Aim: To analyze the development of gliadin-specific immune responses in children with a genetic risk for CD and to determine whether these could be detected before the clinical onset of the disease by using immunological tests.
Background: Clinical manifestations of celiac disease (CD) in the first year of life is uncommon, which is due to the suboptimal sensitivity of tissue transglutaminase IgA antibodies (tTG-IgA) at this age and other possible causes of malabsorption in infants. The development of Deamidate gliadin peptide-specific antibodies (in particular DGP-IgG) in young children was poorly considered in the CD diagnosis.
Methods: We conducted a retrospective cross-sectional study on children between one month and forty-eight months of life, which performed in our health center from 2016 to 2018. Three hundred and fifty children were selected according to strict inclusion criteria: positive for HLA-DQA1 and DQB1 alleles, positive anti tTG-IgA/IgG and/or positive DGP-IgG/IgA. Eighty-two children were selected and divided into two different groups of patients: Group one (forty newborns under twenty-four months of life) and Group two (children from twenty-five months to 48 months of life).
Results: Anti-DGP-IgG antibodies precede anti tTG-IgA seroconversion in children under two years in 80% of cases. Anti-DGP-IgG positive patients had milder symptomatic forms of CD than anti tTG-IgA positive children, characterized by gastrointestinal symptoms in the presence of normal growth, normal serum iron, and low MCH level. At tTG-IgA seroconversion, children present gastrointestinal clinical forms associated with impaired growth. The combined use of tTG-IgA and DGP-IgG antibodies upgrade the diagnostic sensitivity from 50% to 92%.
Conclusion: Anti-DGP-IgG antibodies precede tTG-IgA seroconversion in newborns and identified two distinct clinical phenotypes. At this point, if you wanted to test your newborn patients for CD serology, how would you proceed?
Keywords: Diagnostic tests, Transglutaminase antibodies, Deamidated gliadin peptides.
(Please cite as Assandri R, Montanelli A. Diagnosis of gluten-related enteropathy in a newborn: how and when? Gastroenterol Hepatol Bed Bench 2019;12(4):278-286).
Ludvigsson JL, Leffler DA, Bai JC, Biagi F, Fasano A, Green PHR , et al. The Oslo definitions for coeliac disease and related terms. Gut 2013;62:43–52.
Kooy-Winkelaar Y, van Lummel M, Moustakas AK, Schweizer J, Mearin ML, Mulder CJ, et al. Glutenspecific T cells cross-react between HLA-DQ8 and the HLA-DQ2alpha/DQ8beta transdimer. J Immunol 2011;187:5123-29.
Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L, et al. European Genetics Cluster on Celiac Disease. HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol 2003;64:469-77.
Jabri B, Kasarda DD, Green PH. Innate and adaptive immunity: the yin and yang of celiac disease. Immunol Rev 2005;206:219-31.
Assandri R, Monari M, Colombo A, Montanelli A. Pentraxin 3 serum levels in celiac patients: evidences and perspectives. Recent Pat Food Nutr Agric 2014;30.
Assandri R, Montanelli A. Pentraxin 3 and biopsy status in celiac patients. Gastroenterol Hepatol Bed Bench 2018;11:225-32.
Assandri R, Monari M, Colombo A, Montanelli A. Innate immune system: the no man's land where discover new biomarkers for gluten-related-disorders. Gastroenterol Hepatol Bed Bench 2015;8:95.
Volta U, Granito A, Fiorini E, Parisi C, Piscaglia M, Pappas G, et al. Usefulness of antibodies to deamidated gliadin peptides in celiac disease diagnosis and followup. Dig Dis Sci 2008;53:1582.
Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012;54:136-60.
Amarri S, Alvisi P, De Giorgio R, Gelli MC, Cicola R, Tovoli F, et al. Antibodies to deamidated gliadin peptides: an accurate predictor of coeliac disease in infancy. J Clin Immunol 2013;33:1027–30.
Gould MJ, Brill H, Marcon MA, Munn NJ, Walsh CM. In screening for celiac disease, deamidated gliadin rarely predicts disease when tissue transglutaminase is normal. J Pediatr Gastroenterol Nutr 2019;68:20–5.
