P194 Characterization of Protein Disulfide Isomerases in adult and pediatric Crohn’s Disease and association with inflammation and fibrosis
Bequet, E.(1)*;Salée, C.(2);Bletard, N.(3);Vieujean, S.(4);Massot, C.(5);Fonzé, F.(2);Sarter, H.(6);Ley, D.(7);Colinet, S.(8);Delvenne, P.(3);Seghaye, M.C.(9);Louis, E.(4);Meuwis, M.A.(2);
(1)CHU - CHR Liège, Pediatric and Hepato-Gastroenterology Departments, Liège, Belgium;(2)CHU Liège, Translational Gastroenterology laboratory- GIGA institute, Liège, Belgium;(3)CHU Liège, Pathological Anatomy and Cytology Laboratory, Liège, Belgium;(4)CHU Liège, Hepato-Gastroenterology and Digestive Oncology Department, Liège, Belgium;(5)CHU Liège, Translational Gastroenterology laboratory- GIGA Insittute, Liège, Belgium;(6)CHU Lille, Institute for Translational Research in Inflammation Infinite, Lille, France;(7)CHU Lille, Pediatric Gastroenterology Department, Lille, France;(8)CHC MontLégia, Pediatrics, Liège, Belgium;(9)CHU Liège, Pediatric Department, Liège, Belgium; with the participation of EPIMAD group
Evolution of Crohn's disease (CD) is often marked by fibrostenotic complications and available biotherapies cannot prevent or treat intestinal fibrosis. The pathophysiological mechanisms of intestinal fibrosis are multiple and poorly understood. The intestinal epithelium probably plays a key role. The endoplasmic reticulum stress (ERS) is involved in the pathophysiology of IBD and in fibrosis. Protein disulfide isomerases (PDIs) take part in the ER stress response, but their precise roles and associations with CD remain poorly characterized. We investigated the distribution of selected PDIs within the ileum and colon of adult and pediatric patients with inflammatory or stenosing CD.
Tissues from 72 pediatric and 47 adult CDs, and 26 pediatric and 48 adult patients without IBD were included from 4 tertiary hospitals. The degree of fibrosis and inflammatory infiltrate were evaluated. The distribution of 4 PDIs (AGR2, BiP, PDIA6, ERP44) within the tissues was studied by immunohistochemistry (IHC) using a semiquantitative scoring scale (0 to 4). Statistical tests used were ANOVA or Kruskal-Wallis (with post hoc test), T-Student and Mann-Whitney.
The clinical characteristics of the patients included are described in Table 1. The PDIs provide an IHC signal which was mainly epithelial. The distribution of PDIs differed according to the segment studied (colon or ileum), the age of CD onset, location in the epithelium (surface, median crypt, or bottom of crypt), and the normal, inflammatory, and/or fibrotic features of the tissues. In the ileum of adult and pediatric CDs, the distribution of AGR2 was significantly higher in the epithelium adjacent to fibro-inflammatory tissues (p<0.01). In pediatric cases, AGR2 increased significantly with the fibrosis grade within the surface epithelium of the ileum (Fig. 1). The distributions of the other PDIs (BiP, ERP44 and PDIA6) were rather influenced by the inflammatory infiltrates and varied in adult and pediatric CD. The distribution of BiP was significantly higher in tissues with acute and/or chronic inflammation and independent from fibrosis. In adults, the distribution of PDIA6 in the colonic epithelium was significantly higher in CD cases compared to non-CD cases.
Our results suggest that the studied PDIs may have different roles in the ERS response within the intestinal epithelium in adult and pediatric CD. These PDIs need to be functionally explored further to better understand their specific involvement in inflammation and fibrosis in CD. The increase of AGR2 in fibro-inflammatory tissues, not observed with other PDIs, suggests a specific link between AGR2 and intestinal fibrosis.