A B-Cell Gene Signature Correlates With the Extent of Gluten-Induced Intestinal Injury in Celiac Disease

Abstract

Background & AimsCeliac disease (CeD) provides an opportunity to study autoimmunity and the transition in immune cells as dietary gluten induces small intestinal lesions.MethodsSeventy-three celiac disease patients on a long-term, gluten-free diet ingested a known amount of gluten daily for 6 weeks. A peripheral blood sample and intestinal biopsy specimens were taken before and 6 weeks after initiating the gluten challenge. Biopsy results were reported on a continuous numeric scale that measured the villus-height–to–crypt-depth ratio to quantify gluten-induced intestinal injury. Pooled B and T cells were isolated from whole blood, and RNA was analyzed by DNA microarray looking for changes in peripheral B- and T-cell gene expression that correlated with changes in villus height to crypt depth, as patients maintained a relatively healthy intestinal mucosa or deteriorated in the face of a gluten challenge.ResultsGluten-dependent intestinal damage from baseline to 6 weeks varied widely across all patients, ranging from no change to extensive damage. Genes differentially expressed in B cells correlated strongly with the extent of intestinal damage. A relative increase in B-cell gene expression correlated with a lack of sensitivity to gluten whereas their relative decrease correlated with gluten-induced mucosal injury. A core B-cell gene module, representing a subset of B-cell genes analyzed, accounted for the correlation with intestinal injury.ConclusionsGenes comprising the core B-cell module showed a net increase in expression from baseline to 6 weeks in patients with little to no intestinal damage, suggesting that these individuals may have mounted a B-cell immune response to maintain mucosal homeostasis and circumvent inflammation. DNA microarray data were deposited at the GEO repository (accession number: GSE87629; available: https://www.ncbi.nlm.nih.gov/geo/).

Outcome measures in coeliac disease trials: the Tampere recommendations

“…Peripheral blood B cells may also prove to be a potential source of future biomarkers. 98 The local mucosal production of antibodies targeting extracellular TG2 in vivo has shown potential in diagnosis, 51 but was not informative beyond standard histology in a clinical drug trial with gluten challenge. 99 …”

Genome-Wide Transcriptomic Analysis of Intestinal Mucosa in Celiac Disease Patients on a Gluten-Free Diet and Postgluten Challenge

“… 61 In the present study, we adopted our standard operating procedures and validated quantitative morphometry separately for biopsy morphology and inflammation to measure the continuum of gluten-induced mucosal injury in celiac disease. 13 , 21 , 24 , 62 These methods were also adopted in recent clinical drug and vaccine trials. 22 , 23 , 39 In the present study, we show that the expression of a selected subset of protein-coding genes correlates extremely well with the extent of morphological damage and inflammation in control patients and celiac disease patients on a GFD before and after the gluten challenge (presented as heatmaps in the order of VH:CrD and IEL density in Figure 10 ).…”

“… 9 , 10 B cells, autoantibodies, and TG2, have also been shown to have an important function in celiac disease pathogenetic mechanisms. 9 , 11 , 12 , 13 , 14 Despite the well-studied role of the immune system in celiac disease development, a complete picture of the pathophysiology, especially the early steps leading to the loss of gluten tolerance, is still missing. 13 Currently, a lifelong gluten-free diet (GFD) is the only accepted treatment option for patients with celiac disease.…”

“…The majority of these studies used untreated patient samples, samples from patients on a GFD, and non–celiac disease samples as a control group. Because mucosal damage is dose- and time-dependent, 13 , 21 , 22 and because patients have different levels of gluten consumption at the time of their initial diagnoses, often large amount for decades, these confounding factors may lead to inconsistent results. To circumvent these shortcomings, we sought to exploit the gluten challenge study design 13 , 21 , 22 , 23 , 24 and perform genome-wide transcriptomic analyses of celiac disease small intestinal biopsies from patients on a strict long-term GFD and compare the results with those of biopsies taken from the same celiac disease patients after a standard amount and time on a gluten challenge.…”

Genome-wide transcriptomic analysis of intestinal mucosa in celiac disease patients on a gluten-free diet and post gluten challenge

“…9,10 B cells, autoantibodies, and TG2, have also been shown to have an important function in celiac disease pathogenetic mechanisms. 9,[11][12][13][14] Despite the well-studied role of the immune system in celiac disease development, a complete picture of the pathophysiology, especially the early steps leading to the loss of gluten tolerance, is still missing. 13 Intestinal epithelium, as one of the components in celiac disease development, has also been the focus of research.…”