Transglutaminases in Gluten Sensitive Diseases
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AbstractGluten sensitive diseases (GSDs) are caused by an aberrant immune response towards gluten. In celiac disease (CD) gluten induces a pathological inflammation in the small intestine of genetically predisposed individuals carrying HLA-DQ2 or DQ8. Transglutaminase 2 (TG2), a Ca2+ dependent enzyme that cross-links or deamidates glutamine residues can specifically deamidate gluten peptides. This increases their affinity to DQ2 and DQ8 which is pivotal to the immune response against gluten in CD. In this thesis the simultaneous cross-linking and deamidating activity of TG2 was studied. We found that deamidated products can accumulate under conditions believed to favor cross-linking. The mechanism behind reversible, oxidative inactivation of TG2 was also studied. Gluten-dependent production of anti-TG2 IgA is a hallmark of CD. While highly reactive towards extracellular TG2, these antibodies to not recognize TG2 in a cell surface context, similar to most monoclonal anti-TG2 antibodies. We show that one of the few antibodies reported to recognize cell surface TG2 is in fact specific for CD44 and not TG2. Knowledge funded on the use of the antibody must therefore be revised. TG3 and TG6 are emerging as the primary autoantigens in the GSDs Dermatitis Herpetiformis (DH) and Gluten Ataxia (GA). We have addressed the ability of TG3 and TG6 to deamidate and cross-link themselves to gluten T cell epitopes and report that also TG3 and TG6 can utilize gluten as substrates.
List of papers
|Paper I: The propensity for deamidation and transamidation of peptides by transglutaminase 2 is dependent on substrate affinity and reaction conditions. Stamnaes J, Fleckenstein B, Sollid L M. Biochimica et Biophysica Acta 1784 (2008) 1804–1811. The published version of this paper is available at: https://doi.org/10.1016/j.bbapap.2008.08.011|
|Paper II: The monoclonal antibody 6B9 recognizes CD44 and not cell surface transglutaminase 2. Stamnaes J, Fleckenstein B, Lund-Johansen F, Sollid LM Scandinavian Journal of Immunology 68 (2008) 534–542. The published version of this paper is available at: https://doi.org/10.1111/j.1365-3083.2008.02173.x|
|Paper III: Gluten T-cell epitope targeting by TG3 and TG6; implications for dermatitis herpetiformis and gluten ataxia. Stamnaes J, Dorum S, Fleckenstein B, Aeschlimann D, Sollid LM. Manuscript ready for submission|