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Background: In addition to allergen-specific IgE (sIgE), allergen-specific IgG4 (sIgG4) antibodies are also involved in the immune response resulting from an allergen exposure. The aim of our study was to analyze sIgE and sIgG4 patterns in the most common allergic disorders: bronchial asthma, upper airway disorders and atopic dermatitis. Methods: In this study a screening analysis of blood serum samples from 673 patients aged from 6 months to 17 years with different allergic entities was performed on microarrays. sIgE and sIgG4 levels to the most common allergens were estimated. Results: sIgE response to most pollen allergens is more strongly associated with respiratory diseases than with atopic dermatitis, while sIgE responses to cat and dog dander are more strongly associated with bronchial asthma than with atopic dermatitis and upper airway disorders such as rhinosinusitis and allergic rhinitis. A lower prevalence of sIgG4 to pollen allergens in cases of atopic dermatitis is observed compared with that in cases of asthma and upper airway disorders. Analyzing all the allergic disorders, one can see that sIgG4 response to inhalant allergens is strongly associated with sensitization to the corresponding allergen. Conclusion: Allergen-specific IgE and IgG4 patterns that are relevant to concrete allergic diseases differ by sIgE and sIgG4 prevalences to defined allergens. Keywords: Allergy diagnostics, IgE, IgG4, Microarrays, Sensitization, Asthma, Dermatitis, Rhinitis Background among children and adults with different allergic path- Bronchial asthma, allergic rhinitis and atopic dermatitis ologies. However, most of the studies have assessed only are the most common allergic reactions. The pathologies one particular pathology or only one particular group of individually and their comorbidities are often diagnosed allergens [7, 8]. among many atopic patients in different periods of life Allergen-specific IgG, including subclass G4, partici- . Along with genetics and adverse environmental fac- pates in the development of allergic reactions. The ana- tors, allergens as triggering factors represent major as- lysis of allergen-specific IgG4 is mainly performed in pects of the pathogenic pathways for the mentioned studies that are related to allergen-specific immunother- entities [2–4]. apy (ASIT) , and a change in the sIgG4 level is one of Currently, allergen-specific IgE is considered the only the indicators of the efficiency of ASIT, during which al- notable serological marker of type 1 hypersensitivity. A lergen tolerance occurs . However, in some cases, number of studies [5, 6] have focused on sIgE responses similar processes of tolerance induction with the involve- ment of sIgG4, as a part of the whole pool of allergen-specific IgG, occur among subjects not treated * Correspondence: email@example.com Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, with ASIT . The most representative example is the Vavilova str. 32, Moscow, Russian Federation119991 development of tolerance to food allergens while growing Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Smoldovskaya et al. World Allergy Organization Journal (2018) 11:35 Page 2 of 10 up . However, the sIgG4 response among atopic pa- approved by the local ethics committee of the Filatov tients of different age, states and diseases was less studied, Moscow City Pediatric Clinic No. 13. and IgG4 antibodies are regarded as minor party in hyper- sensitivity reaction manifestation because of low serum Microarray design and manufacturing concentrations. Microarray design and manufacturing technologies were The aim of our study was to analyze the sIgE and described in full in the previous works [13, 14]. Briefly, sIgG4 responses to allergens that are most relevant to the microarray is a matrix of semispherical hydrogel ele- the chosen allergic pathologies. We determined sIgE and ments (0.1 nl in volume) that contain one of the immo- sIgG4 levels in blood serum samples from 673 patients bilized