanoparticles, one of the most widely used nanomaterials, on allergic sensitization and AD in NC/Nga mice, a murine model of AD. We found that cutaneous exposure to the allergen and silica nanoparticles simultaneously did not aggravate AD-like skin lesions in the mice but resulted in low-level IgG production with little change in IgE production (IgE-biased immune response) and increased sensitivity to anaphylaxis. We suggest that an IgE-biased immune response was induced independently of the innate biologic effects of silica nanoparticles. Because a low IgG/IgE ratio is a characteristic feature of human atopic allergy, we believe that minimizing interactions between nanomaterials and allergens may improve the safety of cutaneously applied nanomaterials.
Results and discussion
Effects of co-exposure to mite allergen and silica nanoparticles in a murine model of AD
Total IgE levels in plasma, which are often elevated in AD and other allergic conditions , were measured 24 h after the final treatment. The total IgE level in the Dp-alone group was higher than that in the PBS group (Fig. 2f), and the total IgE level in the Dp + nSP30 group was slightly higher than that in the Dp-alone group (Fig. 2f). Because a Th2-mediated immune response including IgE production is unnecessary for the development of AD-like skin lesions in NC/Nga mice , the high total IgE level induced by cutaneous exposure to Dp + nSP30 likely did not exacerbate the Dp-induced AD-like skin lesions in NC/Nga mice.
Effect of cutaneous exposure to Dp + nSP30 on cutaneous allergic sensitization
To further characterize the systemic immune responses, we enumerated the Dp-specific splenocytes secreting interferon-γ (IFN-γ) and interleukin-4 (IL-4) in each mouse by using cytokine-specific enzyme-linked immunosorbent spot (ELISPOT) assays (Fig. 3d). The numbers of Dp-specific IFN-γ- and IL-4-secreting splenocytes did not differ between the Dp-alone group and the Dp + nSP30 group. In addition, although concentration of IL-21 in the supernatants of splenocytes was significantly lower in the Dp + nSP30 group than in the Dp-alone group, none of the other measured cytokines (IL-5, 10, 13, and 17) differed between these groups (Additional file 3). Therefore, nSP30 might have affected IgG production without altering systemic Th1 and Th2 immune responses. Because IL-21 is a critical factor in IgG production [24, 25], additional study of IL-21 likely would help to clarify the mechanism underlying the reductions in both the IgG1 and IgG2a subtypes.
Recently, the skin was revealed to be the key initial site of allergic sensitization not only for allergic eczema but also for other atopic allergies, including allergic rhinitis, asthma, and food allergies [26–28]. Therefore, skin might play a special role in allergic sensitization. To this end, we assessed the effects of exposure to Dp + nSP30 by various other exposure routes on the IgG response (Additional file 4). Consistent with our previously reported results , nSP30-mediated IgG suppression was not observed after intranasal, oral, or intradermal administration of Dp + nSP30, thus suggesting that the low IgG response was a specific effect induced by cutaneous exposure to Dp + nSP30.
Effect of cutaneous exposure to Dp + nSP30 on susceptibility to anaphylaxis
Effects of sequential cutaneous exposure to allergen and nSP30 on the IgE-biased immune response
Effects of agglomeration of allergen and nSP30 on the IgE-biased immune response
We previously examined the Dp dose-effect in the same NC/Nga model (Hirai T. et al., submitted paper). In that study, levels of both Dp-specific IgE and IgG were correlated with exposure amount of Dp in the range of 30 to 120 μg Dp mouse−1; in the current study, we used a dose of 120 μg Dp mouse−1 for the Dp-alone group. Furthermore, the Th2-related cytokine response in Dp-stimulated splenocytes was lower in the120-μg Dp mouse−1 group than in other (lower) dose groups. In contrast, we show here that the exposure to agglomerates of Dp and nSP30 in PBS induced a dampened Dp-specific IgG response with little change in the Dp-specific IgE and Th1/Th2 immune responses compared with those of the Dp-alone group (Fig. 3 and Additional file 3). Together, these observations suggest that the IgE-biased immune response in the current study was not solely due to the low Dp exposure resulting from the agglomeration of Dp and nSP30. Perhaps the agglomerates of Dp and nSP30 in PBS not only decreased the Dp exposure dose but also behaved as a ‘depot,’ thus controlling the allergen concentration, prolonging allergen exposure, and subsequently causing IgE-biased allergic sensitization. We believe additional studies that focus on the effect of nanoparticles on allergen penetration kinetics in the skin would be beneficial to confirm the safety of cutaneous exposure to nanomaterials. However, we acknowledge the need for additional studies in which the exposure scenario is more representative of that in humans to define the safety of concurrent cutaneous exposure to nanomaterials and allergen.
