{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T19:35:22Z","timestamp":1778787322742,"version":"3.51.4"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T00:00:00Z","timestamp":1622419200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T00:00:00Z","timestamp":1622419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100012550","name":"Nemzeti Kutat\u00e1si, Fejleszt\u00e9si \u00e9s Innovaci\u00f3s Alap","doi-asserted-by":"publisher","award":["NKFIH K120392"],"award-info":[{"award-number":["NKFIH K120392"]}],"id":[{"id":"10.13039\/501100012550","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Emberi Er\u0151forr\u00e1s Fejleszt\u00e9si Operat\u00edv Program","award":["EFOP-3.6.1-16-2016-00022"],"award-info":[{"award-number":["EFOP-3.6.1-16-2016-00022"]}]},{"name":"Interreg Danube Transnational Programme","award":["DTP571 Interreg Danube CD SKILLS"],"award-info":[{"award-number":["DTP571 Interreg Danube CD SKILLS"]}]},{"name":"Gazdas\u00e1gfejleszt\u00e9si \u00e9s Innov\u00e1ci\u00f3s Operat\u00edv Program","award":["GINOP-2.3.2-15-2016-00015"],"award-info":[{"award-number":["GINOP-2.3.2-15-2016-00015"]}]},{"DOI":"10.13039\/501100009232","name":"University of Debrecen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009232","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Amino Acids"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Celiac disease (CeD) is a T-cell-dependent enteropathy with autoimmune features where tissue transglutaminase (TG2)-mediated posttranslational modification of gliadin peptides has a decisive role in the pathomechanism. The humoral immune response is reported to target mainly TG2-deamidated \u03b3-gliadin peptides. However, \u03b1-gliadin peptides, like p57-68, playing a crucial role in the T-cell response, and p31-43, a major trigger of innate responses, also contain B-cell gliadin epitopes and \u03b3-gliadin like motifs. We aimed to identify if there are anti-gliadin-specific antibodies in CeD patients targeting the p31-43 and p57-68 peptides and to examine whether deamidation of these peptides could increase their antigenicity. We explored TG2-mediated deamidation of the p31-43 and p57-68 peptides, and investigated serum antibody reactivity toward the native and deamidated \u03b1 and \u03b3-gliadin peptides in children with confirmed CeD and in prospectively followed infants at increased risk for developing CeD. We affinity-purified antibody populations utilizing different single peptide gliadin antigens and tested their binding preferences for cross-reactivity in real-time interaction assays based on bio-layer interferometry. Our results demonstrate that there is serum reactivity toward p31-43 and p57-68 peptides, which is due to cross-reactive \u03b3-gliadin specific antibodies. These \u03b3-gliadin specific antibodies represent the first appearing antibody population in infancy and they dominate the serum reactivity of CeD patients even later on and without preference for deamidation. However, for the homologous epitope sequences in \u03b1-gliadins shorter than the core QPEQPFP heptapeptide, deamidation facilitates antibody recognition. These findings reveal the presence of cross-reactive antibodies in CeD patients recognizing the disease-relevant \u03b1-gliadins.