Substrate specificity of transglutaminases for gluten peptides
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AbstractThe human immune system has developed intricate mechanisms to protect the body by discriminating between infectious agents and self. Unfortunately, in some cases these mechanisms can be bypassed and immune responses may be elicited by antigens derived from self. The loss of tolerance to autoantigens may lead to the development of autoimmune diseases.
Autoimmune diseases are chronic inflammatory diseases of unknown etiology where both genetic and environmental factors play a role. Human leukocyte antigens (HLA) have been shown to be the most important susceptibility factor for several of the autoimmune diseases, what strongly suggests the involvement of T cells. In many autoimmune diseases the self antigen causing the disease is not known. This is the case for rheumatoid arthritis, multiple sclerosis and type 1 diabetes. For celiac disease however, the trigger of the disease is known to be gluten. Interestingly, although gluten was known to be the environmental factor for years, it was not until a decade ago that a posttranslational modification of gluten mediated by an enzyme called tissue transglutaminase 2 (TG2) was discovered to be critical for the disease. The posttranslationally modified gluten peptides bind the disease associated HLA-molecules with a higher affinity than the unmodified gluten peptides, what results in a multifaceted T-cell response. Thus, posttranslational modifications of self-antigens, or in this case; of food antigens normally tolerated by the body, is one way in which novel epitopes are created that are not tolerated by the immune system. Interestingly, immune responses directed towards enzymatically modified self-antigens were also reported for other autoimmune diseases, e.g. against citrullinated proteins in rheumatoid arthritis and methylated and phosphorylated proteins in systemic lupus erythematosus. As the importance of posttranslational modifications of gluten peptides is acknowledged in celiac disease, further research in this field may be relevant also for other autoimmune diseases.
In this thesis, we have used mass spectrometry-based strategies to investigate the posttranslational gluten modifications catalyzed by the transglutaminase enzymes implicated in gluten sensitive diseases. The main focus has been on TG2 and its important role in T-cell epitope selection in celiac disease.
List of papers
|Paper I A quantitative analysis of transglutaminase 2-mediated deamidation of gluten peptides: implications for the T-cell response in celiac disease S. Dørum, S.W. Qiao, L.M. Sollid, B. Fleckenstein Journal of Proteome Research, 2009, 8(4):1748–1755. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1021/pr800960n|
|Paper II Gluten T-cell epitope targeting by TG3 and TG6; implications for dermatitis herpetiformis and gluten ataxia J. Stamnæs, S. Dørum, B. Fleckenstein, D. Aeschlimann, L.M. Sollid Amino Acids, 2010, Mar 19. [Epub ahead of print], PMID: 20300788 Amino Acids, 2010, 39:1183–1191. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1007/s00726-010-0554-y|
|Paper III The preferred substrates for transglutaminase 2 in a complex wheat gluten digest are peptide fragments harboring celiac disease T-cell epitopes S. Dørum, M.Ø. Arntzen, A. Holm, S.W. Qiao, C.J. Koehler, B. Thiede, L.M. Sollid, B. Fleckenstein. Manuscript submitted to PLoS ONE. Text is available under the Creative Commons Attribution License (CCAL). The published version of this paper is available at: https://doi.org/10.1371/journal.pone.0014056|