allergens: 28 allergen extracts and 3 individual diagnosed with bronchial asthma, upper airway disorders isolated proteins (components of cow milk) (for the list or atopic dermatitis using microarrays with immobilized of allergens see Fig. 1). The allergens for immobilization protein extracts of 31 allergens. Profiles of the groups were purchased from GREER (Lenoir, NC, USA) and with different allergic pathologies were defined, and the were diluted to working concentrations (from 1 to 5 mg/ correlation between sIgE and sIgG4 occurrence was ml depending on the allergen) according to the manu- evaluated. facturer’s recommendations. The list of allergens in- cludes most common allergens in Central Russia ; this list largerly overlaps with the widespread allergens Methods in Central and Northern Europe. Participants and samples Concentrations of the allergens were chosen in such a Patients from the Filatov Moscow City Pediatric Clinic way that the results obtained from the microarrays most No. 13 aged from 6 months to 17 years were enrolled in accurately coincided with the results obtained by the ref- the study (Table 1). The recruitment was carried out erence methods (Specific IgE REAST (ALLERG-O-LIQ) from September, 2016, to September, 2017. Participants and Specific IgG4 ELISA (Dr. Fooke Laboratorien chosen for the study had three different diagnosis ac- GmbH, Germany)) . The sIgE levels were deter- cording to clinical history and medical examination: 1) mined in the range of 0.35–100 IU/ml, and the sIgG4 atopic patients without dermatitis symptoms with lower levels were determined in the range of 100–2500 ng/ml. airway disease or bronchial asthma (145 patients), 2) atopic patients with upper airway disorders (rhinosinusi- Analysis of allergen-specific IgE and IgG4 tis and allergic rhinitis) without asthma and dermatitis The analysis of sIgE and sIgG4 on the microarrays in- symptoms (194 patients), 3) participants with atopic cludes 4 stages: 1) incubation of the microarray with dermatitis without symptoms of airway disorders (334 the serum sample; 2) washing with a washing buffer patients) (Table 1). containing detergent; 3) incubation with the develop- The patients included in groups with airway disorders ing antibodies, a mixture of anti-human IgE and (bronchial asthma and upper airway disorders) had not anti-human IgG4 antibodies conjugated with Cy5 and demonstrated symptoms of allergic skin reaction for a Cy3, respectively; 4) washing with a washing buffer period of 1 year before the study. The patients in the containing detergent . group with atopic dermatitis had not demonstrated After the analysis, fluorescent signals from the gel pads symptoms of allergic airway diseases for a period of with immobilized allergens are detected using a micro- 1 year before the study. The children with well con- array analyzer with laser illumination and a device for trolled and/or well-medicated asthma were not included speckle suppression . Fluorescent signals are calcu- in the group with atopic dermatitis. lated by referencing piecewise linear calibration curves Surplus blood serum samples that remained after rou- constructed on the basis of the signals from the gel pads tine diagnostic procedures were analyzed. Additional with immobilized IgE and IgG4 to obtain the sIgE and blood draws were not performed. The study was sIgG4 concentrations in IU/ml and ng/ml, respectively. Patients were considered sensitized to the allergen if the sIgE level for the allergen exceeded the minimum Table 1 Characterization of the participants of the current study cutoff of 0.35 IU/ml. Nonsensitized, monosensitized and Allergic Male Female polysensitized patients were enrolled in the study. disorders 0–6 7–12 13–17 0–6 7–12 13–17 years years years years years years Data evaluation Asthma 28 37 36 9 21 14 sIgE prevalence was determined as the ratio of patients Upper airway 26 44 36 28 30 30 who exhibit sIgE above the cutoff of 0.35 IU/ml to the disorders total number of patients in the group of interest. sIgG4 