CD3+CD4+LAP+Foxp3-regulatory cells of the colonic lamina propria limit disease extension in ulcerative colitis

Background and Aims: In ulcerative colitis (UC), inflammation begins in the rectum and can extend proximally throughout the entire colon. The extension of inflammation is an important determinant of disease course, and may be limited by the action of regulatory T cells (Tregs). In this cross-sectional study, we evaluated the relationship between UC extension and the proportions of CD3+CD4+Foxp3+ and CD3+CD4+LAP+Foxp3- Tregs in the colonic lamina propria (LP) of 79 UC patients and 29 controls. The role of these cells in UC extension was also investigated in the murine oxazolone-induced colitis model. Methods: Patients: Disease extension was classified according to the Montreal classification. Where possible, endoscopic biopsies of involved and uninvolved tissue were obtained from UC patients. Mouse model: Colitis was induced by intrarectal oxazolone administration. Lamina propria mononuclear cells were isolated from patient biopsies and mouse colon tissue using enzymatic method and the percentage of CD3+CD4+Foxp3+ and CD3+CD4+LAP+Foxp3-cells evaluated by immunofluorescence. Confocal microscopy was applied for the visualization and quantification of CD4+LAP+ cells on tissue histological sections. Results: In UC patients with distal colitis the proportion of LP CD3+CD4+Foxp3+ Tregs was significantly higher in inflamed tissue than uninvolved tissue. As opposite, the proportion of LP CD3+CD4+LAP+ Tregs was significantly higher in uninvolved tissue than involved tissue. Both LP CD3+CD4+Foxp3+ and LP CD3+CD4+LAP+ Tregs proportion in involved tissue was significantly higher than in controls irrespective of the extension of inflammation. In mice with oxazolone-induced distal colitis, treatment with LAP-depleting antibody was associated with the development of extensive colitis. Conclusions: Our findings suggest that CD3+CD4+LAP+Foxp3-Tregs limit the extension of inflammatory lesions in UC patients

IL-13 mRNA tissue content identifies two subsets of adult ulcerative colitis patients with different clinical and mucosa-associated microbiota profiles

BACKGROUND AND AIM: A personalized approach to therapy has great promise to improve disease outcomes. To this end, the identification of different subsets of patients according with the prevalent pathogenic process might guide in the choice of therapeutic strategy. We hypothesize that UC patients might be stratified according to distinctive cytokine profiles and/or to a specific mucosa-associated microbiota. METHODS: In a cohort of clinically and endoscopic active UC patients and controls, we analyzed by qPCR the mucosal cytokine mRNA content and the mucosa-associated microbiota composition assessed by the 16SrRNA gene sequencing. RESULTS: We demonstrate, by means of data-driven approach, the existence of a specific UC patient subgroup characterized by elevated IL-13mRNA tissue content separated by patients with low IL-13 mRNA tissue content. The two subsets differ in clinical-pathological characteristics. High IL-13mRNA patients are younger at diagnosis and show higher prevalence of extensive colitis than low IL-13mRNA ones. They also show a more frequent use of steroid/immunosuppressant/anti-TNFα therapy during a one-year follow-up. The two subgroups show a differential enrichment of mucosa associated microbiota genera with prevalence of Prevotella in patients with high IL-13mRNA tissue content and Sutterella and Acidaminococcus in patients with low IL-13mRNA tissue content. CONCLUSION: Assessment of mucosal IL-13mRNA might help in the identification of the patients' subgroup that might benefit from a therapeutic approach modulating IL-13

Biological therapy for dermatological manifestations of inflammatory bowel disease.

