Antibody Profile, Gene Expression and Serum Cytokines in At-Risk Infants before the Onset of Celiac Disease

Int J Mol Sci. 2023 Apr 6;24(7):6836. doi: 10.3390/ijms24076836.

Abstract

Immunological events that precede the development of villous atrophy in celiac disease (CeD) are still not completely understood. We aimed to explore CeD-associated antibody production (anti-native gliadin (AGA), anti-deamidated gliadin (DGP) and anti-tissue transglutaminase (anti-tTG)) in infants at genetic risk for CeD from the Italian cohorts of the PREVENT-CD and Neocel projects, as well as the relationship between antibody production and systemic inflammation. HLA DQ2 and/or DQ8 infants from families with a CeD case were followed from birth. Out of 220 at-risk children, 182 had not developed CeD by 6 years of age (CTRLs), and 38 developed celiac disease (CeD). The profiles of serum cytokines (INFγ, IL1β, IL2, IL4, IL6, IL10, IL12p70, IL17A and TNFα) and the expression of selected genes (FoxP3, IL10, TGFβ, INFγ, IL4 and IL2) were evaluated in 46 children (20 CeD and 26 CTRLs). Among the 182 healthy CTRLs, 28 (15.3%) produced high levels of AGA-IgA (AGA+CTRLs), and none developed anti-tTG-IgA or DGP-IgA, compared to 2/38 (5.3%) CeD infants (Chi Sq. 5.97, p = 0.0014). AGAs appeared earlier in CTRLs than in those who developed CeD (19 vs. 28 months). Additionally, the production of AGAs in CeD overlapped with the production of DGP and anti-tTG. In addition, gene expression as well as serum cytokine levels discriminated children who developed CeD from CTRLs. In conclusion, these findings suggest that the early and isolated production of AGA-IgA antibodies is a CeD-tolerogenic marker and that changes in gene expression and cytokine patterns precede the appearance of anti-tTG antibodies.

Keywords: anti-gliadin antibodies; anti-tissue transglutaminase antibodies; celiac disease; infants at risk for celiac disease; prospective cohorts; serum cytokines and gene expression; tolerance.

MeSH terms

  • Autoantibodies
  • Celiac Disease* / genetics
  • Child
  • Cytokines / genetics
  • Gliadin
  • Humans
  • Immunoglobulin A
  • Immunoglobulin G
  • Infant
  • Interleukin-10
  • Interleukin-2
  • Interleukin-4
  • Sensitivity and Specificity
  • Transcriptome
  • Transglutaminases / metabolism

Substances

  • Gliadin
  • Cytokines
  • Interleukin-10
  • Interleukin-2
  • Interleukin-4
  • Immunoglobulin G
  • Transglutaminases
  • Autoantibodies
  • Immunoglobulin A

Grants and funding

This study received ESPGHAN Networking funding (2017) for the project “Natural history and risk factors for Celiac disease—NeoCel project” and from Fondazione Italiana Celiachia (Research Grant N. 002_FC_2020 to CG and research fellowship N. 009_FC_2016 to SV). The project was funded under the National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3—Call for proposals No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union—NextGenerationEU; Project Code PE00000003, Concession Decree No. 1550 of 11 October 2022 adopted by the Italian Ministry of University and Research, CUP D93C22000890001, Project Title “ON Foods—Research and innovation network on food and nutrition Sustainability, Safety and Security—Working ON Foods”. GM is funded by Fondazione Italiana Sclerosi Multipla (FISM grant no. 2018/S/5), Ministry of Education, University and Research (MIUR) (Bando PRIN 2017 Prot. 2017K55HLC 001), the MUR PNRR Extended Partnership (INF-ACT no. PE00000007 and MNESYS no. PE00000006) and Ministry of Health (Bando Ricerca Finalizzata 2019 RF-2019-12371111).