Lower Expression of Tight Junction Protein 1 Gene and Increased FOXP3 Expression in the Small Bowel Mucosa in Coeliac Disease and Associated Type 1 Diabetes Mellitus

Abstract

Background: The role of regulatory T cells expressing FOXP3 in the pathogenesis of coeliac disease (CD) and type 1 diabetes (T1D) has been reported. Recent data have placed special focus on the interplay between the intestinal barrier and immunoregulatory processes. We aimed to determine whether the expression of tight junction protein 1 (TJP1), which reflects small bowel mucosa permeability, is changed in CD and T1D. Methods: Transcription levels of TJP1 and FOXP3 genes were evaluated in the small bowel biopsies of 14 children with CD, 12 with CD and coexisting T1D and 40 controls using real-time PCR. Serum IgA and IgG to deamidated gliadin, bovine β-lactoglobulin, bovine α-casein and human tissue transglutaminase (tTG) were determined by ELISA. Results: The highest expression of FOXP3 mRNA was seen in patients with CD and T1D compared to patients with CD alone and controls (p = 0.02). In contrast, the lowest level of TJP1 mRNA expression was found in patients with CD and T1D (p = 0.01). The levels of IgA to deamidated gliadin and tTG were highest in patients with CD and T1D (p = 0.0001 and 0.01, respectively). The expression of FOXP3 mRNA correlated highly with the level of anti-gliadin IgA (p = 0.02) and anti-tTG IgA antibodies (p = 0.004). Conclusion: The significant decline in TJP1 expression in CD patients, particularly in those with coexisting T1D, was accompanied by an increase in FOXP3 expression. This might reflect an attempt to maintain immune tolerance to counterbalance the loss of mucosal integrity in the small intestine in CD associated with T1D.

Studies of Mucosal Immune Regulation in Celiac Disease and Type 1 Diabetes

“…Children with concomitant T1D and CD have previously been reported to express high levels of IL-1, IL-2, IL-4, IFN-, TNF- FOXP3 [181,197,257,364,390]. This is in contrast to our findings, where Swedish children with both T1D and CD seemed to express similar levels of IL-2, FOXP3 and IL-21 as reference children (unpublished results, data not shown).…”

“…IFN- has been shown to disrupt epithelial barrier function by decreasing the levels of the tight junction protein TJP1, also known as zonula occludence protein ZO-1 (reviewed in [362]) [363]. This is supported by studies showing low expression of ZO-1 in untreated CD patients [359,364,365] and particularly in those with concomitant CD and T1D [364]. It have been reported that treatment with a GFD improved and in some cases normalized the TJP1 (ZO-1) levels [365,366].…”

IgG anti-tTG responses in different autoimmune conditions differ in their epitope targets and subclass usage

“…An interesting observation is the similarity in the IgG anti-tTG subclass usage profile between CD and T1DM, two diseases thought to share common pathogenic features such as impaired intestinal mucosal integrity (de Kort et al, 2011), and a shared genetic background (Vorobjova et al, 2011). Certainly the signature antibody responses in both conditions are predominantly IgG1; anti-GAD and IA-2 in T1DM (Bonifacio et al, 1999;Hawa et al, 2000) and anti-tTG and gliadin in CD (Hvatum et al, 1992).…”

Children diagnosed with both Type 1 diabetes and Celiac disease - An Immunological challenge

“…Further, the density of FoxP3 + cells are also correlate with histological grade of atrophic changes in the small bowel [136] . Upregulated FoxP3 expression may counterbalance the loss of mucosal integrity by maintaining immune tolerance in the small intestine of patient with both celiac disease and T1D [137] . Contrary, a low expression of the tight junction protein 1 (TJP1) serving as a marker of intestinal mucosa integrity has been found in patients with both T1D and celiac disease [136,138] .…”