It is well recognized that there are some situations in our daily lives, the development of atopic allergy is inhibited by higher dose exposure to allergen due to high induction of blocking IgG [46–48]. Particularly in these high-dose exposure situations, we suggest that allergen-nanoparticle agglomerates, by inducing IgE-biased immune responses, might play a critical role in the development of atopic allergy. In addition, the IgE-biased immune response induced by cutaneous exposure to agglomerates of allergen and nanoparticles in our mice was similar to those humans with atopic allergies, who often have a low IgG/IgE ratio, as mentioned earlier [40, 41]. Therefore epidemiologic studies that address cutaneous as well as inhalational exposure to nanomaterials may improve our understanding of the onset of atopic allergy.
Recently, Ilves M. et al. described the effects of cutaneous exposure to nano-sized ZnO (nZnO) administered with model antigens, ovalbumin and staphylococcal enterotoxin B, on AD-like skin lesions and antibody responses . Interestingly, the effects observed for nZnO and an antigen were similar to the effects of agglomerates of Dp and nSP30: nZnO suppressed allergen-induced skin inflammation and induced low-level IgG production in the context of a high IgE response. The authors of the previous study  did not address changes of nZnO dispersibility by mixing allergen, but considering that nZnO is predisposed to forming agglomerates and might adsorb a coexisting substance , nZnO might play similar role to that of nSP30. To better understand the hazards of nanomaterials so that we can maximize their potential benefits, we should pay increased attention to the state of nanoparticles (e.g. dispersibility) in administration in nanotoxicology studies. We consider this focus particularly applicable in the hazard evaluation of nanomaterials that are in the presence of other substances, which could interact with them.
Cutaneous exposure to aggregates or agglomerates of nanomaterials is generally considered to be safer than is similar exposure to individual nanoparticles, mainly because agglomerates of nanomaterials have difficulty penetrating the skin . However, Dp and nSP30 induced an IgE-biased immune response only when they formed agglomerates. Although these results represent only indirect effects of nanomaterials, we think that hazard identification is necessary even when nanomaterials are considered to be unable to cross the skin barrier (e.g. when nanomaterials form aggregates or agglomerates). In contrast, surface modification of the nSP30 with carboxyl groups suppressed the adsorption of the allergen and did not induce IgE-biased allergic sensitization (Fig. 6). An increased understanding of the regulatory factors that induce the agglomeration of silica nanoparticles is crucial for appropriate regulation of the surface properties of nanomaterials so that they can be used safely.
Cutaneous exposure to agglomerates of Dp and nSP30 induced an IgE-biased immune response in NC/Nga mice and increased their sensitivity to anaphylaxis. Surprisingly, these results were independent of the innate biologic effects of nSP30; these results required both simultaneous exposure to Dp and nSP30 and their agglomeration. In particular, features of the mice with IgE-biased immune response induced by cutaneous exposure to agglomerates of allergen and nanoparticles resembled those of humans with atopic allergies, who often have a low IgG/IgE ratio; follow-up epidemiologic studies that focus cutaneous compared with inhalational exposure to nanomaterials might improve our understanding of the onset of atopic allergy. In light of our findings, we suggest that minimizing the interaction between nanomaterials and allergens may improve the safety of topically applied products containing nanomaterials.
nSP30 and nSP30C (nSP30C is a surface modified nSP30 with carboxyl groups) silica nanoparticles (diameter, 30 mm) were purchased from Micromod Partikeltechnologie (Rostock/Warnemünde, Germany). Suspensions of silica nanoparticles were stored at room temperature. Immediately prior to use, the suspensions were sonicated at 400 W for 5 min at 25 °C and then vortexed for 1 min.
Female NC/Nga slc mice were purchased from SLC (Kyoto, Japan) and used at 6 wk of age. All animal experiments were performed in accordance with the institutional guidelines of Osaka University and National Institute of Biomedical Innovation regarding the ethical treatment of animals.