Ulcerative colitis and Crohn’s disease are the best known forms of inflammatory bowel disease (IBD) and are considered immune-mediated disorders of unknown etiology that primarily affect the gastrointestinal tract. In addition, other organ systems can be involved, such as skin. Erythema nodosum, pyoderma gangrenosum and psoriasis are the dermatological comorbidities often associated with it. The anti-tumor necrosis factor (TNF)-α drugs (infliximab and adalimumab) have significantly changed the management of these conditions. In this brief review, we provide an overview on the prevalence and clinical aspects of the more commonly reported skin manifestations of IBD and the role of TNF-α inhibitors in their treatment

Involvement of interleukin-15 and interleukin-21, two γ-chain-related cytokines, in celiac disease

Celiac disease (CD), an enteropathy caused by dietary gluten in genetically susceptible individuals, is histologically characterized by villous atrophy, crypt cell hyperplasia, and increased number of intra-epithelial lymphocytes. The nature of CD pathogenesis remains unclear, but recent evidence indicates that both innate and adaptive immune responses are necessary for the phenotypic expression and pathologic changes characteristic of CD. Extensive studies of molecules produced by immune cells in the gut of CD patients have led to identification of two cytokines, namely interleukin (IL)-15 and IL-21, which are thought to play a major role in orchestrating the mucosal inflammatory response in CD. Here we review the current knowledge of the expression and function of IL-15 and IL-21 in CD

Interleukin-25 fails to activate STAT6 and induce alternatively activated macrophages

Interleukin-25 (IL-25), a T helper type 2 (Th2) -related factor, inhibits the production of inflammatory cytokines by monocytes/macrophages. Since Th2 cytokines antagonize classically activated monocytes/macrophages by inducing alternatively activated macrophages (AAMs), we here assessed the effect of IL-25 on the alternative activation of human monocytes/macrophages. The interleukins IL-25, IL-4 and IL-13 were effective in reducing the expression of inflammatory chemokines in monocytes. This effect was paralleled by induction of AAMs in cultures added with IL-4 or IL-13 but not with IL-25, regardless of whether cells were stimulated with lipopolysaccharide or interferon-γ. Moreover, pre-incubation of cells with IL-25 did not alter the ability of both IL-4 and IL-13 to induce AAMs. Both IL-4 and IL-13 activated signal transducer and activator of transcription 6 (STAT6), and silencing of this transcription factor markedly reduced the IL-4/IL-13-driven induction of AAMs. In contrast, IL-25 failed to trigger STAT6 activation. Among Th2 cytokines, only IL-25 and IL-10 were able to activate p38 mitogen-activated protein kinase. These results collectively indicate that IL-25 fails to induce AAMs and that Th2-type cytokines suppress inflammatory responses in human monocytes by activating different intracellular signalling pathways

Extraintestinal manifestations in a large series of Italian inflammatory bowel disease patients

AIM: To investigate prevalence, type and time of onset of extraintestinal manifestations (EIMs) in a series of Italian inflammatory bowel disease (IBD) patients. METHODS: Data of 811 IBD consecutive patients, first referred to our Centre from 2000 to 2011, were retrospectively evaluated. RESULTS: Eight hundred and eleven IBD patients (437 M, 374 F) were studied: 595 ulcerative colitis (UC) (73.4%) and 216 Crohn's disease (CD) (26.6%). Among these, 329 (40.6%) showed EIMs: 210 UC (35.3%) and 119 CD (55.1%) (P < 0.0001). Considering the time of the diagnosis of IBD, 37 EIMs (11.2%) were developed before, 229 (69.6%) after and 63 (19.2%) were simultaneous. The type of EIM were as follows: 240 musculoskeletal (29.6%), in 72 CD patients and in 168 UC (P < 0.0001); 47 mucocutaneous (5.8%), in 26 CD and in 21 UC (P = 0.0049); 26 ocular (3.2%), in 16 CD and in 10 UC (CD 7.4% vs UC 1.7%, P = 0.0093); 6 hepatobiliary (0.8%); 10 endocrinological (1.2%). In particular, with regards to the involvement of the musculoskeletal system, arthritis Type 1 was found in 41 CD (19%) and in 61 UC (10.2%) (P = 0.0012) and Type 2 in 25 CD (11.6%) and in 100 UC (16.8%) (P = 0.0012). CONCLUSION: Mucocutaneous manifestations, arthritis Type 1 and uveitis were significantly more frequent in CD than UC. The complications of the musculoskeletal system were the mostly observed ones, often with symptoms more severe than intestinal ones, confirming the need for close cooperation with rheumatologists