A quantitative analysis of transglutaminase 2-mediated deamidation of gluten peptides: implications for the T-cell response in celiac disease.

Abstract

Celiac disease develops in genetically predisposed individuals as the result of an inappropriate intestinal immune response to dietary gluten proteins. T cells present in the intestine of celiac patients recognize gluten peptides in the context of HLA-DQ2 or -DQ8 molecules. Notably, T-cell recognition is increased after these peptides have been deamidated by the enzyme transglutaminase 2. Several T-cell epitopes of gluten exist, and most of these epitopes derive from the alcohol-soluble gliadin fraction. For some of these epitopes, specific T cells can be isolated from intestinal biopsies from nearly all patients, whereas for others, T-cell reactivity could be demonstrated in only a few patients. One reason for this observation could be that the rate of transglutaminase 2 (TG2)-mediated deamidation significantly differs between these peptides, resulting in different amounts of epitopes generated in vivo. In this study, we established a quantitative, mass spectrometry-based approach to measure the kinetics of TG2-mediated deamidation of gliadin-derived, DQ2-restricted epitopes. Our results demonstrate large variations in the degree of deamidation between different peptides and also between individual glutamine residues within each peptide. In general, alpha-gliadin derived epitopes that are frequently recognized by patient T cells showed a significant higher level of deamidation compared to the majority of epitopes from gamma-gliadin that are less frequently recognized. The degree of deamidation of individual residues within a peptide also seems to influence whether some epitopes are better recognized in context of DO2 or DQ8. Thus, the rate of deamidation by TG2 appears to be a factor of importance for the T-cell response to gluten in celiac disease.

• Authors: Siri Dørum, Shuo-Wang Qiao, Ludvig M Sollid, Burkhard Fleckenstein
• Journal: Journal of proteome research (J Proteome Res) Vol. 8 Issue 4 Pg. 1748-55 (Apr 2009) ISSN: 1535-3893 [Print] United States
• PMID: 19239248 (Publication Type: Journal Article)

Chemical References

• Epitopes, T-Lymphocyte
• Peptides
• Recombinant Proteins
• Glutens
• Gliadin
• Protein Glutamine gamma Glutamyltransferase 2
• Transglutaminases
• GTP-Binding Proteins

Topics

• Amino Acid Sequence
• Celiac Disease (metabolism)
• Epitopes, T-Lymphocyte (immunology)
• GTP-Binding Proteins (pharmacology, physiology)
• Gliadin (immunology)
• Glutens (immunology)
• Humans
• Molecular Sequence Data
• Peptides (analysis, metabolism)
• Protein Glutamine gamma Glutamyltransferase 2
• Protein Processing, Post-Translational (drug effects, physiology)
• Recombinant Proteins (metabolism, pharmacology)
• T-Lymphocytes (immunology)
• Tandem Mass Spectrometry
• Transglutaminases (pharmacology, physiology)