Circulating Zonulin Correlates with Density of Enteroviruses and Tolerogenic Dendritic Cells in the Small Bowel Mucosa of Celiac Disease Patients
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Impaired intestinal integrity, including increased permeability of the small bowel mucosa, has been shown in patients with celiac disease (CD) as well as with type 1 diabetes (T1D). Zonulin (ZO, pre-haptoglobin), a tight junction regulator, plays a particular role in the regulation of intestinal barrier function and in the pathogenesis of the above-mentioned diseases.
To investigate whether enteroviruses (EVs) and immunoregulatory cells are associated with intestinal permeability in patients with CD alone and with coexistent T1D.
Materials and Methods
Altogether 80 patients (mean age 10.68 ± 6.69 years) who had undergone small bowel biopsy were studied. Forty patients with functional dyspepsia and normal small bowel mucosa formed the control group. The circulating ZO level in sera was evaluated using ELISA. The densities of EV, FOXP3+ regulatory T cells (Tregs), indoleamine 2,3-dioxygenase (IDO+) dendritic cells (DCs) and glutamic acid dexarboxylase (GAD)65+ cells in small bowel mucosa were investigated by immunohistochemistry. The expression analysis of FOXP3, tight junction protein 1 (TJP1), gap junction (GJA1), IDO and CD103 genes was evaluated by real-time PCR.
The ZO level was higher in CD patients compared to subjects with a normal small bowel mucosa, particularly in those with Marsh IIIc atrophy (p = 0.01), and correlated with the density of EV (r = 0.63; p = 0.0003) and IDO+ DCs (r = 0.58; p = 0.01) in the small bowel mucosa. The density of GAD65+ epithelial cells was correlated with the density of EV (r = 0.59; p = 0.03) and IDO+ DCs (r = 0.78; p = 0.004) in CD patients. The relative expression of FOXP3 mRNA in the small bowel mucosa tissue was significantly higher in patients with CD, compared to subjects with a normal mucosa, and correlated with the density of EV (r = 0.62; p = 0.017) as well as with the relative expression of IDO mRNA (r = 0.54; p = 0.019).
The CD is associated with elevation of the circulating ZO level, the value of which correlates with the density of EV in CD patients with severe atrophic changes in the small bowel mucosa, particularly in cases of concomitant T1D. The CD is also characterized by the close relationship of the density of GAD65+ epithelial cells with the EV, ZO level and IDO+ DCs.
KeywordsZonulin Enteroviruses Indoleamine 2,3-dioxygenase (IDO+) dendritic cells GAD65 Small bowel mucosa Immunohistochemistry Celiac disease
We would like to thank Dr. Tiina Rägo from the Children’s Clinic of Tartu University Hospital, Tartu, for providing a part of the clinical material and Dr. Kaja Metsküla for performing the GAD65 Autoantibody ELISA assay. Mrs. Anu Kaldmaa from the Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, and Mrs. Merje Jakobson from the Department of Pathology, Tartu University Hospital are acknowledged for their assistance with the laboratory procedures.
This study was supported by Grants from the Estonian Research Foundation (No. 8334), by the EU Regional Developmental Fund and by Grants from the Estonian Ministry of Education and Research (SF 0180035s08 and IUT20-43).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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