Review for 10.1186/s12876-020-01564-w (2020)

Reviewer’s report
Title: 
More fuel to the fire: Some patients with non-celiac self-reported wheat
sensitivity exhibit adaptive immunological responses in duodenal mucosa.
Version: 
0 
Date: 
27 Jul 2020
Reviewer's report:
The study by Antonia Isabel Castillo-Rodal et al. investigated the presence of the
adaptive immune response in patients with non-celiac gluten sensitivity. They
sustain a role of such branch of the immune system finding, on duodenal
biopsies of NCGS patients, an increase of Th1 and Th17 pro-inflammatory
cytokines. The findings of the study are not novel. In fact, although the
pathogenesis of NCG/WS is far from being fully deciphered, evidence supports
the role exerted by both innate and adaptive immunity. 
So far, the few trials
performed respect the role of adaptive immunity have produced controversial
results. It is conceivable that the initial response is provided by innate
immunity,followed by the activation of adaptive immune system in NCG/WS
Nevertheless, there are some suggestion/observation regards the study design:
-cytokine transcripts such as IL17A and IL-21 are not exclusively expressed by
Th17 and Th1 within the intestinal mucosa and therefore that assumption should
be avoided. Therefore to distinguish cell type sources of cytokines being
produced, immunohistochemistry in combination of staining of T cell markers
and cytokines may be used 
- the involvement of innate immunity in NCGS pathogenesis has been
demonstrated by the activation of the pattern recognition receptors known as
Toll-like receptors (TLRs) and IL-8 in the small intestinal mucosa. In this study,
TLRs were not detected and IL-8 was not found increased. Moreover, IFN-g
used as read out of adaptive immune activation, also was not found increased
whereas the authors found increased production of IL-12 in CD and also in
NCGS than in controls, contrary to a hitherto generally suggested. 
Therefore this
main point should by clarified. 
- to support the hypothesis of adaptive immunity involvement in NCGS
pathogenesis, in vitro approach such as 
T cell proliferation assay by Isolation of
CD4+ T cells and co-culture with autologous native Gliadin or ATI-pulsed DC,
should be used.
- why the intraepithelial lymphocytes was not analyzed by
immunohistochemistry?
As it is, I feel the manuscript lacks novel and sufficient data for publication
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