Preparation of the mixtures of Dp and nSP30s
To prepare the mixtures of nSP30s and Dp (Cosmo Bio LSL, Tokyo, Japan), we first combined nSP30s (25 mg mL−1 in water) and concentrated PBS (1.1× to 4.6×; the concentration of the PBS stock used depended on the concentration of nSP30s needed in the final sample, the diluent for which was 1× PBS). We then added the stock solution of Dp (2.78 mg protein mL−1 in PBS) to the solutions containing various concentrations of nSP30s. As soon as the nSP30s and Dp solutions were combined, the mixtures were vortexed for 1 min, allowed to incubate at room temperature for 0.5 to 1.5 h, and vortexed again for 1 min just prior to use.
Physicochemical examination of silica nanoparticles
TEM (H-7650; Hitachi High-Technologies Corporation, Tokyo, Japan) was used to assess the size and shape of the silica nanoparticles. nSP30 and nSP30C nanoparticles were diluted to 0.25 mg mL−1 in PBS or deionized water, and the mean particle diameter and zeta potential at 25 °C were measured by using a Zetasizer Nano ZS (Malvern Instruments, Worcestershire, UK). Specifically, the mean diameters and particle size distributions of the nanoparticles were measured by means of a dynamic light-scattering method, whereas zeta potentials were measured by laser Doppler electrophoresis; both types of measurements were performed by using capillary cells (Malvern Instruments). The pH of each particle suspension was measured by using an ISFET pH meter (Shindengen, Tokyo, Japan).
Skin painting and assessment of allergic response
Using a hair-removal cream (Epilat; Kracie, Tokyo, Japan), we removed the hair from the backs of all mice twice during each experiment (on day 1 and on day 18–20). Mice were treated either with Dp (1 mg mL−1 fin. conc) alone or with silica nanoparticles (nSP30 or nSP30C, 12.5 mg mL−1 fin. conc.) in 120 μL PBS by painting the ventral side of both ears and the depiliated dorsum (20 μL per ear and 80 μL on the back) on alternate days or every third day for 4 wk for a total of 13 applications. Additional mice were painted with Dp only on one day followed by painting with nSP30 alone on the next day; this alternating pattern was repeated for a total of 13 applications of each solution over 4 wk. Regardless of the dose schedule used, any sample remaining from a previous application was removed by gently wiping with a disposable wipe (Kim wipes, Crecia, Tokyo, Japan) wetted with 70 % ethanol.
We used a dial thickness gauge (0.001-mm type; Ozaki Manufacturing, Tokyo, Japan) to measure ear thickness weekly. To evaluate the severity of the IgE-mediated allergic response’ instead, we used a systemic anaphylaxis model. Specifically, at 1 wk after the final skin painting, each mouse was challenged with an intravenous injection of Dp (15 μg in 200 μL PBS). The severity of anaphylactic shock was assessed according to the change in rectal temperature measured by using a digital thermometer (KN-91; Natsume Seisakusho, Tokyo, Japan).
At 24 h after the final topical treatment, the ears of euthanized mice were removed, placed in fixative solution (4 % paraformaldehyde in PBS; Wako, Osaka, Japan), embedded in paraffin, and sectioned. The tissue sections were stained with hematoxylin and eosin or with toluidine blue. Histopathological examination was performed by the Applied Medical Research Laboratory (Osaka, Japan). For each sample, representative symptoms of AD (scab formation, acanthosis and inflammatory cell infiltration) were scored as follows: 0, none; 1, slight; 2, mild; 3, moderate; and 4, severe. In addition, we counted the number of mast cells in 3 random high-power fields (magnification, 400×).
Using hematocrit capillary tubes (Terumo, Tokyo, Japan), we obtained blood samples from the retro-orbital venous plexus once each week during the study period. At 24 h after the final skin painting, blood was collected by cardiocentesis into heparin-treated syringes and centrifuged at 3000 × g at 4 °C; the resulting plasma was stored at −80 °C until analysis.
Quantitation of total IgE concentration
The total IgE concentration in plasma was measured by using an ELISA kit (BD Biosciences, San Diego, CA, USA) according to the manufacturer’s instructions.
