Tissue Transglutaminase but Not Microbial Transglutaminase Is Inhibited by Exogenous Oxidative Substances in Celiac Disease
Round 1
Reviewer 1 Report
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Reviewer 2 Report
Enzymatic modification of gliadin peptides by human transglutaminase 2 (TG2) is a central step in celiac disease (CD) pathogenesis. Microbial transglutaminase (mTG) mimics the enzymatic function of TG2 and might play a role in CD. TG2 is inhibited by endogenous oxidative ERp57 but data about mTG are lacking.
The authors investigated the localization of ERp57 in duodenal biopsies and examined inhibition of TG2 and mTG by competitive and oxidative molecules. Localization of ERp57 was investigated in duodenal biopsies from CD and control patients by electron microcopy
Thy could display various intracellular localization sites of TG2 and ERP57 which suggests a possible interaction between those molecules. Strikingly, we observed higher abundance of ERp57 in RACE and in particular within the ER of this specific cell type. In addition, its amount was reduced within the ER of RACE in CD patient samples indicating a potential pathogenic relevant function of this molecule
TG2 was oxidatively inhibited by up to 95 % by PX12 (p < 0.001) and L- cystine (p < 0.001), whereas mTG remained unaffected. The reduced presence of ERp57 within the ER of CD biopsies suggests a regulatory function of this protein within CD pathogenesis
In conclusion, we showed that the presence of the endogenous TG2 inhibitor ERp57 differs within the ER in duodenal biopsies of CD and control patients. This indicates a potential role of this protein in CD, potentially by inhibiting TG2 activity within the ER and preventing cross presentation of immunogenic gliadin peptides in healthy individuals.
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Reviewer 3 Report
-In this manuscript, the authors researched the “Tissue transglutaminase but not microbial transglutaminase is inhibited by exogenous oxidative substances in celiac disease”. This paper can be interesting in celiac disease domain. They discussed about TG activity at various concentrations. I affirm its acceptance for publication. There are some concerns before it is suggestion.
Minner commentaries:
Q1: What is HLA DQ2/8 positive individuals. It is not clear. Explain about in line 29-30.
Q2: In table 1, caption is placed in right location. Author could revise the both table and their caption structures.
Q3: Significance of T Cell-based molecular activity in various cells has been recently documented. This article more deeply discussed about MHC, CD subsets, and oxidative metabolic difference. I encourage to cite this https://doi.org/10.3390/ijms222212190 and https://doi.org/10.3390/ijms22031160
Q4: In table 2, caption is placed in right location. Author could revise the both table and their caption structure. Author should give abbreviations in both tables.
Q5: I found numerous English language errors (grammars, spelling and style-related), this manuscript will require a detailed proof-reading. Author should check sentence space issues.
Q6: The mTG and TG2 enzyme activity was well described. In Fig. 4, author specified about that the cystine 0.1mM, cystine 1mM, cystine 10mM. Same time in line 197-198, author should correct in figures.
Q7: In line 314-324, in conclusion, author should explain what is the effective concentration for TG2 activity inhibition. Author should explain about this in conclusion part.
Author Response
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