Dermatitis 104 38 11 134 35 12 prevalence was determined as the ratio of patients who Smoldovskaya et al. World Allergy Organization Journal (2018) 11:35 Page 3 of 10 Fig. 1 Age-adjusted sIgE prevalences (the rate of patients who exhibit sIgE above 0.35 IU/ml) among the patients diagnosed with bronchial asthma, upper airway disorders (such as rhinosinusitis and rhinitis) or atopic dermatitis exhibit sIgG4 above the value of 100 ng/ml to the total The statistical significance of the differences in sIgG4 number of patients in the group of interest. response for sensitized and non-sensitized patients was sIgE prevalence and sIgG4 prevalence were adjusted estimated according to the results of the Fisher’s exact by age with the average population as a standard  test calculated by MedCalc. The differences were consid- using the Epitools package inR. Relationships ered statistically significant for pairwise comparisons between allergic sensitization and diseases were analyzed with p < 0.05. using a logistic regression model. To compare sIgE and The diagrams were plotted using Microsoft Excel sIgG4 prevalences among patients with different dis- 2010. eases, adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CIs) were calculated via multinomial logistic regression analysis with the age Results and gender as covariates using IBM SPSS Statistics In the current study, sIgE and sIgG4 levels of 673 blood 22.214.171.124. serum samples from patients aged from 6 months to Smoldovskaya et al. World Allergy Organization Journal (2018) 11:35 Page 4 of 10 Table 2 Adjusted ORs (aORs) for sIgE and sIgG4 prevalences among patients diagnosed with bronchial asthma, upper airway disorders (such as rhinosinusitis and rhinitis) or atopic dermatitis for inhalant allergens Allergens Asthma versus Upper Airway Disorders Asthma versus Dermatitis Upper Airway Disorders versus Dermatitis aOR 95% CI aOR 95% CI aOR 95% CI sIgE to inhalant allergens Pollen allergens Alder 0.809 (0.521;1.257) 2.980 (1.863;4.766) 3.682 (2.384;5.684) Birch 1.015 (0.653;1.578) 2.705 (1.725;4.242) 2.664 (1.76;4.032) Hazelnut (p) 0.889 (0.571;1.385) 3.700 (2.251;6.081) 4.160 (2.617;6.611) Oak 0.921 (0.568;1.494) 3.086 (1.714;5.555) 3.349 (1.928;5.815) Wormwood 0.849 (0.487;1.478) 1.253 (0.669;2.349) 1.477 (0.83;2.629) Mugwort 0.856 (0.518;1.415) 1.395 (0.8;2.434) 1.629 (0.979;2.712) Dandelion 0.668 (0.37;1.208) 1.031 (0.52;2.041) 1.542 (0.844;2.819) Bermuda grass 1.460 (0.873;2.44) 5.192 (2.569;10.491) 3.556 (1.792;7.055) Orchard grass 1.265 (0.772;2.074) 3.740 (1.999;6.997) 2.956 (1.622;5.385) Meadow fescue 1.146 (0.705;1.865) 3.179 (1.754;5.761) 2.773 (1.577;4.875) Perennial rye grass 1.139 (0.701;1.852) 3.075 (1.706;5.543) 2.698 (1.543;4.718) Timothy grass 1.123 (0.697;1.81) 3.405 (1.904;6.091) 3.032 (1.747;5.262) Cultivated rye 1.145 (0.685;1.913) 2.601 (1.389;4.868) 2.272 (1.249;4.133) Indoor allergens Cat dander 1.808 (1.154;2.833) 2.344 (1.461;3.761) 1.411 (0.897;2.221) Dog dander 2.225 (1.365;3.628) 2.401 (1.451;3.975) 1.079 (0.646;1.803) D. pteronyssinus 1.390 (0.735;2.629) 1.478 (0.72;3.032) 1.063 (0.522;2.165) D. farinae 1.802 (0.947;3.431) 1.760 (0.873;3.549) 0.976 (0.474;2.012) Alternaria tenuis 1.212 (0.552;2.665) 1.243 (0.525;2.942) 1.025 (0.452;2.326) Cockroach, German 0.218 (0.025;1.909) 0.886 (0.048;16.465) 4.065 (0.406;40.654) sIgG4 to inhalant allergens Pollen allergens Alder 1.102 (0.679;1.787) 3.311 (1.845;5.943) 3.006 (1.728;5.229) Birch 0.864 (0.557;1.338) 2.379 (1.505;3.76) 2.754 (1.807;4.199) Hazelnut (p) 0.941 (0.547;1.618) 2.643 (1.358;5.146) 2.810 (1.505;5.248) Oak 0.925 (0.381;2.246) 4.063 (1.204;13.71) 4.391 (1.412;13.652) Wormwood 0.942 (0.432;2.058) 2.963 (1.048;8.383) 3.144 (1.193;8.288) Mugwort 1.147 (0.624;2.109) 1.938 (0.97;3.873) 1.690 (0.875;3.263) Dandelion 0.339 (0.132;0.87) 0.811 (0.275;2.388) 2.390 (1.057;5.407) Bermuda grass 0.446 (0.119;1.67) 1.371 (0.301;6.245) 3.076 (0.972;9.735) Orchard grass 1.140 (0.337;3.854) 2.593 (0.598;11.248) 2.274 (0.566;9.139) Meadow fescue 1.189 (0.473;2.992) 5.462 (1.32;22.598) 