Abstract
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 γ-gliadin peptides. However, α-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 γ-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 α and γ-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 γ-gliadin specific antibodies. These γ-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 α-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 α-gliadins.
Highlights
Celiac disease (CeD) is a chronic, T-cell mediated enteropathy with autoimmune features induced by gluten ingestion in genetically susceptible people
To directly examine the deamidation patterns of synthetic α-gliadin peptides, p31-43 (LGQQQPFPPQQPY) and p5768 (QLQPFPQPQLPY) peptides were treated with recombinant human TG2, respectively
Α/β and γ-gliadins are potent initiators of the T-cell response in CeD (Qiao et al 2005; Tollefsen et al 2006; Dørum et al 2010), B-cells seem to prefer reacting to γ-gliadins (Srinivasan et al 2013; Dørum et al 2016)
Summary
Celiac disease (CeD) is a chronic, T-cell mediated enteropathy with autoimmune features induced by gluten ingestion in genetically susceptible people. Gluten is the external dietary antigen that triggers the coupled production of anti-gliadin peptide-specific antibodies and anti-tissue transglutaminase autoantibodies (anti-TG2) through disease progression (Sollid and Jabri 2013). Gluten comprises the prolamin proteins found in certain cereals: wheat (gliadin, glutenin), barley (hordein) and rye (secalin) (Balakireva and Zamyatnin 2016). Wheat gliadin molecules contain the most immunogenic sequence motifs. Gliadin molecules can be divided into three subcategories: α/β, γ and ω-gliadins. Gliadins as prolamin proteins contain high amounts of proline and glutamine residues in the form of repeated sequence motifs, and this renders them resistant to the human intestinal proteases and preserves their antigenic nature (Shan et al 2005)
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