Changes in Non-Deamidated versus Deamidated Epitope Targeting and Disease Prediction during the Antibody Response to Gliadin and Transglutaminase of Infants at Risk for Celiac Disease.

Ádám Diós,Katharina Werkstetter,Ilma R Korponay-Szabó,Bharani Srinivasan,Rudolf Valenta,Sibylle Koletzko,Judit Gyimesi

doi:10.3390/ijms23052498

Abstract

Celiac disease (CeD) is a conditional autoimmune disorder with T cell-mediated immune response to gluten coupled with antibody production to gliadin and the self-protein tissue transglutaminase (TG2). TG2 contributes to the CeD pathomechanism by deamidating gliadin, thereby generating more immunogenic peptides. Anti-gliadin antibodies may appear before the autoantibody production. The scope of this study was to dissect these early antibody responses by investigating serum samples collected during the PreventCD prospective double-blind study, where infants with high CeD risk were randomized to 200 mg daily gluten intake or placebo from 4 to 6 months of age, followed by frequent blood testing on regular gluten consumption in both groups. After primary gluten intake, children with or without later CeD produced IgA and IgG antibodies which preferentially recognized non-deamidated gliadin peptides. At CeD development with anti-TG2 seroconversion, there was a significant increase in the antibody reaction toward deamidated gliadin peptides (DGP), with maturation in the binding strength for the PEQPFP gamma-gliadin core peptide. The earliest produced autoantibodies targeted TG2’s celiac epitope 2. Our results reveal a qualitative change in the gliadin-directed humoral immune response at the time when anti-TG2 antibodies appear, but anti-DGP antibodies in the absence of anti-TG2 antibodies are not disease-predictive.

Highlights

Celiac disease is a T cell-mediated enteropathy with autoimmune features induced by the consumption of gluten-containing cereals in genetically susceptible subjects
The lack of significance may be related to the considerable differences in antibody avidity/affinity between the subjects, but probably due to the small number of cases in each group, as only a few serum samples contained high enough amounts of anti-gliadin antibodies and were available in sufficient volumes for affinity purification. These results indicate that during Celiac disease (CeD) development, there is an increase in the production of deamidated gliadin peptides (DGP)-targeted antibodies, as reflected in their increasing serum concentrations, which has been shown in earlier studies [22], and an increase in DGP-binding strength of the anti-gliadin antibodies compared to non-deamidated gliadin peptides (NGP)
In infants and young children at genetic risk for CeD, the early immune response after starting gluten intake is against both NGP and DGP, but appears to preferentially target

Summary

Introduction

Celiac disease is a T cell-mediated enteropathy with autoimmune features induced by the consumption of gluten-containing cereals in genetically susceptible subjects. The multifunctional enzyme TG2 can mediate deamidation of certain glutamine residues in the prolamin peptides or cross-link them to lysine donors. Both these posttranslational modifications may contribute to CeD pathogenesis [5]. The recognition motif for the TG2-mediated deamidation is QXP [6], which is present in the majority of the gliadin sequences recognized by T and B cells [7,8]. Since deamidation of these prolamin peptides further improves their fitting to the antigen-binding pocket of the CeD-associated HLA-DQ molecules [9], this process may exponentially amplify the immune response

Objectives

Methods

Results

Discussion

Conclusion