OAT AVENIN TRIGGERS ACUTE SYMPTOMS AND IMMUNE ACTIVATION IN SOME PEOPLE WITH CELIAC DISEASE BUT ADVERSE IMMUNE AND CLINICAL EFFECTS ARE ABSENT WITH EXTENDED INGESTION

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.