title: Increased density of tolerogenic dendritic cells in the small bowel mucosa of celiac patients.
abstract: OBJECTIVE
  To investigate the densities of dendritic cells (DCs) and FOXP3(+) regulatory T cells (Tregs) and their interrelations in the small bowel mucosa in untreated celiac disease (CD) patients with and without type 1 diabetes (T1D).
  
  
  METHODS
  Seventy-four patients (45 female, 29 male, mean age 11.1 ± 6.8 years) who underwent small bowel biopsy were studied. CD without T1D was diagnosed in 18 patients, and CD with T1D was diagnosed in 15 patients. Normal small bowel mucosa was found in two T1D patients. Thirty-nine patients (mean age 12.8 ± 4.9 years) with other diagnoses (functional dyspepsia, duodenal ulcer, erosive gastritis, etc.) formed the control group. All CD patients had partial or subtotal villous atrophy according to the Marsh classification: Marsh grade IIIa in 9, grade IIIb in 21 and grade IIIc in 3 cases. Thirty-nine patients without CD and 2 with T1D had normal small bowel mucosa (Marsh grade 0). The densities of CD11c(+), IDO(+), CD103(+), Langerin (CD207(+)) DCs and FOXP3(+) Tregs were investigated by immunohistochemistry (on paraffin-embedded specimens) and immunofluorescence (on cryostat sections) methods using a combination of mono- and double-staining. Sixty-six serum samples were tested for IgA-tissue transglutaminase (tTG) using a fully automated EliA™ Celikey(®) IgA assay (Pharmacia Diagnostics, Freiburg, Germany).
  
  
  RESULTS
  The density of CD11c(+) DCs was significantly increased in CD patients compared with patients with normal mucosa (21.67 ± 2.49 vs 13.58 ± 1.51, P = 0.007). The numbers of FOXP3(+) cells were significantly higher in CD patients (10.66 ± 1.50 vs 1.92 ± 0.37, P = 0.0002) and in patients with CD and coexisting T1D (8.11 ± 1.64 vs 1.92 ± 0.37, P = 0.002) compared with patients with normal mucosa. The density of FOXP3(+) cells significantly correlated with the histological grade of atrophic changes in the small bowel mucosa according to the March classification (r = 0.62; P < 0.0001) and with levels of IgA antibody (r = 0.55; P < 0.0001). The densities of IDO(+) DCs were significantly higher in CD patients (21.6 ± 2.67 vs 6.26 ± 0.84, P = 0.00003) and in patients with CD and coexisting T1D (19.08 ± 3.61 vs 6.26 ± 0.84, P = 0.004) compared with patients with normal mucosa. A significant correlation was identified between the densities of IDO(+) DCs and FOXP3(+) T cells (r = 0.76; P = 0.0001). The mean values of CD103(+) DCs were significantly higher in CD patients (10.66 ± 1.53 vs 6.34 ± 0.61, P = 0.01) and in patients with CD and associated T1D (11.13 ± 0.72 vs 6.34 ± 0.61, P = 0.00002) compared with subjects with normal small bowel mucosa. The mean value of Langerin(+) DCs was higher in CD patients compared with persons with normal mucosa (7.4 ± 0.92 vs 5.64 ± 0.46, P = 0.04).
  
  
  CONCLUSIONS
  The participation of diverse DC subsets in the pathological processes of CD and the possible involvement of tolerogenic DCs in Tregs development to maintain intestinal immunological tolerance in CD patients are revealed.
authors.affiliation: Tamara Vorobjova, Raivo Uibo, Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, 51014 Tartu, Estonia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Vorobjova
authors.affiliation: Tamara Vorobjova, Raivo Uibo, Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, 51014 Tartu, Estonia.
authors.forename: Oivi
authors.initials: O
authors.lastname: Uibo
authors.affiliation: Tamara Vorobjova, Raivo Uibo, Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, 51014 Tartu, Estonia.
authors.forename: Kaire
authors.initials: K
authors.lastname: Heilman
authors.affiliation: Tamara Vorobjova, Raivo Uibo, Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, 51014 Tartu, Estonia.
authors.forename: Raivo
authors.initials: R
authors.lastname: Uibo
mesh_terms: D000293:Adolescent; D001284:Atrophy; D001323:Autoantibodies / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D016022:Case-Control Studies; D002446:Celiac Disease / Q000097:blood / Q000175:diagnosis / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000276:immunology; D016099:Endoscopy, Gastrointestinal; D005260:Female; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000097:blood; D007150:Immunohistochemistry; D007223:Infant; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D007421:Intestine, Small / Q000276:immunology* / Q000473:pathology; D008297:Male; D011237:Predictive Value of Tests; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D011503:Transglutaminases / Q000276:immunology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D007070:Immunoglobulin A; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: CD11c+, CD103+, IDO+, Langerin (CD207+) dendritic cells; Celiac disease; Children; FOXP3+ regulatory T cells; Immunofluorescence; Immunohistochemistry; Small bowel mucosa; Type 1 diabetes