Blood-Based T-Cell Diagnosis of Celiac Disease

Abstract

Background & aims: Current diagnosis of celiac disease (CeD) is inaccurate in patients consuming a gluten-free diet (GFD). Blood-based diagnostics targeting gluten-specific T cells, such as 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 (IL-2) release (WBAIL-2) for detecting gluten-specific T cells to aid in CeD diagnosis.

Methods: WBAIL-2 was assessed in 181 adults; 88 with CeD (75 consuming a GFD, 13 consuming gluten) and 93 controls (32 consuming a GFD with nonceliac gluten sensitivity, 61 healthy). In vitro IL-2 release in whole blood after gluten peptide stimulation was measured. The assay's performance was compared with tetramer-based methods, and serum IL-2 levels were monitored before and after a single-dose gluten challenge. Correlations between IL-2 levels, tetramer-positive T-cell frequencies, and symptoms were examined.

Results: The WBAIL-2 assay demonstrates high accuracy for CeD diagnosis, even in patients consuming a strict GFD. Optimized dual cutoffs 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-positive gluten-specific CD4⁺ T cells and serum IL-2 levels after a gluten challenge. Elevated WBAIL-2 levels predicted gluten-induced symptom severity, such as vomiting. The assay required only small blood volumes and performed comparably with tetramer-based methods.

Conclusions: 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.

Keywords: Celiac Disease; Diagnostics; Interleukin-2; T cells.