Blood-based T cell diagnosis of celiac disease

Moscatelli, Olivia G., Russell, Amy K., Henneken, Lee M., Fothergill, Linda, Motyer, Allan, Reid, Hugh, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Bryant, Vanessa, Anderson, Robert P., Hardy, Melinda Y. and Tye-Din, Jason A. 2025. Blood-based T cell diagnosis of celiac disease. Gastroenterology 10.1053/j.gastro.2025.05.022

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Abstract

Current diagnosis of celiac disease (CeD) is inaccurate in patients following a gluten-free diet (GFD). Blood-based diagnostics targeting gluten-specific T cells, like tetramer assays, are highly sensitive and specific but are impractical for clinical use. We evaluated the potential of a simple whole blood assay measuring interleukin-2 release (WBAIL-2) for detecting gluten-specific T cells to aid in CeD diagnosis. WBAIL-2 was assessed in 181 adults; 88 with CeD (75 on GFD, 13 consuming gluten) and 93 controls (32 on GFD with non-celiac gluten sensitivity, 61 healthy). In vitro IL-2 release in whole blood after gluten peptide stimulation was measured. The assay's performance was compared to tetramer-based methods, and serum IL-2 levels were monitored before and after a single-dose gluten challenge. Correlations between IL-2 levels, tetramer+ T-cell frequencies, and symptoms were examined. The WBAIL-2 assay demonstrates high accuracy for CeD diagnosis, even in patients following a strict GFD. Optimized dual cut-offs in HLA-DQ2.5+ patients showed high sensitivity (90%) and specificity (95%), with lower sensitivity (56%) in HLA-DQ8+ CeD. WBAIL-2 correlated strongly with the frequency of tetramer+ gluten-specific CD4+ T cells and serum IL-2 levels after gluten challenge. Elevated WBAIL-2 levels predicted gluten-induced symptom severity, such as vomiting. The assay required only small blood volumes and performed comparably to tetramer-based methods. Gluten-stimulated IL-2 secretion indicates the presence of pathogenic gluten-specific CD4+ T cells and is a useful diagnostic for CeD. WBAIL-2 and serum IL-2 after gluten could be complementary and allow biopsy-free CeD diagnosis. WBAIL-2 may help diagnose and monitor other CD4+ T cell-driven diseases. [Abstract copyright: Copyright © 2025 AGA Institute. Published by Elsevier Inc. All rights reserved.]

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Publisher:	Elsevier
ISSN:	0016-5085
Date of First Compliant Deposit:	1 July 2025
Date of Acceptance:	2 May 2025
Last Modified:	01 Jul 2025 14:15
URI:	https://orca.cardiff.ac.uk/id/eprint/179460

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