Patient factors influencing acute gluten reactions and cytokine release in treated coeliac disease

Abstract

Background Patients with coeliac disease (CD) commonly report a variety of adverse symptoms to gluten, but descriptions of the symptomatic response in the literature may have been confounded by the presence of food components such as fermentable carbohydrates (FODMAPs) causing symptoms of irritable bowel syndrome independent of gluten. In recent unmasked and masked low FODMAP gluten challenge studies in small groups of treated CD patients, nausea and vomiting were shown to be the key symptoms associated with serum interleukin (IL)-2 release. Our objective was to utilise a large and diverse cohort of people with CD undertaking a standardised gluten food challenge to characterise the demographic, genetic and clinical factors influencing the severity and timing of acute gluten reactions and IL-2 production. Methods A total of 295 adults treated for CD were observed for 6 h after an unmasked food challenge consisting of 10 g vital wheat gluten (low in FODMAPs) in 100 ml water. Assessments included patient-reported outcomes, serum IL-2 and adverse events. Responses were analysed according to patient characteristics, HLA-DQ genotype, duodenal histology and response to a second gluten challenge. Results Peak symptom severity was at 3 h (median severity 5/10). Peak IL-2 was at 4 h (median 4 pg/ml, range undetectable to 1028 pg/ml). Older age, older age at diagnosis, HLA-DQ2.5 positivity and homozygosity for HLA-DQB1*02 were each significantly associated with IL-2 elevations after gluten. Patients positive for HLA-DQ2.5, DQ8, DQ2.2 or DQ7 showed elevated IL-2 after gluten. Patient factors were not significantly associated with severity of digestive symptoms, but symptoms were correlated to one another and serum IL-2. Gluten challenge after 5 months caused more vomiting and higher IL-2 levels, but responses correlated with the first. Conclusions Gluten-induced symptoms and cytokine release is common in adults with treated CD. Age, genetics and previous response to gluten predict these acute reactions to gluten challenge. Structured symptom assessment and serum IL-2 after standardised gluten challenge may inform on patient diagnosis, the role of gluten in symptomatology and the need for adjunctive treatment. Trial registration ClinicalTrials.gov, NCT03644069 Registered 21 May 2018.

Whole blood interleukin-2 release test to detect and characterize rare circulating gluten-specific T cell responses in coeliac disease

“…Whether additional α‐gliadin epitopes restricted by HLA‐DQ8 or DQ2·2 might be identified is an open question, and would require CD patients with these genetic backgrounds to be studied in the future. IL‐2 is, however, likely to be the preferred cytokine for whole blood release assays in these patients, as IL‐2 has recently been invoked in systemic cytokine release that follows gluten challenge in CD patients negative for HLA‐DQ2·5 [29]. Including a cross‐validation using HLA‐DQ2·5‐gluten‐peptide tetramers and flow cytometry would have been valuable to corroborate estimates of responding CD4 + T cells made by Poisson distribution analysis, but due to the availability of suitable samples was not possible.…”

The Gluten Gene: Unlocking the Understanding of Gluten Sensitivity and Intolerance

“…CD is limited to genetically predisposed individuals who carry HLA-DQ2.5, HLA-DQ8, HLA-DQ2.2 and/or rarely HLA-DQ7 haplotypes located on the short arm of chromosome 6. [60][61][62][63][64] The results of several Genome-wide association studies (GWAS), for example, most recently in a prospective study of 6010 children that carried HLA genotypes associated with increased risk of type-1 diabetes and CD, have also reported the role of non-HLA genes in CD presentation. 65 Other immunologic and environmental factors are also involved in the development of CD.…”

The Evolving Landscape of Biomarkers in Celiac Disease: Leading the Way to Clinical Development

“…Homozygosity of the HLA-DQB1*02 allele, which encodes the beta chain of HLA-DQ2, may impact the number of gliadin-specific T cells that are activated after gluten exposure. Patients with HLA-DQ2 who are homozygous for the HLA-DQB1*02 allele appear more likely to respond to a gluten challenge with increased serum IL-2 and to have higher maximum serum concentrations of IL-2 than other genotypes ( 24 , 34 ). In turn, this subset of patients may have a slower intestinal recovery rate after gluten challenge ( 14 ) and may be more likely to progress to RCD2 ( 35 ).…”