Detection of Dp-specific antibody
The levels of Dp-specific antibody in plasma were determined by ELISA. To detect IgG, IgG1, IgG2a, IgG2b and IgG3, we coated ELISA plates (Maxisorp, type 96 F; Nunc A/S, Roskilde, Denmark) with Dp in PBS (50 μg mL−1). The coated plates were incubated with 2 % Block Ace (Dainippon Sumitomo Pharmaceuticals, Osaka, Japan). Plasma samples were diluted by 2 % Block Ace and these dilutions were added to the Dp-coated plates. After incubation with plasma, the coated plates were incubated with a horseradish peroxidase–conjugated goat anti-mouse IgG, IgG1, IgG2a, IgG2b or IgG3 solution (SouthernBiotech, Birmingham, AL, USA) for two hours at room temperature. After the incubation, the color reaction was developed with tetramethyl benzidine (Moss, Inc.; Pasadena, MD, USA), stopped with 2 N H2SO4, and measured at OD450–620 on a microplate reader.
To detect Dp-specific IgE, we coated ELISA plates (Maxisorp, type 96 F) with purified rat anti-mouse IgE (2 μg mL−1; R35-72, BD Biosciences;), incubated them with Block Ace, and added samples of diluted plasma as described earlier. Treated plates were incubated with biotin-conjugated Dp (5 μg mL−1) followed by horseradish peroxidase–coupled streptavidin (Southern Biotechnology Associates). Color detection was performed as described earlier.
Isolation of splenocytes
Spleens were removed aseptically and placed in RPMI 1640 (Wako) supplemented with 10 % fetal bovine serum, 10 mL L−1 of a 100× nonessential amino acid solution (Gibco, Invitrogen, Carlsbad, CA, USA), 50 μM 2-mercaptoethanol (Gibco), and 1 % antibiotic cocktail (10,000 U mL−1 penicillin, 10,000 μg mL−1 streptomycin, 25 μg mL−1 amphotericin B; Gibco). Single-cell suspensions of splenocytes were treated with ammonium chloride to lyse the red blood cells; treated splenocytes then were washed, counted, and suspended in RPMI 1640.
To determine antigen-specific cytokine (IFN-γ and IL-4) responses, splenocytes (5 × 105 cells well−1) were stimulated with Dp antigen (100 μg mL−1) in vitro. After 24 h incubation at 37 °C (95 % room air, 5 % CO2), stimulated splenocytes were washed, and the numbers of IFN-γ- and IL-4-producing cells were determined by using an ELISPOT assay kit (BD Biosciences) according to the manufacturer’s instructions.
Measurement of amount of Dp adsorbed to silica nanoparticles
Solutions of Dp (1 mg mL−1 fin. conc.) + each nSP immediately after preparation in PBS or water for 30 min at 25 °C were centrifuged (2 h, 40,000 × g, 4 °C). The amount of Dp in the supernatant then was determined spectrophotometrically (OD280; Nanodrop 2000, Thermo Scientific, Kanagawa, Japan).
Statistical analyses were performed with Ekuseru-Toukei 2010 software (Social Survey Research Information Co., Ltd., Tokyo, Japan). All data are presented as means ± SEMs. Significant differences between control groups and experimental groups were determined by using the Dunnett test; a P value less than 0.05 was considered significant.
Methods for additional files are available in (Additional file 5).
This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) and from the Japan Society for the Promotion of Science (JSPS); by a Grant-in-Aid for JSPS Fellows; by Health Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan (MHLW); by The Takeda Science Foundation; by The Research Foundation for Pharmaceutical Sciences; by The Japan Food Chemical Research Foundation; by the Urakami Foundation; and by the Uehara Memorial Foundation.