4.593 (1.168;18.064) Perennial rye grass 1.745 (0.645;4.721) 4.491 (1.215;16.598) 2.573 (0.693;9.556) Timothy grass 0.926 (0.395;2.171) 2.673 (0.855;8.358) 2.888 (0.998;8.358) Cultivated rye 0.395 (0.08;1.952) 2.725 (0.345;21.526) 6.896 (1.303;36.492) Indoor allergens Cat dander 1.496 (0.913;2.453) 1.671 (0.992;2.814) 1.117 (0.673;1.852) Dog dander 1.067 (0.607;1.876) 1.813 (0.975;3.372) 1.699 (0.948;3.045) Smoldovskaya et al. World Allergy Organization Journal (2018) 11:35 Page 5 of 10 Table 2 Adjusted ORs (aORs) for sIgE and sIgG4 prevalences among patients diagnosed with bronchial asthma, upper airway disorders (such as rhinosinusitis and rhinitis) or atopic dermatitis for inhalant allergens (Continued) Allergens Asthma versus Upper Airway Disorders Asthma versus Dermatitis Upper Airway Disorders versus Dermatitis aOR 95% CI aOR 95% CI aOR 95% CI D. pteronyssinus 0.984 (0.469;2.063) 1.661 (0.75;3.682) 1.688 (0.804;3.544) D. farinae 0.681 (0.314;1.479) 1.333 (0.568;3.128) 1.957 (0.932;4.109) Alternaria tenuis 0.387 (0.08;1.876) 0.687 (0.127;3.705) 1.775 (0.568;5.553) Cockroach, German 0.264 (0.03;2.311) 1.152 (0.084;15.738) 4.362 (0.662;28.717) aORs were calculated using logistic regression analysis with the age and gender as covariates 17 years with allergic reactions (bronchial asthma – 145 homologous to major tree pollen proteins from Bet samples, upper airway disorders – 194 samples, and v1-like family [19, 20]. atopic dermatitis – 334 samples) were obtained. sIgG4 responses to food allergens are observed in pa- Results of the determination of allergen-specific IgE tients with all allergic diseases (Fig. 2). Among inhalant and IgG4 as well as sIgE and sIgG4 prevalence for differ- allergens, the highest adjusted sIgG4 prevalence is ent allergens in different age groups are presented in observed for the allergens most responsible for Additional file 1. Sensitization rates to each selected al- sensitization, i.e. detectable sIgE production (birch lergen, adjusted by age for different patient groups, are pollen, alder pollen, cat dander, and dog dander). presented in Fig. 1. The most significant differences be- Figure 3 indicates that detectable sIgG4 levels to inhal- tween sIgE prevalences in different diseases are observed ant allergens and some plant food allergens are common for inhalant allergens. For these allergens, ORs adjusted in sensitized patients with detectable sIgE levels, whereas by age and gender are shown in Table 2. no reliable difference is observed in rates of patients Patients with airway disorders (bronchial asthma and with sIgG4 to food allergens of animal origin between upper airway disorders) are mostly sensitized to pollen sensitized and non-sensitized groups. allergens. Notably, the adjusted sIgE prevalence for most Significant differences in adjusted sIgG4 prevalence pollen allergens distinguishes less than 10% for the are observed between the groups with atopic dermatitis patients with asthma and with upper airway disorders and with airway disorders for a variety of inhalant (Fig. 1). Sensitization to the majority of pollen aller- (mostly pollen) and food allergens (Tables 2 and 3). gens is more associated with airway diseases than with atopic dermatitis (i.e. aOR is significantly higher Discussion than 1, see Table 2). This study is aimed at the sIgE and sIgG4 responses Indoor allergens also have a significant impact, espe- among atopic patients from 6 months to 17 years of age cially the animal epithelium allergens of cat dander and with allergic diseases: bronchial asthma, upper airway dog dander. sIgE sensitization to these allergens is more disorders or atopic dermatitis. The age range was chosen common for patients with bronchial asthma than for pa- as 0 to 17 years because it is known that there are no- tients affected by only upper airway disorders or atopic ticeable changes in immunoglobulin patterns among al- dermatitis (Fig. 1). For these cases, as shown in Table 2, lergic patients during this period of life [21, 22]. After when comparing