Jason A Tye-Din1,2,3, Gry I Skodje4,5,6, Vikas K Sarna4,7,8, John L Dzuris9, Amy K Russell1, Gautam Goel9, Suyue Wang9, Kaela E Goldstein9, Leslie J Williams9, Ludvig M Sollid4,7,8, Knut Ea Lundin4,7,8, Robert P Anderson9. 1. Immunology Division, Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Australia. 2. Murdoch Children's Research Institute, Parkville, Australia. 3. Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Australia. 4. KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway. 5. Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. 6. Unit for Clinical Nutrition, Division of Cancer Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. 7. Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway. 8. Department of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway. 9. ImmusanT, Inc., Cambridge, USA.
Abstract
BACKGROUND: Diagnosing coeliac disease (CD) in patients on a gluten-free diet (GFD) is difficult. Ingesting gluten elevates circulating interleukin (IL)-2, IL-8 and IL-10 in CD patients on a GFD. OBJECTIVE: We tested whether cytokine releaseafter gluten ingestion differentiates patients with CD from those with self-reported gluten sensitivity (SR-GS). METHODS:Australian patients with CD (n = 26) and SR-GS (n = 18) on aGFD consumed bread (estimated gluten 6 g). Serum at baseline and at 3 and 4 h was tested for IL-2, IL-8 and IL-10. Separately, Norwegian SR-GS patients (n = 49) had plasma cytokine assessment at baseline and at 2, 4 and 6 h after food bars containing gluten (5.7 g), fructan or placebo in a previous double-blind crossover study. RESULTS: Gluten significantly elevated serum IL-2, IL-8 and IL-10 at 3 and 4 h in patients with CD but not SR-GS. The highest median fold-change from baseline at 4 h was for IL-2 (8.06, IQR: 1.52-24.0; P < 0.0001, Wilcoxon test). The two SR-GS cohorts included only one (1.5%) confirmed IL-2 responder, and cytokine responses to fructan and placebo were no different to gluten. Overall, cytokine release after gluten was present in 22 (85%) CD participants, but 2 of the 4 non-responders remained clinically well after 1 y on an unrestricted diet. Hence, cytokine release occurred in 22 (92%) of 24 'verified' CD participants. CONCLUSIONS: Gluten challenge with high-sensitivity cytokine assessment differentiates CD from SR-GS in patients on a GFD and identifies patients likely to tolerate gluten reintroduction. Systemic cytokine release indicating early immune activation by gluten in CD individuals cannot be detected in SR-GS individuals.
RCT Entities:
BACKGROUND: Diagnosing coeliac disease (CD) in patients on a gluten-free diet (GFD) is difficult. Ingesting gluten elevates circulating interleukin (IL)-2, IL-8 and IL-10 in CDpatients on a GFD. OBJECTIVE: We tested whether cytokine release after gluten ingestion differentiates patients with CD from those with self-reported gluten sensitivity (SR-GS). METHODS: Australian patients with CD (n = 26) and SR-GS (n = 18) on a GFD consumed bread (estimated gluten 6 g). Serum at baseline and at 3 and 4 h was tested for IL-2, IL-8 and IL-10. Separately, Norwegian SR-GSpatients (n = 49) had plasma cytokine assessment at baseline and at 2, 4 and 6 h after food bars containing gluten (5.7 g), fructan or placebo in a previous double-blind crossover study. RESULTS: Gluten significantly elevated serum IL-2, IL-8 and IL-10 at 3 and 4 h in patients with CD but not SR-GS. The highest median fold-change from baseline at 4 h was for IL-2 (8.06, IQR: 1.52-24.0; P < 0.0001, Wilcoxon test). The two SR-GS cohorts included only one (1.5%) confirmed IL-2 responder, and cytokine responses to fructan and placebo were no different to gluten. Overall, cytokine release after gluten was present in 22 (85%) CDparticipants, but 2 of the 4 non-responders remained clinically well after 1 y on an unrestricted diet. Hence, cytokine release occurred in 22 (92%) of 24 'verified' CDparticipants. CONCLUSIONS: Gluten challenge with high-sensitivity cytokine assessment differentiates CD from SR-GS in patients on a GFD and identifies patients likely to tolerate gluten reintroduction. Systemic cytokine release indicating early immune activation by gluten in CD individuals cannot be detected in SR-GS individuals.
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