- Auffan M, Rose J, Bottero JY, Lowry GV, Jolivet JP, Wiesner MR. Towards a definition of inorganic nanoparticles from an environmental, health and safety perspective. Nat Nanotechnol. 2009;4(10):634–41. doi:10.1038/nnano.2009.242.PubMedView ArticleGoogle Scholar
- Cheng Z, Al Zaki A, Hui JZ, Muzykantov VR, Tsourkas A. Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science. 2012;338(6109):903–10. doi:10.1126/science.1226338.PubMed CentralPubMedView ArticleGoogle Scholar
- Bowman DM, van Calster G, Friedrichs S. Nanomaterials and regulation of cosmetics. Nat Nanotechnol. 2010;5(2):92. doi:10.1038/nnano.2010.12.PubMedView ArticleGoogle Scholar
- Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol. 2010;7(11):653–64. doi:10.1038/nrclinonc.2010.139.PubMed CentralPubMedView ArticleGoogle Scholar
- Peters R, Kramer E, Oomen AG, Rivera ZE, Oegema G, Tromp PC, et al. Presence of nano-sized silica during in vitro digestion of foods containing silica as a food additive. ACS Nano. 2012;6(3):2441–51. doi:10.1021/nn204728k.PubMedView ArticleGoogle Scholar
- Yamashita K, Yoshioka Y, Higashisaka K, Mimura K, Morishita Y, Nozaki M, et al. Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nat Nanotechnol. 2011;6(5):321–8. doi:10.1038/nnano.2011.41.PubMedView ArticleGoogle Scholar
- Setyawati MI, Tay CY, Chia SL, Goh SL, Fang W, Neo MJ, et al. Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE-cadherin. Nat Commun. 2013;4:1673. doi:10.1038/ncomms2655.PubMedView ArticleGoogle Scholar
- Kulbok PA, Baldwin JH. From preventive health behavior to health promotion: advancing a positive construct of health. ANS Adv Nurs Sci. 1992;14(4):50–64.PubMedView ArticleGoogle Scholar
- Janssen NA, Brunekreef B, van Vliet P, Aarts F, Meliefste K, Harssema H, et al. The relationship between air pollution from heavy traffic and allergic sensitization, bronchial hyperresponsiveness, and respiratory symptoms in Dutch schoolchildren. Environ Health Perspect. 2003;111(12):1512–8.PubMed CentralPubMedView ArticleGoogle Scholar
- Bartra J, Mullol J, del Cuvillo A, Davila I, Ferrer M, Jauregui I, et al. Air pollution and allergens. J Investig Allergol Clin Immunol. 2007;17 Suppl 2:3–8.PubMedGoogle Scholar
- McCreanor J, Cullinan P, Nieuwenhuijsen MJ, Stewart-Evans J, Malliarou E, Jarup L, et al. Respiratory effects of exposure to diesel traffic in persons with asthma. N Engl J Med. 2007;357(23):2348–58.PubMedView ArticleGoogle Scholar
- Tsuji JS, Maynard AD, Howard PC, James JT, Lam CW, Warheit DB, et al. Research strategies for safety evaluation of nanomaterials, part IV: risk assessment of nanoparticles. Toxicol Sci. 2006;89(1):42–50.PubMedView ArticleGoogle Scholar
- Som C, Wick P, Krug H, Nowack B. Environmental and health effects of nanomaterials in nanotextiles and facade coatings. Environ Int. 2011;37(6):1131–42. doi:10.1016/j.envint.2011.02.013.PubMedView ArticleGoogle Scholar
- Rancan F, Gao Q, Graf C, Troppens S, Hadam S, Hackbarth S, et al. Skin penetration and cellular uptake of amorphous silica nanoparticles with variable size, surface functionalization, and colloidal stability. ACS Nano. 2012;6(8):6829–42. doi:10.1021/nn301622h.PubMedView ArticleGoogle Scholar
- Dhanirama D, Gronow J, Voulvoulis N. Cosmetics as a potential source of environmental contamination in the UK. Environ Technol. 2012;33(13–15):1597–608.PubMedView ArticleGoogle Scholar
- Li N, Xia T, Nel AE. The role of oxidative stress in ambient particulate matter-induced lung diseases and its implications in the toxicity of engineered nanoparticles. Free Radic Biol Med. 2008;44(9):1689–99. doi:10.1016/j.freeradbiomed.2008.01.028.PubMed CentralPubMedView ArticleGoogle Scholar
