A number of previous reports concluded that all celiac disease patients tolerate oats. These reports have formed the basis for approving oats in the gluten-free diet for the treatment of celiac disease. The findings reported here demonstrate that oat intolerance exists in some celiac disease patients, and the study provides a molecular explanation for this intolerance.
Oats are less related to wheat than are barley and rye. In oats, the prolamines represent much less of the total seed proteins than in the other cereals [25
]. In addition, avenins contain about half the amount of proline residues (10%) as the prolamins of wheat (gliadins and glutenins), barley (hordeins), and rye (secalines). On this basis, it is intriguing that the identified avenin epitopes are located in the regions of avenins with the highest content of proline residues, regions also rich in glutamine. This is analogous to the localization of the T-cell epitopes in α- and γ-gliadins [23
]. The immunogenicity of gliadin peptides is influenced both by the glutamine residues, which become specifically deamidated by TG2, and by the proline residues, which protect the peptides from proteolysis in the gastrointestinal tract, determine the specificity of TG2, and are crucial for the selective binding to HLA-DQ2 [1
]. This study shows that the same features apply to T-cell epitopes of avenin.
In humans it is impossible to directly demonstrate that T-cells induce disease. In celiac disease this relates equally to T-cells reactive to gluten and to T-cells reactive to avenin. The fact that avenin-reactive intestinal T-cells, like gluten-reactive T-cells from celiac disease patients, are uniquely restricted by HLA-DQ2 and are activated by TG2-treated peptides speaks strongly in favor of their involvement in the disease pathogenesis. The finding of avenin-specific intestinal T-cells also in individuals with celiac disease that are clinically tolerant to oats does not, as we see it, contradict this assumption. Some patients with celiac disease stay in remission for extended time periods during gluten challenge even if it is likely that they have gluten-reactive T-cells in their intestinal mucosa. Since avenin is less immunogenic than wheat gluten, one would expect an extended time for relapse to be at least as common during oats consumption.
It is highly unlikely that the intolerance and the mucosal inflammation observed in our patients could be explained by contamination of the oat flour by wheat, barley, or rye proteins. All the oats consumed were produced in a quality-assessed production line. Our data indicate that avenin can drive mucosal inflammation in that the incubation of the intestinal biopsies with avenin enriches for activated, avenin-reactive T-cells. A substantial proportion of the avenin-reactive T-cells appear to be specific to avenin. The T-cell clone we established from an avenin-challenged biopsy was reactive to avenin but did not cross-react to wheat gluten, and the T-cell lines from biopsies challenged with avenin responded more strongly to avenin than to gluten in four of five participants. Cross-reactivity at the T-cell clonal level has been demonstrated between wheat gluten, hordein, and secalin antigens [22
] and likely also exists between gluten and avenin [22
]. Even if some of the avenin-reactive T-cells were originally primed to gluten and responded to avenin because of cross-reactivity, they would still participate in an avenin-driven immune response.
T-cell reponses to the avenin epitopes described in this paper have been found in T-cell lines derived from intestinal biopsies of patients with celiac disease that were stimulated with gliadin [22
]. It is unknown whether any of the patients from whom these T-cells were isolated had clinical symptoms or mucosal inflammation related to oats ingestion. Thus, to our knowledge, the current study is the first to demonstrate a mechanistic link between clinical symptoms of oat intolerance, mucosal inflammation, and avenin-reactive T-cells.
Oat intolerance can cause complications in the large group of celiac disease patients who are now regularly consuming oats. At this stage we do not know how frequently such complications may occur. Presumably such complications will not be very common, but only extended clinical follow-up of oats-consuming celiac disease patients will establish the frequency. Monitoring of T-cell responses to avenin epitopes may potentially identify individuals who are at risk of developing oat intolerance. Based on our data, such monitoring will also identify some individuals who are clinically tolerant to oats and who have minimal or no mucosal pathology after a limited oats challenge. Possibly some of these patients may have latent oat intolerance that will develop into overt disease after prolonged exposure, but this remains speculative. Our observations demonstrate that even if oats seem to be well tolerated by many celiac disease patients, there are patients who have an intestinal T-cell response to oats. Until the prevalence of oat intolerance in celiac disease patients is established, clinical follow-up of celiac disease patients eating oats is advisable. Clinicians should be aware that oat intolerance may be a reason for villous atrophy and inflammation in patients with celiac disease who are eating oats but otherwise are adhering to a strict gluten-free diet.
Celiac disease is a digestive disease that damages part of the gut (the small intestine) and interferes with absorption of nutrients from food. Patients with celiac disease do not tolerate a protein called gluten, which is found in wheat, rye, and barley. When people with celiac disease eat foods containing gluten, their immune system responds by damaging the small intestine. The disease is quite serious in some patients, but eating a strictly gluten-free diet can eliminate all of the symptoms. Unfortunately, wheat, barley, and rye products like flour are found in many common foods, and patients have to avoid them for the rest of their lives. Previous studies suggested that oats were safe for patients with celiac disease, and as a result, they often form part of a gluten-free diet.
What Did the Researchers Find?
Contrary to other studies, this one demonstrates that oats intolerance does exist in some patients with celiac disease. These patients have an immune reaction to oats that is similar to the reaction most celiac disease patients have to wheat, barley, and rye.
What Does This Mean for Patients?
It appears that oats are not safe for all patients with celiac disease. Patients who eat oats as part of a gluten-free diet should discuss their diet and any symptoms with their doctors; doctors should keep in mind that patients might develop symptoms when they eat oats.
What Are the Problems with the Study?
The researchers studied only a small number of patients, and this study cannot tell us how common oats intolerance is among celiac disease patients.
Where Can I Find More Information?