bronchial asthma and upper airway dis- the age of 18–20 years the sIgE profiles do not change orders for cat dander aOR = 1.808, 95% CI (1.154;2.833), significantly . for dog dander aOR = 2.225, 95% CI (1.365;3.628); when Although genetic predispositions to asthma and upper comparing bronchial asthma and atopic dermatitis for airway disorders are associated with different genetic cat dander aOR = 2.344, 95% CI (1.461;3.761), for dog polymorphisms, both diseases have common profiles of dander aOR = 2.401, 95% CI (1.451;3.975). inflammatory mediators and cell-mediated responses in- The adjusted prevalence of sensitization to food aller- volving eosinophils in the allergic inflammation . gens of animal origin is higher in asthma and atopic Subsequently, the corresponding similarity in the physio- dermatitis patients than in patients with upper airway logical processes affects the prevalence of sIgE to the al- disorders. However, this difference is most commonly lergens involved. not statistically significant (i.e. 95% CI for aORs contains For all explored allergens, with few exceptions, 1, Table 3). Sensitization to a number of plant food namely, cat and dog dander, considerable differences be- allergens (hazelnut, carrot, peach and apple) is ob- tween sIgE profiles for patients with asthma and upper served mostly for patients sensitized to tree pollens. airway disorders are not observed (Fig. 1). Daniel J. It is strongly influenced by pollen sensitization, be- Stoltz et al.  reported that increased asthma risk at cause mentioned allergens contain major components the age of 6 years is more strongly associated with Smoldovskaya et al. World Allergy Organization Journal (2018) 11:35 Page 6 of 10 Table 3 Adjusted ORs (aORs) for sIgE and sIgG4 prevalences among patients diagnosed with bronchial asthma, upper airway disorders (such as rhinosinusitis and rhinitis) or atopic dermatitis for food allergens Allergens Asthma versus Upper Airway Disorders Asthma versus Dermatitis Upper Airway Disorders versus Dermatitis aOR 95% CI aOR 95% CI aOR 95% CI sIgE to food allergens Animal food allergens Egg white 1.782 (0.977;3.25) 1.693 (0.976;2.939) 0.950 (0.55;1.64) Cow milk 1.526 (0.518;4.499) 0.645 (0.253;1.646) 0.423 (0.168;1.066) α-lactalbumin, cow milk 1.057 (0.289;3.866) 0.527 (0.165;1.686) 0.499 (0.181;1.374) β-lactoglobulin, cow milk 3.264 (0.286;37.209) 0.852 (0.183;3.96) 0.261 (0.033;2.049) Casein, cow milk 1.227 (0.363;4.149) 0.875 (0.293;2.619) 0.714 (0.26;1.962) Codfish 3.560 (1.215;10.432) 2.646 (1.039;6.739) 0.743 (0.237;2.329) Plant food allergens Wheat flour 1.442 (0.464;4.483) 1.935 (0.64;5.85) 1.342 (0.472;3.811) Peanut 1.455 (0.528;4.01) 1.290 (0.494;3.367) 0.887 (0.345;2.278) Hazelnut (f) 2.874 (1.059;7.798) 1.626 (0.687;3.847) 0.566 (0.202;1.587) Carrot 1.075 (0.587;1.969) 3.089 (1.449;6.584) 2.873 (1.388;5.946) Apple 0.789 (0.506;1.23) 3.164 (1.927;5.195) 4.011 (2.535;6.346) Peach 0.772 (0.179;3.327) 1.863 (0.392;8.866) 2.413 (0.609;9.561) sIgG4 to inhalant allergens Animal food allergens Egg white 0.297 (0.091;0.973) 2.305 (1.06;5.014) 7.762 (2.666;22.6) Cow milk 1.001 (0.557;1.803) 1.493 (0.841;2.653) 1.490 (0.878;2.531) α-lactalbumin, cow milk 0.865 (0.537;1.395) 1.262 (0.789;2.02) 1.458 (0.94;2.264) β-lactoglobulin, cow milk 1.105 (0.688;1.776) 1.765 (1.106;2.818) 1.597 (1.048;2.437) Casein, cow milk 1.213 (0.76;1.939) 2.037 (1.273;3.262) 1.678 (1.1;2.56) Codfish 1.288 (0.623;2.663) 3.841 (1.613;9.151) 2.981 (1.285;6.92) Plant food allergens Wheat flour 1.164 (0.75;1.809) 1.960 (1.262;3.044) 1.683 (1.128;2.512) Peanut 0.974 (0.622;1.524) 1.823 (1.134;2.931) 1.871 (1.206;2.905) Hazelnut (f) 0.919 (0.594;1.425) 1.971 (1.257;3.093) 2.144 (1.418;3.243) Carrot 1.261 (0.68;2.338) 2.137 (1.08;4.232) 1.694 (0.878;3.269) Apple 1.090 (0.667;1.781) 2.004 (1.171;3.43) 1.838 (1.112;3.041) Peach 1.348 (0.774;2.351) 2.593 (1.428;4.711) 1.923 (1.088;3.4) aORs were calculated using logistic regression analysis with the age and gender as covariates sensitization to dog and cat dander at 1 and 3 years