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Gluten T cell epitope targeting by TG3 and TG6; implications for dermatitis herpetiformis and gluten ataxia

Abstract

Transglutaminase 2 (TG2) is well characterized as the main autoantigen of celiac disease. The ability of TG2 to deamidate and crosslink gluten peptides is essential for the gluten-dependent production of TG2 specific autoantibodies. In patients with primarily extraintestinal manifestation of gluten sensitivity the repertoire of autoantibodies may be different. In dermatitis herpetiformis (DH), TG3 appears to be the target autoantigen whereas in gluten ataxia (GA) autoantibodies reactive with TG6 are present. A functional role for TG3 and TG6 in these diseases has yet to be described. It is also not known whether these enzymes can use gluten peptides implicated in the pathology as substrates. We here report that similar to TG2, TG3 and TG6 can specifically deamidate gluten T cell epitopes. However, the fine specificities of the enzymes were found to differ. TG2 can form covalent complexes with gluten by iso-peptide and thioester bonds. We found that both TG3 and TG6 were able to complex with gluten peptides through thioester linkage although less efficiently than TG2, whereas TG6 but not TG3 was able to form iso-peptide linked complexes. Our findings lend credence to the notion that TG3 and TG6 are involved in the gluten-induced autoimmune responses of DH and GA.

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Abbreviations

CD:

Celiac disease

DH:

Dermatitis herpetiformis

GA:

Gluten ataxia

TGase:

Transglutaminase

TG2:

Transglutaminase 2

TG3:

Transglutaminase 3

TG6:

Transglutaminase 6

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Acknowledgments

This work was funded by grants from the Research Council of Norway, Sheffield Hospital Charitable Trust (grant number 7877) and Coeliac UK.

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Correspondence to Jorunn Stamnaes.

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Stamnaes, J., Dorum, S., Fleckenstein, B. et al. Gluten T cell epitope targeting by TG3 and TG6; implications for dermatitis herpetiformis and gluten ataxia. Amino Acids 39, 1183–1191 (2010). https://doi.org/10.1007/s00726-010-0554-y

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Keywords

  • Gluten
  • Autoantibodies
  • TG3
  • TG6
  • Dermatitis herpetiformis
  • Gluten ataxia