- Matsuda H, Watanabe N, Geba GP, Sperl J, Tsudzuki M, Hiroi J, et al. Development of atopic dermatitis-like skin lesion with IgE hyperproduction in NC/Nga mice. Int Immunol. 1997;9(3):461–6.PubMedView ArticleGoogle Scholar
- Banerjee S, Resch Y, Chen KW, Swoboda I, Focke-Tejkl M, Blatt K, et al. Der p 11 is a major allergen for house dust mite-allergic patients suffering from atopic dermatitis. J Investig Dermatol. 2015;135(1):102–9. doi:10.1038/jid.2014.271.PubMedView ArticleGoogle Scholar
- Fuiano N, Diddi G, Delvecchio M, CI C. Prevalence of positive atopy patch test in an unselected pediatric population. Clin Mol Allergy. 2015;13(1):2. doi:10.1186/s12948-015-0011-2.PubMed CentralPubMedView ArticleGoogle Scholar
- Aioi A, Tonogaito H, Suto H, Hamada K, Ra CR, Ogawa H, et al. Impairment of skin barrier function in NC/Nga Tnd mice as a possible model for atopic dermatitis. Br J Dermatol. 2001;144(1):12–8.PubMedView ArticleGoogle Scholar
- Flohr C, Johansson SG, Wahlgren CF, Williams H. How atopic is atopic dermatitis? J Allergy Clin Immunol. 2004;114(1):150–8. doi:10.1016/j.jaci.2004.04.027.PubMedView ArticleGoogle Scholar
- Yagi R, Nagai H, Iigo Y, Akimoto T, Arai T, Kubo M. Development of atopic dermatitis-like skin lesions in STAT6-deficient NC/Nga mice. J Immunol. 2002;168(4):2020–7.PubMedView ArticleGoogle Scholar
- Coffman RL, Savelkoul HF, Lebman DA. Cytokine regulation of immunoglobulin isotype switching and expression. Semin Immunol. 1989;1(1):55–63.PubMedGoogle Scholar
- Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, et al. A critical role for IL-21 in regulating immunoglobulin production. Science. 2002;298(5598):1630–4. doi:10.1126/science.1077002.PubMedView ArticleGoogle Scholar
- Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity. 2008;29(1):127–37. doi:10.1016/j.immuni.2008.06.001.PubMedView ArticleGoogle Scholar
- Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38(4):441–6.PubMedView ArticleGoogle Scholar
- Weidinger S, O’Sullivan M, Illig T, Baurecht H, Depner M, Rodriguez E, et al. Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J Allergy Clin Immunol. 2008;121(5):1203–9. doi:10.1016/j.jaci.2008.02.014. 5.PubMedView ArticleGoogle Scholar
- Lack G. Update on risk factors for food allergy. J Allergy Clin Immunol. 2012;129(5):1187–97. doi:10.1016/j.jaci.2012.02.036.PubMedView ArticleGoogle Scholar
- Hirai T, Yoshikawa T, Nabeshi H, Yoshida T, Tochigi S, Ichihashi K, et al. Amorphous silica nanoparticles size-dependently aggravate atopic dermatitis-like skin lesions following an intradermal injection. Part Fibre Toxicol. 2012;9:3. doi:10.1186/1743-8977-9-3.PubMed CentralPubMedView ArticleGoogle Scholar
- Kawakami T, Ando T, Kimura M, Wilson BS, Kawakami Y. Mast cells in atopic dermatitis. Curr Opin Immunol. 2009;21(6):666–78. doi:10.1016/j.coi.2009.09.006.PubMed CentralPubMedView ArticleGoogle Scholar
- Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S73–80. doi:10.1016/j.jaci.2009.11.017.PubMed CentralPubMedView ArticleGoogle Scholar
- Strait RT, Morris SC, Finkelman FD. IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and Fc gamma RIIb cross-linking. J Clin Invest. 2006;116(3):833–41. doi:10.1172/JCI25575.PubMed CentralPubMedView ArticleGoogle Scholar
- Uermosi C, Beerli RR, Bauer M, Manolova V, Dietmeier K, Buser RB, et al. Mechanisms of allergen-specific desensitization. J Allergy Clin Immunol. 2010;126(2):375–83. doi:10.1016/j.jaci.2010.05.040.PubMedView ArticleGoogle Scholar
- Cassard L, Jonsson F, Arnaud S, Daeron M. Fcgamma receptors inhibit mouse and human basophil activation. J Immunol. 2012;189(6):2995–3006. doi:10.4049/jimmunol.1200968.PubMedView ArticleGoogle Scholar
