High endothelial venules associated with T cell subsets in the inflamed gut of newly diagnosed inflammatory bowel disease patients

• Published in: Clinical and experimental immunology Vol. 188; no. 1; pp. 163 - 173
• Main Authors: Horjus Talabur Horje, C. S., Smids, C., Meijer, J. W. R., Groenen, M. J., Rijnders, M. K., van Lochem, E. G., Wahab, P. J.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-04-2017; John Wiley and Sons Inc
• Subjects: Adult; Biomarkers; Case-Control Studies; Female; Follow-Up Studies; Hepeviridae; high endothelial venules; Humans; Immunophenotyping; inflammatory bowel disease; Inflammatory Bowel Diseases - diagnosis; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - metabolism; Intestinal Mucosa - blood supply; Intestinal Mucosa - pathology; Lymphocyte Count; lymphocyte homing; Male; Neovascularization, Pathologic; Original; Phenotype; T lymphocytes; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; tertiary lymphoid organ; Venules - pathology; Young Adult; T lymphocytes; tertiary lymphoid organ; inflammatory bowel disease; lymphocyte homing; high endothelial venules
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.12918

Summary
Naive and central memory T lymphocytes (TN and TCM) can infiltrate the inflamed gut mucosa in inflammatory bowel disease (IBD) patients. Homing of these subsets to the gut might be explained by ectopic formation of tertiary lymphoid organs (TLOs), containing high endothelial venules (HEVs). We aimed to evaluate the presence of HEVs and TLOs in inflamed intestinal mucosa of newly diagnosed, untreated IBD patients in relation to the presence of TN and TCM lymphocytes. IBD patients (n = 39) and healthy controls (n = 8) were included prospectively. Biopsy samples of inflamed and normal intestine, respectively, were analysed by immunohistochemistry for lymphocytes (CD3/CD20), blood vessels (CD31) and peripheral lymph node addressin (PNAd) expression (MECA‐79). TN and TCM lymphocyte subsets were identified by flow cytometric immunophenotyping. A higher number of HEVs was found in the inflamed colon of patients with ulcerative colitis [median 3·05 HEV/mm2; interquartile range (IQR) = 0–6·39] and ileum of Crohn's disease patients (1·40; 0‐4·34) compared to healthy controls (both 0; P = 0·033). A high density of colonic HEVs (HEVhigh) was associated with increased infiltration of TN and TCM in the inflamed gut (median 87%; IQR = 82–93% of T cell population), compared to HEVlow patients (58%; 38–81%; P = 0·003). The number of colonic follicles was higher in HEVhigh patients (median 0·54/mm2; IQR 0·28–0·84) compared to HEVlow patients (0·25/mm2; 0·08–0·45; P = 0·031) and controls (0·31/mm2; 0·23–0·45; P = 0·043). Increased homing of TN and TCM lymphocytes to inflamed gut tissue in IBD patients might be facilitated by ectopic formation of extrafollicular HEVs and TLOs in a subgroup of patients.
In conclusion, higher numbers of extrafollicular HEVs were demonstrated in IBD patients compared to healthy controls. Increased density of extrafollicular HEVs and TLOs in IBD patients was strongly associated with mucosal infiltration of TN+TCM lymphocytes, while low density of HEVs correlated with higher numbers of mucosal TEM cells. This suggests that the homing of TN and TCM lymphocytes to non‐lymphoid gut tissue in IBD patients might be facilitated by extrafollicular HEVs and de novo TLO formation.