than 86 years old) in the study : there were no significant with the absence of sensitization at younger age. Similar differences in sIgE prevalences between patients with interrelation is not observed for allergic rhinitis; that is asthma and rhinitis not only for pollen allergens but for why the authors suggested that sensitization to perennial cat and dog dander too. allergens is more closely linked to asthma development. Unlike upper airway disorders, atopic dermatitis and Our investigations are in agreement: sIgE sensitization bronchial asthma have a strong connection with food al- to cat or dog dander are more strongly associated with lergens [27, 28], which agrees with our results: sIgE asthma then with upper airway disorders (for cat dander prevalences for food allergens are higher for these path- – aOR = 1.808, 95% CI (1.154;2.833); for dog dander – ologies, though the difference is not statistically signifi- aOR = 2.225, 95% CI (1.365;3.628)). cant, probably because of the insufficient sampling size. Our data on sIgE sensitization partly coincides with As the study has not included healthy controls, we the results observed among adult population (22– have compared sIgE prevalence in our study with the Smoldovskaya et al. World Allergy Organization Journal (2018) 11:35 Page 7 of 10 Fig. 2 Age-adjusted sIgG4 prevalences (the rate of patient who exhibit sIgG4 above 100 ng/ml) among the patients diagnosed with bronchial asthma, upper airway disorders (such as rhinosinusitis and rhinitis) or atopic dermatitis sIgE prevalence in random population from Russian Ka- In contrast to IgE, the functions of IgG antibodies of relia, that was analyzed in the study of Ruokolainen L et different subclasses in the allergic pathologic process are al.  (Additional file 2 in Supplementary materials). still being discussed. The food-specific IgG response of From the Additional file 2 one can see that sensitization different subclasses is mostly considered as part of the rate for analyzed inhalant allergens in a random popula- normal reaction to natural exposure to food products tion is lower than normalized sensitization rate in the [11, 30]. Food allergens are the most common antigens groups with atopic patients from our study. As the ran- that lead to the production of sIgG, and its subclass dom population from the study of Ruokolainen L et al. sIgG4 accordingly . The data regarding sIgG4 ob- included some atopic patients (5,1% with atopic eczema, tained in our study confirm these findings (Fig. 2). Previ- 1,2% with asthma) we assume that the sensitization rate ously, we have studied the changes in sIgG4 prevalence in the group containing only healthy donors would be among pediatric patients depending on the age and our even lower, so the mentioned tendency would be correct results showed that the prevalence of sIgG4 to food anti- for the control group of healthy donors too. gens increases throughout the age . According to a Smoldovskaya et al. World Allergy Organization Journal (2018) 11:35 Page 8 of 10 Fig. 3 The rate of patients with sIgG4 > 100 ng/ml among sensitized and non-sensitized to each allergen groups of patients. Comparison of proportions by the Fisher exact test is noted by p-values: * – p < 0.05; ** – p < 0.01, *** – p < 0.001 number of studies [12, 32], this increase might be the affirmed. This finding can be explained by the evolution hallmark of tolerance induction. of sIgG4 as subjects age. Notably, IgG4 represents a small portion of total IgG. The observed interrelation of sIgG4 and sIgE re- Thus, the evolution of IgG in the young population is sponses for inhalant allergens combined with the differ- not associated with the evolution of IgG4 but with the ences in sIgE profiles between patients with airway IgG1 subclass, which is the main fraction of IgG . disorders and those with atopic dermatitis leads to sig- Xinyuan Huang et al.  demonstrated that the pro- nificant distinctions in the sIgG4 profiles for pollen aller- duction of the total IgG specific to inhalant allergens