{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T13:49:55Z","timestamp":1765374595462,"version":"3.46.0"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background: The diagnosis and treatment of allergic diseases remain challenging because the results of allergy testing do not always correlate with clinical manifestations. For instance, although a specific IgE (sIgE) test for a particular allergen may be positive, some patients remain asymptomatic due to the development of immune tolerance. Recently, specific IgG4 (sIgG4) has been suggested as a potential indicator of immune tolerance. However, data in children are limited. Therefore, this study aimed to evaluate the clinical usefulness of sIgG4 testing and its potential role in assessing immune tolerance in pediatric allergic disease by measuring sIgE and sIgG4 levels. Methods: A total of 415 children with suspected allergic diseases were enrolled. All subjects underwent sIgE and sIgG4 testing for casein, egg white, peanut, Dermatophagoides farinae (D. farinae), dog dander, and birch. sIgE positivity was defined as a level of 0.35 kU\/L or higher for each allergen. Test results and clinical characteristics were reviewed, and the association between symptom occurrence during actual allergen exposure and sIgG4 level or sIgG4\/sIgE ratio was analyzed. Results: Among the 415 children, 253 were male (61%) and 162 were female (39%), with a median age of 5.77 years (IQR, 2.67\u20139.15). For inhalant allergens, sIgG4 levels did not differ between symptomatic and asymptomatic patients; however, the sIgG4\/sIgE ratio was significantly higher in asymptomatic patients (D. farinae: p &lt; 0.001, dog dander: p &lt; 0.001, birch: p = 0.003)). For food allergens, significant differences in sIgE, sIgG4, and sIgG4\/sIgE ratio were observed for casein (sIgE: p &lt; 0.001, sIgG4: p &lt; 0.001, sIgG4\/sIgE: p &lt; 0.001) and egg white (sIgE: p &lt; 0.001, sIgG4: p &lt; 0.001, sIgG4\/sIgE: p &lt; 0.001), while no significant associations were found for peanut. Conclusions: The correlation between sIgG4 and clinical symptom occurrence varied depending on the allergen. Although sIgG4 alone appears to have limited clinical value for inhalant allergens, the sIgG4\/sIgE ratio may serve as a useful indicator of immune tolerance. For casein and egg white, both sIgG4 and the sIgG4\/sIgE ratio demonstrated potential clinical utility for identifying immune tolerance; however, further investigation is needed to validate the role of sIgG4-based indicators in pediatric allergy management.<\/jats:p>","DOI":"10.3390\/children12121679","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T12:20:57Z","timestamp":1765369257000},"page":"1679","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Analysis of Specific IgG4 Antibody and sIgG4\/sIgE Antibody Ratio as Marker of Immune Tolerance to IgE-Mediated Response in Allergic Children"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9843-0188","authenticated-orcid":false,"given":"HyeonA","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8516-9803","authenticated-orcid":false,"given":"Ben","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2129-7232","authenticated-orcid":false,"given":"Bong Seok","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2022060531","DOI":"10.1542\/peds.2022-060531","article-title":"Patterns in the Development of Pediatric Allergy","volume":"152","author":"Gabryszewski","year":"2023","journal-title":"Pediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1542\/peds.2011-2382","article-title":"Allergy testing in childhood: Using allergen-specific IgE tests","volume":"129","author":"Sicherer","year":"2012","journal-title":"Pediatrics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"573","DOI":"10.3892\/br.2015.455","article-title":"Analysis of total immunoglobulin E and specific immunoglobulin E of 3,721 patients with allergic disease","volume":"3","author":"Chang","year":"2015","journal-title":"Biomed. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/2045-7022-3-3","article-title":"The skin prick test\u2013European standards","volume":"3","author":"Heinzerling","year":"2013","journal-title":"Clin. Transl. Allergy"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1016\/j.pedn.2011.03.003","article-title":"Guidelines for the diagnosis and management of food allergy in the United States: Summary of the NIAID-sponsored expert panel report","volume":"26","author":"Boyce","year":"2011","journal-title":"J. Pediatr. Nurs."},{"key":"ref_6","first-page":"S1","article-title":"Allergy diagnostic testing: An updated practice parameter","volume":"100","author":"Bernstein","year":"2008","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_7","first-page":"540","article-title":"Marasmus and kwashiorkor by nutritional ignorance related to vegetarian diet and infants with atopic dermatitis in South Korea","volume":"37","year":"2004","journal-title":"Korean J. Nutr."},{"key":"ref_8","first-page":"19","article-title":"The skin prick test","volume":"32","author":"Frati","year":"2018","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1097\/MPG.0b013e318054b0c3","article-title":"Diagnosis of food allergy in children: Toward a standardization of food challenge","volume":"45","author":"Niggemann","year":"2007","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.jpeds.2010.09.027","article-title":"Oral food challenges in children with a diagnosis of food allergy","volume":"158","author":"Fleischer","year":"2011","journal-title":"J. Pediatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1111\/j.1398-9995.2008.01705.x","article-title":"Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report","volume":"63","author":"Stapel","year":"2008","journal-title":"Allergy"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1476-7961-10-1","article-title":"The usefulness of casein-specific IgE and IgG4 antibodies in cow\u2019s milk allergic children","volume":"10","author":"Ito","year":"2012","journal-title":"Clin. Mol. Allergy"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1034\/j.1399-3038.1999.00040.x","article-title":"Food allergy: When and how to perform oral food challenges","volume":"10","author":"Sicherer","year":"1999","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s40413-018-0220-5","article-title":"Allergen-specific IgE and IgG4 patterns among patients with different allergic diseases","volume":"11","author":"Smoldovskaya","year":"2018","journal-title":"World Allergy Organ. