Society: AGA

Background: Contamination-free oats are considered safe for most patients with celiac disease (CeD). However, we and others have isolated pro-inflammatory oat protein (avenin)-specific CD4+ T cells from the blood and duodenum of some people with CeD, a finding that carries troubling implications for safe oats ingestion in CeD. Does the presence of avenin-specific T cells identify CeD patients susceptible to harm from oats?
Aim: To determine the frequency of symptoms and immune activation in patients with CeD after single-bolus ingestion of purified avenin and then assess symptomatic, immune and clinical (safety) effects after extended avenin ingestion.
Methods: For the first time, food-grade avenin was purified from contamination-free oats to enable feeding studies at high doses not achievable using oats. We employed a series of single-bolus avenin challenges in HLA-DQ2.5+ CeD adults with assessment of symptoms and serum interleukin (IL)-2 at 4 hrs, a highly sensitive marker of gluten-specific T cell activation. Avenin was given in increasing amounts (0.05, 0.1, 0.5, 1, 4, and 6 g) with 4-wk washout periods. Subsequently, in patients with IL-2 responses, avenin was consumed daily for 6 wks at the highest tolerated dose that triggered IL-2. T-cells were assessed using avenin-specific tetramers, serum cytokines (MSD and O-link Inflammation 96-panel) and duodenal histology was examined pre- and post- challenge. A CeD patient undertook a 6 wk wheat gluten challenge as a positive control.
Results: Surprisingly, avenin induced a significant acute IL-2 elevation in 11/29 (38%) CeD patients (mean 16-fold elevation) and adverse symptoms such as pain, diarrhea and vomiting were induced in 60%, with severity correlated to higher IL-2 elevation. Five IL-2 responders then undertook 6-wk avenin challenge. Activated avenin-specific tetramer+ effector memory CD4+ T cells were increased on day 6. Interestingly, after 6 wks of avenin, these had returned to baseline and IL-2 responses after avenin were undetectable; all patients were tolerating avenin without the acute initial symptoms. In the duodenum, a similar frequency of tetramer+ cells were seen at baseline and at 6 wks. Notably, duodenal histology after 6 wks avenin remained normal, in contrast to significant deterioration in the wheat challenged patient. Serum inflammatory cytokines were not elevated by avenin except in one highly symptomatic CeD patient to a similar degree as the wheat challenged patient.
Conclusion: Purified avenin induces acute symptoms and T-cell responses in a subset of “sensitive” CeD patients. Reassuringly, our findings suggest that in most CeD patients oats is unable to sustain a pathogenic immune response above the threshold required for mucosal deterioration, in contrast to wheat gluten. These findings help resolve the discrepancy between clinical oats safety and oats immunity in CeD.

Hugh Reid

Appearances