More fuel to the fire: some patients with non-celiac self-reported wheat sensitivity exhibit adaptive immunological responses in duodenal mucosa

Abstract

Background In contrast to the well-characterized Celiac Disease (CD), the clinical scenarios encompassed by the non-celiac self-reported wheat sensitivity (NCSRWS) might be related to different antigens that trigger distinct immune-inflammatory reactions. Although an increased number of intestinal intraepithelial lymphocytes is observed at the inception of both diseases, the subsequent immunopathogenic pathways seem to be different. We aimed to describe the cytokine profile observed in the duodenal mucosa of patients with NCSRWS. Methods In a blind, cross-sectional study, we included duodenal biopsies from 15 consecutive untreated patients with active CD, 9 individuals with NCSRWS and 10 subjects with dyspepsia without CD and food intolerances. Immunohistochemistry and flow-cytometry were used to determine the presence of pro-inflammatory cytokine expressing monocytes and monocyte-derived dendritic cells involved in innate immune activation, cytokine-driven polarization and maintenance of Th1 and Th17/Th 22, and anti-inflammatory/profibrogenic cytokines. Results The percentage of cells expressing all tested cytokines in the lamina propria and the epithelium was higher in CD patients than in the control group. Cytokines that induce and maintain Th1 and Th17 polarization were higher in CD than in NCSRWS and controls, also were higher in NCSRWS compared to controls. Similar differences were detected in the expression of IL-4 and TGF-1, while IL-10-expressing cells were lower in NCSRWS patients than in controls and CD subjects. Conclusions NCSRWS patients exhibit components of both, innate and adaptive immune mechanisms but to a lesser extent compared to CD.

Non-Celiac Gluten/Wheat Sensitivity: Clinical Characteristics and Microbiota and Mycobiota Composition by Response to the Gluten Challenge Test

“…In patients with NCGS/WS, a systemic immune activation has been demonstrated; it was documented by increased serum levels of soluble CD14 and LPS-binding protein, as well as antibody reactivity to bacterial LPS and flagellin [ 10 ], enhanced expression of Toll-like receptor 2 (TLR2) [ 5 ], increased antibodies against gluten proteins [ 17 , 47 ], raised interferon gamma, interleukin (IL)-1 beta, IL-2, IL-12, IL-15, transforming growth factor (TNF) beta1, and TNF-α-expressing duodenal cells [ 3 , 29 ], increased serum levels of IL-8 and IL-15 [ 48 ], moderate intra-epithelial infiltration of eosinophils and lymphocytes, with increased inflammatory and regulatory CD4+ cells [ 6 , 13 , 17 , 47 , 49 , 50 ], and a high frequency of associated autoimmune diseases [ 7 , 51 ]. It has been hypothesized that individuals with NCGS/WS with a prevalent pathogenetic role for the FODMAPs, instead of gluten, may be a different patient population with less-prominent immunologic characteristics [ 6 ].…”

“…The pathogenesis of NCGS/WS is still uncertain; a higher intestinal expression of toll-like receptors suggesting a stronger implication of the innate immune mechanisms, the infiltration of immune cells in the gut mucosa, increased expression of antibodies, and dysregulated gene expression profiling and epigenetic mechanisms have been described [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Furthermore, impaired intestinal barrier and permeability and gut dysbiosis have been advocated as key factors by several studies [ 1 , 2 , 4 , 10 , 11 ].…”

“…Furthermore, the double-blind placebo-controlled (DBPC) crossover gluten challenge test, which remains at present the gold standard test for NCGS/WS diagnosis, is cumbersome and not easy to perform in daily clinical practice. Indeed, many studies referred to self-reported diagnosis [ 3 , 9 , 10 , 13 , 17 ], but only 8% to 34% of the individuals with self-reported gluten sensitivity worsened their symptoms after gluten ingestion, thus suggesting that self-reporting overemphasized the syndrome [ 18 , 19 , 20 , 21 , 22 ].…”

Diploid Wheats: Are They Less Immunogenic for Non-Celiac Wheat Sensitive Consumers?

“…This indicates that an adaptive immune response may also play a role in the NCWS pathogenesis. Additional compelling evidence for the role of adaptive immunity in NCWS came from other groups, showing an increased production of Tumor Necrosis Factor (TNF)-α and of IL-17, in the intestinal tissue of NCWS patients, compared to healthy individuals [ 18 , 19 ].…”

Non-Celiac Gluten Sensitivity: An Update

“…On the other hand, the production of tumor necrosis factor (TNF) α by CD45 + , CD3 + , CD4 + , and CD8 + cells and IL-17 by CD4 + cells is higher in the rectal tissue of active NCGS patients than in healthy controls, suggesting that the adaptive immune system is involve in the pathogenesis of NCGS [ 57 ]. Others have reported an increased percentage of cells that express cytokines that induce and maintain Th1 and Th17 responses, such as IL-12, IL-15, and IL-2, and cells that express TNF-α and IL-1β suggesting a concomitant role of both the innate and adaptive immune system in NCGS [ 58 ]. Therefore, evidence suggests that both the innate and adaptive immune systems trigger the intestinal inflammation that occurs in NCGS cases.…”