TNF-α, IL-17, and IL-22 production in the rectal mucosa of nonceliac wheat sensitivity patients: role of adaptive immunity

Abstract

In recent years, a new gluten- or wheat-related disease has emerged, a condition labelled "non-celiac gluten sensitivity" (NCGS) or "non-celiac wheat sensitivity" (NCWS). NCWS pathogenesis is still uncertain and attributed to very different mechanisms. We aimed to study the different T lymphocyte subsets in the rectal mucosa of NCWS patients, to demonstrate the possible contribution of adaptative immune response. Twelve patients (11 females, 1 male, age range 23-61 years, median 32) with a definitive diagnosis of NCWS were recruited at random for the present study. They underwent rectal endoscopy with multiple mucosal biopsies at the end of a double-blind placebo-controlled (DBPC) wheat challenge when they reported the reappearance of the symptoms. As controls we included 11 "healthy patients", sex- and age-matched with the patients, who underwent colonoscopy evaluation for rectal bleeding due to hemorrhoids. Cells freshly obtained from rectal tissue were stained to detect anti-CD45, anti-CD3, anti-CD4, and anti-CD8. Furthermore, intracellular staining was performed with anti-Tumor Necrosis Factor (TNF)-α, anti-interleukin (IL)-17, and anti-IL-22. Production of TNF-α by CD45+, CD3+, CD4+ and CD8+ cells, as well as of IL-17 by CD4+ cells, was higher in the rectal tissue of NCWS patients than in controls. On the contrary, IL-22 production by CD8+ cells was lower in NCWS patients than in the controls. In NCWS patients diagnosed by DBPC wheat challenge, there is a complex immunological activation, with a significant role for the adaptive response.

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 ].…”

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“…Increased levels of mast cells in the duodenum have also been reported [ 55 ], and this correlates with a higher intensity of abdominal pain and bloating in NCGS individuals [ 56 ]. 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 ].…”

Nutrition in Patients with Lactose Malabsorption, Celiac Disease, and Related Disorders

“…Studies reveal an increased expression of transforming growth factor α, interleukin 10, CD14, granulocyte-macrophage colony-stimulating factor, C-X-C motif chemokine ligand 10, and lipopolysaccharide-binding protein in NGCS patients [ 81 , 99 , 100 ]. However, the production of tumor necrosis factor and IL-17 in rectal tissue of NCGS subjects suggests an adaptive immune response [ 101 ]. AGA positivity in NCGS patients also supports the involvement of an adaptive immunopathology [ 90 , 91 ].…”