The Molecular Basis for Oat Intolerance in Patients with Celiac Disease

DOI: 10.1371/journal.pmed.0010001 The Molecular Basis for Oat Intolerance in Patients with Celiac Disease Helene Arentz-Hansen 0 1 2 3 Burkhard Fleckenstein 0 1 2 3 yvind Molberg 0 1 2 3 Helge Scott 0 1 2 3 Frits Koning 0 1 2 3 Gu nther Jung 0 1 2 3 Peter Roepstorff 0 1 2 3 Knut E. A. Lundin 0 1 2 3 Ludvig M. Sollid 0 1 2 3 0 Academic Editor: Marco Londei, University College London , United Kingdom 1 Author Contributions: M, KEAL, and LMS designed the study. HAH , BF, M, HS, FK, GJ, PR, KEAL , and LMS analyzed the data. FK and GJ contributed synthetic peptides for the study. HAH , BF, M, HS, FK, GJ, KEAL, and LMS contributed to writing the paper 2 1 Institute of Immunology, Rikshospitalet University Hospital, University of Oslo , Oslo , Norway , 2 Department of Biochemistry and Molecular Biology, University of Southern Denmark , Odense, Denmark , 3 Institute of Pathology, Rikshospitalet University Hospital, University of Oslo , Oslo , Norway , 4 Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, Netherlands, 5 Institute of Organic Chemistry, University of Tu bingen , Tu bingen, Germany , 6 Department of Medicine, Rikshospitalet University Hospital , Oslo , Norway 3 Citation: Arentz-Hansen H , Fleck- enstein B, Molberg , Scott H, Koning F, et al. (2004) The molec- ular basis for oat intolerance in celiac disease patients. PLoS Med 1(1): e1 A B S T R A C T Celiac disease is a small intestinal inflammatory disorder characterized by malabsorption, nutrient deficiency, and a range of clinical manifestations. It is caused by an inappropriate immune response to dietary gluten and is treated with a gluten-free diet. Recent feeding studies have indicated oats to be safe for celiac disease patients, and oats are now often included in the celiac disease diet. This study aimed to investigate whether oat intolerance exists in celiac disease and to characterize the cells and processes underlying this intolerance. - We conclude that some celiac disease patients have avenin-reactive mucosal T-cells that can cause mucosal inflammation. 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. Clinical follow-up of celiac disease patients eating oats is advisable. Celiac disease is a chronic inflammatory condition caused by an inappropriate immune response of intestinal T-cells reactive to gluten proteins of wheat and similar prolamin proteins of related cereals [1]. The majority of the peptides recognized by intestinal T-cells are more immunogenic following deamidation by tissue transglutaminase (TG2). These peptides are invariably presented by HLA-DQ2 or -DQ8, the same HLA molecules that confer genetic predisposition to celiac disease [1]. Gluten-reactive intestinal T-cells can be isolated from virtually all patients with celiac disease but not from normal individuals. The disease goes into remission when harmful cereals are avoided. A gluten-free diet is thus the standard treatment of this disorder. Oats have traditionally been excluded from the gluten-free diet. Several feeding studies, however, have indicated that patients with celiac disease and dermatitis herpetiformis tolerate oats without signs of intestinal inflammation [29]. Of note, some of these studies have high patient-dropout rates that may have masked cases of oat intolerance. An in vitro study found no signs of T-cell activation in small intestinal biopsies of celiac disease patients challenged with avenin (the prolamin fraction of oats) [10], and avenins have been predicted to contain only a few glutamines that can be deamidated by TG2, presumably making avenins less immunogenic [11,12]. On this basis, oats have been allowed in the gluten-free diet in several countries [13]. It remains to be proven that all celiac disease patients tolerate oats following long-term exposure. A recent study of 39 Finnish patients randomized to eat a gluten-free diet with 50 g of oats daily or a standard gluten-free diet for 1 y reported more intestinal symptoms and more gut inflammation in the group of patients eating oats, although the mucosal integrity was not disturbed [14]. In an open challenge study of 19 adult celiac disease patients using pure oats, one patient developed villous atrophy [15]. This finding prompted us to investigate the phenomenon of oat intolerance further in a selected series of nine adult celiac disease patients, three of whom had clinical oat intolerance. The goal of the study was to characterize the intestinal T-cell response to oats avenin proteins in these patients in detail and to relate this to clinical symptoms and intestinal biopsy findings. Participants We studied nine adults with celiac disease who had a history of exposure to pure oats. The oats were derived from a quality-controlled production line and were shown to be free from contamination of other cereals as des (...truncated)