Keir, Mary

Abstract Targeting interactions between α4β7 integrin and endothelial adhesion molecule MAdCAM-1 to inhibit lymphocyte migration to the gastrointestinal tract is an effective therapy in inflammatory bowel disease (IBD). Following lymphocyte entry into the mucosa, a subset of these cells expresses αEβ7 integrin, which is expressed on proinflammatory lymphocytes, to increase cell retention. The factors governing lymphocyte migration into the intestinal mucosa and αE integrin expression in healthy subjects and IBD patients remain incompletely understood. We evaluated changes in factors involved in lymphocyte migration and differentiation within tissues. Both ileal and colonic tissue from active IBD patients showed upregulation of ICAM-1, VCAM-1, and MAdCAM-1 at the gene and protein levels compared with healthy subjects and/or inactive IBD patients. β1 and β7 integrin expression on circulating lymphocytes was similar across groups. TGF-β1 treatment induced expression of αE on both β7+ and β7− T cells, suggesting that cells entering the mucosa independently of MAdCAM-1/α4β7 can become αEβ7+. ITGAE gene polymorphisms did not alter protein induction following TGF-β1 stimulation. Increased phospho-SMAD3, which is directly downstream of TGF-β, and increased TGF-β–responsive gene expression were observed in the colonic mucosa of IBD patients. Finally, in vitro stimulation experiments showed that baseline β7 expression had little effect on cytokine, chemokine, transcription factor, and effector molecule gene expression in αE+ and αE− T cells. These findings suggest cell migration to the gut mucosa may be altered in IBD and α4β7−, and α4β7+ T cells may upregulate αEβ7 in response to TGF-β once within the gut mucosa.

Objective Both endoscopy and histology may be included in the definition of mucosal healing in UC. This study aimed to establish the association between patient-reported outcomes, specifically symptom measures, and the presence of inflammation as measured by endoscopy and histology in UC. Design Using patient data from an observational multicentre study of UC (n=103), rectal bleeding (RB) and stool frequency (SF) symptom subscores of the Mayo Clinic Score (MCS) were compared with the endoscopic subscore (MCSe) and histology. Faecal calprotectin and biopsy cytokine expression were also evaluated. Results When identifying UC patients with inactive disease, RB scores were superior to SF scores and the combination (sensitivity/specificity: MCSe=0/1, RB 77%/81%, SF 62%/95%, RB+SF 54%/95%; MCSe=0, RB 87%/66%, SF 76%/83%, RB+SF 68%/86%). Across different definitions of mucosal healing (MCSe≤1; 0; or 0 plus inactive histology), a larger subset of patients reported increased SF (39%, 25% and 27%, respectively) compared with RB (24%, 13% and 10%). Faecal calprotectin and inflammatory cytokine expression were higher in patients with active disease compared with patients with mucosal healing, but there were no differences between patients using increasingly stringent definitions of mucosal healing. Conclusions Endoscopically inactive disease is associated with absence of RB but not with complete normalisation of SF. Achieving histological remission did not improve symptomatic relief. In addition, in these patients, higher inflammatory biomarker levels were not observed. These data suggest that non-inflammatory changes, such as bowel damage, may contribute to SF in UC.