Elevated Serum Interleukin-2 After Gluten Correlates With Symptoms and Is a Potential Diagnostic Biomarker for Coeliac Disease

Jason A. Tye-Din; A. James M. Daveson; Hooi C. Ee; Gautam Goel; James MacDougall; Sarah Acaster; Kaela E. Goldstein; John L. Dzuris; Kristin M. Neff; Kenneth E. Truitt; Robert P. Anderson


Aliment Pharmacol Ther. 2019;50(8):901-910. 

In This Article

Abstract and Introduction


Background: Coeliac disease patients on a gluten-free diet experience reactions to gluten, but these are not well characterised or understood. Systemic cytokine release was recently linked to reactivation of gluten immunity in coeliac disease.

Aim: To define the nature and time-course of symptoms and interleukin-2 changes specific for coeliac disease patients.

Methods: 25 coeliac disease patients on a gluten-free diet and 25 healthy volunteers consumed a standardised 6 gram gluten challenge. Coeliac Disease Patient-Reported Outcome survey and global digestive symptom assessment were completed hourly up to 6 hours after gluten. Adverse events over 48 hours were recorded. Serum interleukin-2 was measured at baseline, and 2, 4 and 6 hours.

Results: Serum interleukin-2 was always undetectable in healthy controls, whereas it was undetectable at baseline and elevated >0.5 pg/ml at 4 hours in 92% of coeliac disease patients. All patient-reported outcome severity scores increased significantly after gluten in coeliac disease patients (P < .001 Wilcoxon signed rank test), but not in controls. Symptoms began after 1 hour, and peaked in the third. Nausea and vomiting characterised severe reactions, but mild reactions were limited to headache and tiredness. Peak interleukin-2 correlated with symptom severity, particularly for nausea and vomiting.

Conclusions: Serum interleukin-2 elevations correlate with timing and severity of symptoms after gluten in coeliac disease. Standardised bolus gluten food challenge and interleukin-2 assessment could provide a valuable clinical test to monitor and diagnose coeliac disease in patients established on a gluten-free diet.


The use of acute single-dose oral food challenge is well established as an informative diagnostic manoeuvre and trial monitoring approach for food allergy, but has not previously been shown to be useful in coeliac disease.[1,2] Coeliac disease is caused by ingestion of dietary gluten and activation of gluten-specific CD4 + T cells; chronic gluten exposure results in characteristic histological abnormalities in the duodenal mucosa and production of autoantibodies specific for transglutaminase.[3] Symptoms caused by gluten in coeliac disease are generally considered nonspecific, and delayed for days or weeks after gluten is reintroduced into the diet.[4,5] Thus, acute provocation testing has not played a role in the diagnosis of coeliac disease.[6]

There has been widespread adoption of gluten-free diet by patients who have not been medically evaluated, but may have coeliac disease.[7,8] Diagnostic tests for coeliac disease, serology and duodenal histology normalise with strict gluten exclusion.[6] Genetic testing can rule out coeliac disease in patients on gluten-free diet, but its clinical utility is limited because of the high prevalence of coeliac-associated HLA-DQ genotypes.[9,10] Consequently, gluten challenge for 2–6 weeks followed by gastroscopy with duodenal biopsy and serology is recommended to evaluate coeliac disease in patients on gluten-free diet.[6] There is no standardisation of diagnostic gluten challenges, and this approach is often impractical because troubling symptoms prevent the continuation of gluten challenge for the period required to rule out coeliac disease.

Recently, we found that consuming gluten-containing food increases symptoms on the day it is consumed, and elevates serum interleukin-2 within hours in patients on gluten-free diet who have coeliac disease.[11] Activated gluten-specific CD4 + T cells are implicated as the source of interleukin-2 because similar elevations of interleukin-2 follow administration of antigenic gluten peptides in patients with coeliac disease on gluten-free diet. Furthermore, coeliac disease patients administered antigenic gluten peptides also experience acute digestive symptoms that mimic symptoms reported by coeliac disease patients after presumed gluten exposure.[12,13] These observations suggested that standardising a potent gluten challenge could enable a diagnostic oral challenge test that would also allow evaluation of cytokine responses and their relationship to acute symptoms caused by gluten exposure in coeliac disease patients on gluten-free diet.

The aim of the present study was to define the nature and time-course of symptoms and interleukin-2 changes specific for coeliac disease patients on gluten-free diet following an oral food challenge test that could serve as a diagnostic tool in coeliac disease.