<\/jats:p>","DOI":"10.1007\/s00726-021-03006-7","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:41:34Z","timestamp":1622508094000},"page":"1051-1063","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Gamma-gliadin specific celiac disease antibodies recognize p31-43 and p57-68 alpha gliadin peptides in deamidation related manner as a result of cross-reaction"],"prefix":"10.1007","volume":"53","author":[{"given":"\u00c1d\u00e1m","family":"Di\u00f3s","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Elek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ildik\u00f3","family":"Szab\u00f3","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Szilvia","family":"Horv\u00e1th","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judit","family":"Gyimesi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R\u00f3bert","family":"Kir\u00e1ly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Werkstetter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sibylle","family":"Koletzko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L\u00e1szl\u00f3","family":"F\u00e9s\u00fcs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0554-2629","authenticated-orcid":false,"given":"Ilma R.","family":"Korponay-Szab\u00f3","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,5,31]]},"reference":[{"issue":"4","key":"3006_CR1","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1084\/jem.191.4.603","volume":"191","author":"H Arentz-Hansen","year":"2000","unstructured":"Arentz-Hansen H, K\u00f6rner R, Molberg O, Quarsten H, Vader W, Kooy YM, Lundin KE, Koning F, Roepstorff P, Sollid LM, McAdam SN (2000) The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase. J Exp Med 191(4):603\u2013612. https:\/\/doi.org\/10.1084\/jem.191.4.603","journal-title":"J Exp Med"},{"issue":"10","key":"3006_CR2","doi-asserted-by":"publisher","first-page":"644","DOI":"10.3390\/nu8100644","volume":"8","author":"AV Balakireva","year":"2016","unstructured":"Balakireva AV, Zamyatnin AA (2016) Properties of gluten intolerance: gluten structure, evolution, pathogenicity and detoxification capabilities. Nutrients 8(10):644. https:\/\/doi.org\/10.3390\/nu8100644","journal-title":"Nutrients"},{"issue":"8","key":"3006_CR3","doi-asserted-by":"publisher","first-page":"e12246","DOI":"10.1371\/journal.pone.0012246","volume":"5","author":"MV Barone","year":"2010","unstructured":"Barone MV, Nanayakkara M, Paolella G, Maglio M, Vitale V, Troiano R, Ribecco MTS, Lania G, Zanzi D, Santagata S, Auricchio R, Troncone R, Auricchio S (2010) Gliadin peptide P31\u201343 localises to endocytic vesicles and interferes with their maturation. PLoS ONE 5(8):e12246. https:\/\/doi.org\/10.1371\/journal.pone.0012246","journal-title":"PLoS ONE"},{"issue":"11","key":"3006_CR4","doi-asserted-by":"publisher","first-page":"20518","DOI":"10.3390\/ijms151120518","volume":"15","author":"MV Barone","year":"2014","unstructured":"Barone MV, Troncone R, Auricchio S (2014) Gliadin peptides as triggers of the proliferative and stress\/innate immune response of the celiac small intestinal mucosa. Int J Mol Sci 15(11):20518\u201320537. https:\/\/doi.org\/10.3390\/ijms151120518","journal-title":"Int J Mol Sci"},{"issue":"1","key":"3006_CR5","doi-asserted-by":"publisher","first-page":"e0147777","DOI":"10.1371\/journal.pone.0147777","volume":"11","author":"RS Choung","year":"2016","unstructured":"Choung RS, Marietta EV, Van Dyke CT, Brantner TL, Rajasekaran J, Pasricha PJ, Wang T, Bei K, Krishna K, Krishnamurthy HK, Snyder MR, Jayaraman V, Murray JA (2016) Determination of B-cell epitopes in patients with celiac disease: peptide microarrays. PLoS ONE 11(1):e0147777. https:\/\/doi.org\/10.1371\/journal.pone.0147777","journal-title":"PLoS ONE"},{"issue":"11","key":"3006_CR6","doi-asserted-by":"publisher","first-page":"e14056","DOI":"10.1371\/journal.pone.0014056","volume":"5","author":"S D\u00f8rum","year":"2010","unstructured":"D\u00f8rum S, Arntzen M\u00d8, Qiao S-W, Holm A, Koehler CJ, Thiede B, Sollid LM, Fleckenstein B (2010) The preferred substrates for transglutaminase 2 in a complex wheat gluten digest are peptide fragments harboring celiac disease t-cell epitopes. PLoS ONE 5(11):e14056. https:\/\/doi.org\/10.1371\/journal.pone.0014056","journal-title":"PLoS