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.jaci.2011.11.053","article-title":"Significance of ovomucoid-and ovalbumin-specific IgE\/IgG4 ratios in egg allergy","volume":"129","author":"Caubet","year":"2012","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.jaci.2009.05.022","article-title":"Clinical efficacy and immune regulation with peanut oral immunotherapy","volume":"124","author":"Jones","year":"2009","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1046\/j.1365-2222.1999.00525.x","article-title":"Monitoring allergen immunotherapy of pollen-allergic patients: The ratio of allergen-specific IgG4 to IgG1 correlates with clinical outcome","volume":"29","author":"GEHLHAR","year":"1999","journal-title":"Clin. Exp. Allergy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/j.1399-3038.2008.00738.x","article-title":"High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life","volume":"20","author":"Norrman","year":"2009","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.jaip.2013.03.011","article-title":"Relationship of dog-and cat-specific IgE and IgG4 levels to allergic symptoms on pet exposure","volume":"1","author":"Burnett","year":"2013","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"139","DOI":"10.4168\/aard.2015.3.2.139","article-title":"Usefulness of casein specific IgE and IgG antibodies to immediate type cow\u2019s milk allergy","volume":"3","author":"Lim","year":"2015","journal-title":"Allergy Asthma Respir. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/S0140-6736(00)04168-4","article-title":"Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: A population-based cross-sectional study","volume":"357","author":"Vaughan","year":"2001","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.jaci.2008.09.007","article-title":"Immunologic changes in children with egg allergy ingesting extensively heated egg","volume":"122","author":"Sampson","year":"2008","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1034\/j.1399-3038.1999.00030.x","article-title":"Development of immunoglobulin G and immunoglobulin E antibodies to cow\u2019s milk proteins and ovalbumin after a temporary neonatal exposure to hydrolyzed and whole cow\u2019s milk proteins","volume":"10","author":"Juvonen","year":"1999","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/j.jaci.2004.03.024","article-title":"Mechanisms of immunotherapy","volume":"113","author":"Till","year":"2004","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jaci.2010.11.030","article-title":"Mechanisms of allergen-specific immunotherapy","volume":"127","author":"Akdis","year":"2011","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Qin, L., Tang, L.-F., Cheng, L., and Wang, H.-Y. (2022). The clinical significance of allergen-specific IgG4 in allergic diseases. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1032909"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1111\/j.1365-2222.2007.02749.x","article-title":"Maintenance of tolerance to cow\u2019s milk in atopic individuals is characterized by high levels of specific immunoglobulin G4","volume":"37","author":"Ruiter","year":"2007","journal-title":"Clin. Exp. Allergy"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1067\/mai.2001.111592","article-title":"Specific IgE levels in the diagnosis of immediate hypersensitivity to cows\u2019 milk protein in the infant","volume":"107","year":"2001","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1111\/cea.12273","article-title":"Ovalbumin-specific IgE\/IgG4 ratio might improve the prediction of cooked and uncooked egg tolerance development in egg-allergic children","volume":"44","author":"Pascal","year":"2014","journal-title":"Clin. Exp. Allergy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1710-1492-8-9","article-title":"Predictive value of IgE\/IgG 4 antibody ratio in children with egg allergy","volume":"8","author":"Okamoto","year":"2012","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1016\/j.jaci.2015.01.012","article-title":"IgG4 inhibits peanut-induced basophil and mast cell activation in peanut-tolerant children sensitized to peanut major allergens","volume":"135","author":"Santos","year":"2015","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.jaci.2007.11.039","article-title":"Peanut epitopes for IgE and IgG4 in peanut-sensitized children in relation to severity of peanut allergy","volume":"121","author":"Flinterman","year":"2008","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S196","DOI":"10.1016\/j.jaci.2006.12.136","article-title":"Peanut allergy and peanut-specific IgG4 characteristics among Xhosa children in Cape Town","volume":"119","author":"Levin","year":"2007","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1111\/cea.13286","article-title":"Ratios of specific IgG4 over IgE antibodies do not improve prediction of peanut allergy nor of its severity compared to specific IgE alone","volume":"49","author":"Datema","year":"2019","journal-title":"Clin. Exp. Allergy"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.jaci.2017.07.029","article-title":"Allergen sensitization in a birth cohort at midchildhood: Focus on food component IgE and IgG4 responses","volume":"141","author":"Wilson","year":"2018","journal-title":"J. Allergy Clin. Immunol."}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/12\/12\/1679\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T12:55:31Z","timestamp":1765371331000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/12\/12\/1679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,10]]},"references-count":35,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["children12121679"],"URL":"https:\/\/doi.org\/10.3390\/children12121679","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,10]]}}}