Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease.
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
24 Jun 2024
24 Jun 2024
Historique:
received:
22
06
2023
accepted:
13
05
2024
medline:
25
6
2024
pubmed:
25
6
2024
entrez:
24
6
2024
Statut:
aheadofprint
Résumé
Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten.
Identifiants
pubmed: 38914866
doi: 10.1038/s41590-024-01867-0
pii: 10.1038/s41590-024-01867-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Academy of Finland (Suomen Akatemia)
ID : 310011
Investigateurs
Karin Kull
(K)
Jari Koskenpato
(J)
Mika Scheinin
(M)
Marja-Leena Lähdeaho
(ML)
Michael Schumann
(M)
Yurdagül Zopf
(Y)
Andreas Stallmach
(A)
Ansgar W Lohse
(AW)
Stefano Fusco
(S)
Jost Langhorst
(J)
Helga Paula Török
(HP)
Valerie Byrnes
(V)
Juozas Kupcinskas
(J)
Øistein Hovde
(Ø)
Jørgen Jahnsen
(J)
Luc Biedermann
(L)
Jonas Zeitz
(J)
Informations de copyright
© 2024. The Author(s).
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