ONE"},{"key":"3006_CR7","doi-asserted-by":"publisher","first-page":"25565","DOI":"10.1038\/srep25565","volume":"6","author":"S D\u00f8rum","year":"2016","unstructured":"D\u00f8rum S, Steinsb\u00f8 \u00d8, Bergseng E, Arntzen M\u00d8, de Souza GA, Sollid LM (2016) Gluten-specific antibodies of celiac disease gut plasma cells recognize long proteolytic fragments that typically harbor T-cell epitopes. Sci Rep 6:25565. https:\/\/doi.org\/10.1038\/srep25565","journal-title":"Sci Rep"},{"issue":"3","key":"3006_CR8","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1042\/BJ20130696","volume":"455","author":"K Kanchan","year":"2013","unstructured":"Kanchan K, Erg\u00fclen E, Kir\u00e1ly R, Simon-Vecsei Z, Fuxreiter M, F\u00e9s\u00fcs L (2013) Identification of a specific one amino acid change in recombinant human transglutaminase 2 that regulates its activity and calcium sensitivity. Biochem J 455(3):261\u2013272. https:\/\/doi.org\/10.1042\/BJ20130696","journal-title":"Biochem J"},{"issue":"5","key":"3006_CR9","doi-asserted-by":"publisher","first-page":"e2294","DOI":"10.1371\/journal.pone.0002294","volume":"3","author":"B Mor\u00f3n","year":"2008","unstructured":"Mor\u00f3n B, Bethune MT, Comino I, Manyani H, Ferragud M, L\u00f3pez MC, Cebolla A, Khosla C, Sousa C (2008) Toward the assessment of food toxicity for celiac patients: characterization of monoclonal antibodies to a main immunogenic gluten peptide. PLoS ONE 3(5):e2294. https:\/\/doi.org\/10.1371\/journal.pone.0002294","journal-title":"PLoS ONE"},{"issue":"2","key":"3006_CR10","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1046\/j.1365-2249.2000.01312.x","volume":"121","author":"AA Osman","year":"2000","unstructured":"Osman AA, G\u00fcnnel T, Dietl A, Uhlig HH, Amin M, Fleckenstein B, Richter T, Mothes T (2000) B cell epitopes of gliadin. Clin Exp Immunol 121(2):248\u2013254. https:\/\/doi.org\/10.1046\/j.1365-2249.2000.01312.x","journal-title":"Clin Exp Immunol"},{"issue":"3","key":"3006_CR11","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.4049\/jimmunol.173.3.1757","volume":"173","author":"SW Qiao","year":"2004","unstructured":"Qiao SW, Bergseng E, Molberg \u00d8, Xia J, Fleckenstein B, Khosla C, Sollid LM (2004) Antigen presentation to celiac lesion-derived T cells of a 33-mer gliadin peptide naturally formed by gastrointestinal digestion. J Immunol 173(3):1757\u20131762. https:\/\/doi.org\/10.4049\/jimmunol.173.3.1757","journal-title":"J Immunol"},{"issue":"1","key":"3006_CR12","doi-asserted-by":"publisher","first-page":"254","DOI":"10.4049\/jimmunol.175.1.254","volume":"175","author":"SW Qiao","year":"2005","unstructured":"Qiao SW, Bergseng E, Molberg \u00d8, Jung G, Fleckenstein B, Sollid LM (2005) Refining the rules of gliadin T cell epitope binding to the disease-associated DQ2 molecule in celiac disease: importance of proline spacing and glutamine deamidation. J Immunol 175(1):254\u2013261. https:\/\/doi.org\/10.4049\/jimmunol.175.1.254","journal-title":"J Immunol"},{"issue":"3","key":"3006_CR13","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1053\/j.gastro.2017.05.016","volume":"153","author":"M R\u00e1ki","year":"2017","unstructured":"R\u00e1ki M, Dahal-Koirala S, Yu H, Korponay-Szab\u00f3 IR, Gyimesi J, Castillejo G, Jahnsen J, Qiao SW, Sollid LM (2017) Similar responses of intestinal T cells from untreated children and adults with celiac disease to deamidated gluten epitopes. Gastroenterology 153(3):787-798.e4. https:\/\/doi.org\/10.1053\/j.gastro.2017.05.016","journal-title":"Gastroenterology"},{"issue":"6","key":"3006_CR14","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1111\/j.1365-2036.2008.03797.x","volume":"28","author":"S Rashtak","year":"2008","unstructured":"Rashtak S, Ettore MW, Homburger HA, Murray