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Binding of Autoantibodies to the Core Region of Tissue Transglutaminase Is a Feature of Paediatric Coeliac Disease

Comerford, Ross*; Byrne, Greg; Feighery, Conleth; Kelly, Jacinta*

Journal of Pediatric Gastroenterology & Nutrition: October 2012 - Volume 55 - Issue 4 - p 445–450
doi: 10.1097/MPG.0b013e318251419f
Gastroenterology

Objectives: Production of autoantibodies to the enzyme tissue transglutaminase (tTG) is a hallmark of coeliac disease (CD). We have previously demonstrated that the immumoglobulin (Ig) A response to tTG in adult CD specifically targets its catalytic core region, containing the active-site triad of amino acids. The aim of the present study was to investigate this phenomenon in paediatric patients with CD, and to elucidate the contribution of each active-site residue to epitopes recognised. The specificity of the IgG anti-tTG response was also investigated and compared with that of the IgA anti-tTG response, in both paediatric and adult patients with CD.

Methods: Wild-type and novel variants of tTG were generated via site-directed mutagenesis and expressed as glutathione-S-transferase–fusion proteins in Escherichia coli BL-21. The mutagenic variants of tTG had substitutions of 1, 1, or all of the 3 of the catalytic triad amino acids. All of the recombinant tTGs were tested for their antigenicity in IgA and IgG enzyme-linked immunosorbent assays with cohorts of paediatric (n = 63) and adult (n = 30) CD sera.

Results: Substitution of even 1 amino acid in the catalytic triad resulted in a significant reduction of CD IgA and IgG anti-tTG binding, with all of the mutant proteins displaying diminished antigenicity compared with the wild-type protein.

Conclusions: The core region of tTG is specifically targeted from early on in disease course by CD patient autoantibodies of both the IgA and IgG class.

*National Children's Research Centre, Dublin

Dublin Institute of Technology

St James’ Hospital, Dublin, Ireland.

Address correspondence and reprint requests to Ross Comerford, National Children's Research Centre, Our Lady's Hospital For Sick Children, Crumlin, Dublin 12, Ireland (e-mail: comerfr@tcd.ie).

Received 31 August, 2011

Accepted 12 February, 2012

The research was funded by the National Children's Research Centre, Dublin, Ireland.

The authors report no conflicts of interest.

Copyright 2012 by ESPGHAN and NASPGHAN