Celiac Disease Causes Epithelial Disruption and Regulatory T Cell Recruitment in the Oral Mucosa

Abstract

Celiac disease (CD) is a chronic autoimmune disease characterized by an immune-triggered enteropathy upon gluten intake. The only current treatment available is lifelong Gluten Free Diet (GFD). Several extraintestinal manifestations have been described in CD, some affecting the oral mucosa. Thus, we hypothesized that oral mucosa could potentially be a target for novel biomarkers and an administration route for CD treatment. Six de novo diagnosed and seven CD patients under GFD for at least 1 year were recruited. Non-celiac subjects (n = 8) were recruited as control group. Two biopsies of the cheek lining were taken from each subject for mRNA analysis and immunohistochemical characterization. We observed a significant decrease in the expression of epithelial junction proteins in all CD patients, indicating that oral mucosa barrier integrity is compromised. FoxP3+ population was greatly increased in CD patients, suggesting that Tregs are recruited to the damaged mucosa, even after avoidance of gluten. Amphiregulin mRNA levels from Peripheral Blood Mononuclear Cells (PBMCs) and epithelial damage in the oral mucosa correlated with Treg infiltration in all the experimental groups, suggesting that recruited Tregs might display a “repair” phenotype. Based on these results, we propose that oral mucosa is altered in CD and, as such, might have diagnostic potential. Furthermore, due to its tolerogenic nature, it could be an important target for oral immunotherapy.

Nature vs. nurture: FOXP3, genetics, and tissue environment shape Treg function

“…Interestingly, upregulation of IL-33R (ST2) and its downstream target cytokine, amphiregulin, is a trait shared among many Tregs that are transitioning towards tissue phenotype; indicative of an acquired ability to participate in tissue repair in response to inflammation or injury (Figure 3) (89,(123)(124)(125). The growth factor amphiregulin is expressed by tissue Tregs in response to alarmin cytokines released by injured tissue cells, including IL-33 (114)(115)(116). The ramifications of this discovery show that Tregs upregulate receptors necessary to Induced regulatory T cells.…”

Word of mouth: Oral mucosa composition in health and immune disease

“…These publications advance the knowledge of the immune system of the oral mucosa in health and disease. The role of neutrophils seems to not be significant in the buccal mucosa for other inflammatory diseases, although this might be due to the location of the tissue (gingiva vs buccal mucosa) 2,4,6 . In this regard, oral mucosa is affected in periodontal, allergic and celiac disease, among others; thus, a full characterization of neutrophil, Th2 and Treg response in the oral mucosa could serve as a powerful, accessible tool to understand local and systemic disease.…”

“…Thus, we hypothesize that the Treg cells observed in CD patients are recruited to protect against further tissue damage and maintain barrier integrity. 6 These publications advance the knowledge of the immune system of the oral mucosa in health and disease. The role of neutrophils seems to not be significant in the buccal mucosa for other inflammatory diseases, although this might be due to the location of the tissue (gingiva vs buccal mucosa).…”

“…The role of neutrophils seems to not be significant in the buccal mucosa for other inflammatory diseases, although this might be due to the location of the tissue (gingiva vs buccal mucosa). 2,4,6 In this regard, oral mucosa is affected in periodontal, allergic and celiac disease, among others; thus, a full characterization of neutrophil, Th2 and Treg response in the oral mucosa could serve as a powerful, accessible tool to understand local and systemic disease. Moreover, other cell populations, such as innate lymphoid cells, and the function of the many antigenpresenting cells of the human oral mucosa should be further investigated to understand their role when oral tolerance is lost.…”

Comparison of Microbial Populations in Saliva and Feces from Healthy and Celiac Adolescents with Conventional and Molecular Approaches after Cultivation on Gluten-Containing Media: An Exploratory Study

“…Inflammation in CD occurs due to abnormal immune responses after gluten intake in genetically susceptible individuals [1]. Microbiota from different intestinal tract niches and their metabolites can be associated with CD in several ways [2][3][4][5][6]. Salivary and fecal microbiota differ between CD patients and healthy controls [2][3][4]7]; however, no disease-specific microbial signatures have been described.…”