JA (2008) Combination testing for antibodies in the diagnosis of coeliac disease: comparison of multiplex immunoassay and ELISA methods. Aliment Pharmacol Ther 28(6):805\u2013813. https:\/\/doi.org\/10.1111\/j.1365-2036.2008.03797.x","journal-title":"Aliment Pharmacol Ther"},{"issue":"12","key":"3006_CR15","doi-asserted-by":"publisher","first-page":"2370","DOI":"10.1373\/clinchem.2004.036111","volume":"50","author":"E Schwertz","year":"2004","unstructured":"Schwertz E, Kahlenberg F, Sack U, Richter T, Stern M, Conrad K, Zimmer KP, Mothes T (2004) Serologic assay based on gliadin-related nonapeptides as a highly sensitive and specific diagnostic aid in celiac disease. Clin Chem 50(12):2370\u20132375. https:\/\/doi.org\/10.1373\/clinchem.2004.036111","journal-title":"Clin Chem"},{"issue":"5","key":"3006_CR16","doi-asserted-by":"publisher","first-page":"1732","DOI":"10.1021\/pr050173t","volume":"4","author":"L Shan","year":"2005","unstructured":"Shan L, Qiao S-W, Arentz-Hansen H, Molberg \u00d8, Gray GM, Sollid LM, Khosla C (2005) Identification and analysis of multivalent proteolytically resistant peptides from gluten: implications for celiac sprue. J Proteome Res 4(5):1732\u20131741. https:\/\/doi.org\/10.1021\/pr050173t","journal-title":"J Proteome Res"},{"issue":"17","key":"3006_CR17","doi-asserted-by":"publisher","first-page":"e93961","DOI":"10.1172\/jci.insight.93961","volume":"2","author":"O Snir","year":"2017","unstructured":"Snir O, Chen X, Gidoni M, du Pr\u00e9 MF, Zhao Y, Steinsb\u00f8 \u00d8, Lundin KEA, Yaari G, Sollid LM (2017) Stereotyped antibody responses target posttranslationally modified gluten in celiac disease. JCI Insight 2(17):e93961. https:\/\/doi.org\/10.1172\/jci.insight.93961","journal-title":"JCI Insight"},{"issue":"4","key":"3006_CR18","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1038\/nri3407","volume":"13","author":"LM Sollid","year":"2013","unstructured":"Sollid LM, Jabri B (2013) Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat Rev Immunol 13(4):294\u2013302. https:\/\/doi.org\/10.1038\/nri3407","journal-title":"Nat Rev Immunol"},{"issue":"1\u20132","key":"3006_CR19","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/s00251-019-01141-w","volume":"72","author":"LM Sollid","year":"2020","unstructured":"Sollid LM, Tye-Din JA, Qiao SW, Anderson RP, Gianfrani C, Koning F (2020) Update 2020: nomenclature and listing of celiac disease-relevant gluten epitopes recognized by CD4+ T cells. Immunogenetics 72(1\u20132):85\u201388. https:\/\/doi.org\/10.1007\/s00251-019-01141-w","journal-title":"Immunogenetics"},{"issue":"4","key":"3006_CR20","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1007\/s00726-013-1537-6","volume":"45","author":"B Srinivasan","year":"2013","unstructured":"Srinivasan B, Focke-Tejkl M, Swoboda I, Constantin C, Mittermann I, Pahr S, Vogelsang H, Huber W-D, Valenta R (2013) A combined biochemical, biophysical and immunological approach towards the identification of celiac disease-specific wheat antigens. Amino Acids 45(4):889\u2013900. https:\/\/doi.org\/10.1007\/s00726-013-1537-6","journal-title":"Amino Acids"},{"issue":"2","key":"3006_CR21","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1111\/j.1365-2249.2010.04119.x","volume":"161","author":"SM Stenman","year":"2010","unstructured":"Stenman SM, Lindfors K, Ven\u00e4l\u00e4inen JI, Hautala A, M\u00e4nnist\u00f6 PT, Garcia-Horsman JA, Kaukovirta-Norja A, Auriola S, Mauriala T, M\u00e4ki M, Kaukinen K (2010) Degradation of coeliac disease-inducing rye secalin by germinating cereal enzymes: diminishing toxic effects in intestinal epithelial cells. Clin Exp Immunol 161(2):242\u2013249. https:\/\/doi.org\/10.1111\/j.1365-2249.2010.04119.x","journal-title":"Clin Exp