Simell S, Hoppu S, Hekkala A, Simell T, Stahlberg MR, Viander M, et al. Fate of five celiac disease-associated ntibodies during normal diet in genetically at-risk children observed from birth in a natural history study. Am J Gastroenterol 2007;102:2026–35.
Prause C, Ritter M, Probst C, Daehnrich C, Schlumberger W, Komorowski L, et al. Antibodies againstdeamidated gliadin as new and accurate biomarkers of childhoodcoeliac disease. J Pediatr Gastroenterol Nutr 2009;49:52–8.
Basso D, Guariso G, Fogar P, Meneghel A, Zambon CF, Navaglia F, et al. Antibodies against synthetic deamidated gliadin peptides for celiac disease diagnosis and follow-up in children. Clin Chem 2009;55:150–7.
Volta U, Granito A, Parisi C, Fabbri A, Fiorini E, Piscaglia M, et al. Deamidated gliadin peptide antibodies as a routine test for celiac disease: a prospective analysis. J Clin Gastroenterol 2010;44:186–90.
Lammi A, Arikoski P, Hakulinen A, Schwab U, Uusitupa M, Heinonen S, et al. Development of gliadin-specific immune responses in children with HLA-associated genetic risk for celiac disease. Scand J Gastroenterol 2016;2:168-77.
Liu E, Li M, Emery L, Taki I, Barriga K, Tiberti C, et al. Natural history of antibodies to deamidated gliadin peptides and transglutaminase in early childhood celiac disease. J Pediatr Gastroenterol Nutr 2007;45:293–300.
Lammi A, Arikoski P, Simell S, Kinnunen T, Simell V, Paavanen-Huhtala S, et al. Antibodies to deamidated gliadin peptide in diagnosis of celiac disease in children. J Pediatr Gastroenterol Nutr 2015;60:626–31.
Fallang LE, Bergseng E, Hotta K, Berg-Larsen A, Kim CY, Sollid LM, et al .Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation. Nat Immunol 2009;10:1096–101.
Liu E, Rewers M, Eisenbarth GS. Genetic testing: who should do the testing and what is the role of genetic testing in the setting of celiac disease? Gastroenterol 2005;128:S33–7.
Wessels MM, van Veen II, Vriezinga SL, Putter H, Rings EH, Mearin ML. Complementary serologic investigations in children with celiac disease is unnecessary during follow-up. J Pediatr 2016;169:55-60.
Vallée L. Iron and neurodevelopment. Arch Pediatr 2017;24:5S18-5S22. [In French]
Ruiz-Ojeda FJ, Anguita-Ruiz A, Leis R, Aguilera CM ; Genetic factors and molecular mechanisms of vitamin D and obesity relationship. Ann Nutr Metab 2018;73:89-99.
Palova´-Jelınkova´ L, Danova´ K, Drasarova´ H, Dvorak M, Funda DP, Fundova, P, et al. Pepsin digest of wheat gliadin fraction increases production of IL-1b via TLR4/MyD88/TRIF/ MAPK/NF-jB signaling pathway and an NLRP3 inflammasome activation. PLoS One 2013;8:e62426
Sangman MK, Toufic M, Jabri B. Innate immunity: actuating the gears of celiac disease pathogenesis. Best pract Res Clin Gastroenterol 2015;29:425–35.
Araya RE, Jury J, Bondar C, Verdu EF, Chirdo FG. Intraluminal administration of poly I:C causes an enteropathy that is exacerbated by administration of oral dietary antigen. Plos One 2014;9:e99236.
Pane JA, Webster NL, Coulson BS. Rotavirus activates lymphocytes from non-obese diabetic mice by triggering toll-like receptor 7 signaling and interferon production in plasmacytoid dendritic cells. Plos Pathog 2014;10:e1003998.
Chiang CY, Engel A, Opaluch AM, Ramos I, Maestre AM, Secundino I, et al. Cofactors required for TLR7-and TLR9 dependent innate immune responses. Cell Host Microbe 2012;11:306-18.
Todd JA. Constitutive antiviral immunity at the expense of autoimmunity. Immunity 2014;40:164-9.