Celiac Disease in Children, Particularly with Accompanying Type 1 Diabetes, Is Characterized by Substantial Changes in the Blood Cytokine Balance, Which May Reflect Inflammatory Processes in the Small Intestinal Mucosa

Abstract

Cytokines play a pivotal role in the maintenance of intestinal homeostasis inducing pro- or anti-inflammatory response and mucosal barrier function in celiac disease (CD) and type 1 diabetes (T1D). We aimed to compare the levels of pro- and anti-inflammatory cytokines in CD patients without and with coexisting T1D, as well as to evaluate its association with the presence of enteroviruses (EV), regulatory T cells (Tregs), and dendritic cells (DCs) in small bowel mucosa. Altogether, 72 patients (median age 10.1 years) who had undergone small bowel biopsy were studied. The study group consisted of 24 patients with CD (median age 6.5 years), 9 patients with CD and concomitant T1D (median age 7.0 years), two patients with T1D (median age 8.5 years), and 37 patients (median age 14.0 years) with functional gastrointestinal disorders (FGD) and a normal small bowel mucosa as controls. The levels of 33 cytokines in serum were measured by multiple analysis using the Milliplex® MAP Magnetic Bead assay. The densities of FOXP3+ Tregs, CD11c+ DC, indoleamine 2,3-dioxygenase+ (IDO+) DC, langerin+ (CD207+) DCs, and EV were evaluated by immunohistochemistry as described in our previous studies. Circulating anti-EV IgA and IgG were evaluated using ELISA. The most important finding of the study is the significant increase of the serum levels of IL-5, IL-8, IL-13, IL-15, IL-17F, IL-22, IL-27, IP-10, MIP-1β, sIL-2Rα, sTNFRII, and TNFα in CD patients compared to controls and its correlation with the degree of small bowel mucosa damage graded according to the Marsh classification. The leptin level was higher in females in all study groups. The levels of IL-2, IL-6, IL-12 (P70), IL-15, IP-10, and IFNγ correlated significantly with the density of FOXP3+ Tregs in lamina propria of the small bowel mucosa, which supports the evidence about the signaling role of these cytokines in the peripheral maintenance of FOXP3+ Tregs. At the same time, a significant negative correlation occurred between the level of IL-4 and density of FOXP3+ Tregs in controls. Another important finding of our study was the correlation of IL-17F, IP-10, sTNFRII, MCP-1, and GM-CSF with the density of EV-positive cells in the lamina propria of the small bowel mucosa. Correlation of MIP-1 (CCL-4) with CD103+ DC and langerin+ DC densities may point to their significance in the recruitment of immune cells into the lamina propria and in driving the inflammatory response in CD patients. Our results suggest the predominance of Th1 and Th17 immune responses over EV VP1 protein in CD and T1D patients. The significant elevation of Th2 cytokines, like IL-5 and IL-13, but not IL-4, in CD patients and its correlation with the degree of small bowel mucosa damage could reflect the role of these cytokines in gut defense and inflammation.

Effects of Probiotic Bacteria Lactobacillaceae on the Gut Microbiota in Children With Celiac Disease Autoimmunity: A Placebo-Controlled and Randomized Clinical Trial

“…Prevotella is a genus in the phyla Bacteroides, whose concentration has found to be correlated with inflammation. Interestingly, celiac disease has been proposed to be driven by a Th-17 immune response (26), and Prevotella species have induced a similar response in autoimmune arthritis (25).…”

Prevotella Induces the Production of Th17 Cells in the Colon of Mice

“…Then, the serum was removed and assayed on a multiplex LUMINEX xMAP MAGPIX instrument (Millipore Corporation). Antibody beads, controls, wash buffer, serum matrix, and standards were prepared for the MILLIPLEX® MAP Kit Mouse Th17 Magnetic Bead Panel (Millipore Corporation) following the manufacturer's instructions [ 28 ]. Concentrations of eight cytokines (IL-6, TNF- α , IL-1 β , IL-17A, IL-10, IL-4, IFN- γ , and IL-2) were detected using the Mouse Th17 Magnetic Bead Panel according to its instructions.…”

Effects of In Vivo Gluten Challenge on PBMC Gene Expression Profiles in Diet Treated Celiac Disease

“…Of the pathways that were predicted to be activated among DEGs induced by gluten exposure (challenged CD versus unchallenged CD, and challenged CD versus challenged HC analyses, Figure S2B), Role of IL-17F in Allergic Inflammatory Airway Diseases was interesting. IL-17F was recently shown to be increased in CD patient serum, and was found to correlate with the density of enteroviruses (EV)-positive cells in the lamina propria of CD patients (30). Its enrichment following gluten exposure and predicted activation could indicate its increased inflammatory activity in CD, especially in the presence of possible active or historic microbial infection.…”