Immunol"},{"issue":"8","key":"3006_CR22","doi-asserted-by":"publisher","first-page":"2226","DOI":"10.1172\/JCI27620","volume":"116","author":"S Tollefsen","year":"2006","unstructured":"Tollefsen S, Arentz-Hansen H, Fleckenstein B, Molberg O, R\u00e1ki M, Kwok WW, Jung G, Lundin KEA, Sollid LM (2006) HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease. J Clin Invest 116(8):2226\u20132236. https:\/\/doi.org\/10.1172\/JCI27620","journal-title":"J Clin Invest"},{"issue":"5","key":"3006_CR23","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1084\/jem.20012028","volume":"195","author":"LW Vader","year":"2002","unstructured":"Vader LW, de Ru A, van der Wal Y, Kooy YMC, Benckhuijsen W, Mearin ML, Drijfhout JW, van Veelen P, Koning F (2002) Specificity of tissue transglutaminase explains cereal toxicity in celiac disease. J Exp Med 4 195(5):643\u2013649. https:\/\/doi.org\/10.1084\/jem.20012028","journal-title":"J Exp Med 4"},{"issue":"14","key":"3006_CR24","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1056\/NEJMoa1404172","volume":"371","author":"SL Vriezinga","year":"2014","unstructured":"Vriezinga SL, Auricchio R, Bravi E, Castillejo G, Chmielewska A, Crespo Escobar P, Kola\u010dek S, Koletzko S, Korponay-Szabo IR, Mummert E, Polanco I, Putter H, Ribes-Koninckx C, Shamir R, Szajewska H, Werkstetter K, Greco L, Gyimesi J, Hartman C, Hogen Esch C, Hopman E, Ivarsson A, Koltai T, Koning F, Martinez-Ojinaga E, te Marvelde C, Pavic A, Romanos J, Stoopman E, Villanacci V, Wijmenga C, Troncone R, Mearin ML (2014) Randomized feeding intervention in infants at high risk for celiac disease. N Engl J Med 371(14):1304\u20131315. https:\/\/doi.org\/10.1056\/NEJMoa1404172","journal-title":"N Engl J Med"},{"issue":"4","key":"3006_CR25","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1053\/j.gastro.2017.06.002","volume":"153","author":"KJ Werkstetter","year":"2017","unstructured":"Werkstetter KJ, Korponay-Szab\u00f3 IR, Popp A, Villanacci V, Salemme M, Heilig G, Lillevang ST, Mearin ML, Ribes-Koninckx C, Thomas A, Troncone R, Filipiak B, M\u00e4ki M, Gyimesi J, Najafi M, Dolin\u0161ek J, Dydensborg Sander S, Auricchio R, Papadopoulou A, V\u00e9csei A, Szitanyi P, Donat E, Nenna R, Alliet P, Penagini F, Garnier-Lenglin\u00e9 H, Castillejo G, Kurppa K, Shamir R, Hauer AC, Smets F, Corujeira S, van Winckel M, Buderus S, Chong S, Husby S, Koletzko S, ProCeDE study group (2017) Accuracy in diagnosis of celiac disease without biopsies in clinical practice. Gastroenterology 153(4):924\u2013935. https:\/\/doi.org\/10.1053\/j.gastro.2017.06.002","journal-title":"Gastroenterology"}],"container-title":["Amino Acids"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00726-021-03006-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00726-021-03006-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00726-021-03006-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T18:24:22Z","timestamp":1624991062000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00726-021-03006-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,31]]},"references-count":25,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2021,7]]}},"alternative-id":["3006"],"URL":"https:\/\/doi.org\/10.1007\/s00726-021-03006-7","relation":{},"ISSN":["0939-4451","1438-2199"],"issn-type":[{"value":"0939-4451","type":"print"},{"value":"1438-2199","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,31]]},"assertion":[{"value":"9 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors have no conflicts of interest to declare that are relevant to the content of this article. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Ethical Committee of the Heim P\u00e1l National Pediatric Institute, Budapest, Hungary.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}}]}}