- Jutel M, Jaeger L, Suck R, Meyer H, Fiebig H, Cromwell O. Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol. 2005;116(3):608–13. doi:10.1016/j.jaci.2005.06.004.PubMedView ArticleGoogle Scholar
- Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens. J Allergy Clin Immunol. 2014;133(3):621–31. doi:10.1016/j.jaci.2013.12.1088.PubMedView ArticleGoogle Scholar
- Nel AE, Madler L, Velegol D, Xia T, Hoek EM, Somasundaran P, et al. Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater. 2009;8(7):543–57. doi:10.1038/nmat2442.PubMedView ArticleGoogle Scholar
- Jiang J. Oberdo¨rster Gn, Biswas P. Characterization of size, surface charge, and agglomeration state of nanoparticle dispersions for toxicological studies. J Nanoparticle Res. 2009;11(1):77–89.View ArticleGoogle Scholar
- Boverhof DR, David RM. Nanomaterial characterization: considerations and needs for hazard assessment and safety evaluation. Anal Bioanal Chem. 2010;396(3):953–61. doi:10.1007/s00216-009-3103-3.PubMedView ArticleGoogle Scholar
- Chapman MD, Platts-Mills TA. Measurement of IgG, IgA and IgE antibodies to Dermatophagoides pteronyssinus by antigen-binding assay, using a partially purified fraction of mite extract (F4P1). Clin Exp Immunol. 1978;34(1):126–36.PubMed CentralPubMedGoogle Scholar
- Platts-Mills TA. Local production of IgG, IgA and IgE antibodies in grass pollen hay fever. J Immunol. 1979;122(6):2218–25.PubMedGoogle Scholar
- Soderstrom L, Lilja G, Borres MP, Nilsson C. An explorative study of low levels of allergen-specific IgE and clinical allergy symptoms during early childhood. Allergy. 2011;66(8):1058–64. doi:10.1111/j.1398-9995.2011.02578.x.PubMedView ArticleGoogle Scholar
- Morokata T, Ishikawa J, Yamada T. Antigen dose defines T helper 1 and T helper 2 responses in the lungs of C57BL/6 and BALB/c mice independently of splenic responses. Immunol Lett. 2000;72(2):119–26.PubMedView ArticleGoogle Scholar
- Riedl MA, Landaw EM, Saxon A, Diaz-Sanchez D. Initial high-dose nasal allergen exposure prevents allergic sensitization to a neoantigen. J Immunol. 2005;174(11):7440–5.PubMedView ArticleGoogle Scholar
- Baroli B. Penetration of nanoparticles and nanomaterials in the skin: fiction or reality? J Pharm Sci. 2010;99(1):21–50. doi:10.1002/jps.21817.PubMedView ArticleGoogle Scholar
- Platts-Mills TA, Vaughan JW, Blumenthal K, Pollart Squillace S, Sporik RB. Serum IgG and IgG4 antibodies to Fel d 1 among children exposed to 20 microg Fel d 1 at home: relevance of a nonallergic modified Th2 response. Int Arch Allergy Immunol. 2001;124(1–3):126–9.PubMedView ArticleGoogle Scholar
- Matsui EC, Diette GB, Krop EJ, Aalberse RC, Smith AL, Curtin-Brosnan J, et al. Mouse allergen-specific immunoglobulin G and immunoglobulin G4 and allergic symptoms in immunoglobulin E-sensitized laboratory animal workers. Clin Exp Allergy. 2005;35(10):1347–53. doi:10.1111/j.1365-2222.2005.02331.x.PubMedView ArticleGoogle Scholar
- Jeal H, Draper A, Harris J, Taylor AN, Cullinan P, Jones M. Modified Th2 responses at high-dose exposures to allergen: using an occupational model. Am J Respir Crit Care Med. 2006;174(1):21–5. doi:10.1164/rccm.200506-964OC.PubMedView ArticleGoogle Scholar
- Ilves M, Palomaki J, Vippola M, Lehto M, Savolainen K, Savinko T, et al. Topically applied ZnO nanoparticles suppress allergen induced skin inflammation but induce vigorous IgE production in the atopic dermatitis mouse model. Part Fibre Toxicol. 2014;11:38. doi:10.1186/s12989-014-0038-4.PubMed CentralPubMedView ArticleGoogle Scholar
- Schilling K, Bradford B, Castelli D, Dufour E, Nash JF, Pape W, et al. Human safety review of “nano” titanium dioxide and zinc oxide. Photochem Photobiol Sci. 2010;9(4):495–509. doi:10.1039/b9pp00180h.PubMedView ArticleGoogle Scholar
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