gens, for which significant differences in adjusted sIgE correlates with sensitization to the antigen in question. prevalence were observed while comparing different al- Schwarz A et al.  showed that sIgG to inhalant aller- lergic diseases (Table 2). gens as well as sIgG4 subclass to a variety of food aller- Due to the positive correlation between the presence of gens are observed mostly among sensitized patients at sIgE and significant sIgG4 to inhalant allergens in the the age of 2 years. In  sIgG4 to inhalant allergens serum samples, we assume that lower sensitization rates was not observed due to the extremely low sIgG4 preva- to inhalant allergens in healthy donors in comparison with lence to these antigens (< 5%) at the studied age. atopic patients lead to the lower rates of sIgG4 response The median age of the participants in our study is to inhalant allergens in the group of healthy population. higher than that in , which corresponds to the in- Similar observation was made by Dubakienė et al. for creased sIgG4 prevalence in our cohort; it explains no- one of the inhalant allergens, D. pteronyssinus. ticeable sIgG4 prevalence to inhalant allergens observed Overall, this analysis of sIgE response to inhalant aller- in the present experiments. Our study is focused only on gens among atopic patients shows that sIgE prevalence to sIgG4, however, the present analysis of sIgG4 alone is pollen allergens is significantly reduced in patients with also of interest because subjects with the prevailing atopic dermatitis compared with those with asthma and sIgG4 response are usually present along with the sub- upper airway disorders. In addition, cat and dog jects with the prevailing sIgG1 response . sensitization are more strongly associated with bronchial In the present study, a significant difference is ob- asthma than with atopic dermatitis and upper airway dis- served in the rates of patients with sIgG4 response be- orders. The increased sIgG4 response to pollen allergens tween the groups of sensitized and non-sensitized among patients with respiratory allergic diseases can be patients for most inhalant allergens assessed (Fig. 3). In considered a consequence of the fact that sIgG4 response contrast, significant differences for food allergens that is most common among patients with detectable sIgE and are analogous to the food components in the study  of the features of the sIgE profiles for these pathologies, as (β-lactoglobulin – Bos d5, casein – Bos d8) were not illustrated by experimental data analysis in our study. Smoldovskaya et al. World Allergy Organization Journal (2018) 11:35 Page 9 of 10 Conclusions Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published The obtained data demonstrate that different allergic dis- maps and institutional affiliations. ease entities are characterized by individual features of allergen-specific IgE and IgG4 production, which leads to Author details Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, specific manifestations of allergic inflammation. A more Vavilova str. 32, Moscow, Russian Federation119991. Filatov Moscow City comprehensive study of patients’ sIgE and sIgG4 profiles Pediatric Clinic No. 13, Moscow, Russia. with respect to the clinical performance and functions of Received: 24 May 2018 Accepted: 24 October 2018 allergen-specific antibodies would allow more effective diagnosis and treatment of atopic patients. References 1. Platts-Mills TAE, Lee BW, Arruda LK, Chew FT. Allergens as risk factors for Additional files allergic disease. In: Pawankar R, Canonica GW, Holgate ST, Lockey RF, Blaiss MS, editors. WAO white book on allergy: update 2013. Wisconsin: WAO; Additional file 1: Results of the determination of allergen-specific IgE 2013. p. 86–90. and IgG4 on the microarrays. The data are shown in qualitative format: 0 2. Ober C, Hoffjan S. Asthma genetics 2006: the long and winding road to - antibody concentration do not reach the cutoff of 0.35 IU/ml for sIgE or gene discovery. 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