关键词： inflammatory bowel disease   innate immunity   adaptive immunity   molecular targets   biologic therapies   Anti-TNF   Anti-integrins   inflammatory cytokines  

摘要： Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition causing inflammation of gastrointestinal and systemic cells, with an increasing prevalence worldwide. Many factors are known to trigger and maintain inflammation in IBD including the innate and adaptive immune systems, genetics, the gastrointestinal microbiome and several environmental factors. Our knowledge of the involvement of the immune system in the pathophysiology of IBD has advanced rapidly over the last two decades, leading to the development of several immune-targeted treatments with a biological source, known as biologic agents. The initial focus of these agents was directed against the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) leading to dramatic changes in the disease course for a proportion of patients with IBD. However, more recently, it has been shown that a significant proportion of patients do not respond to anti-TNF-alpha directed therapies, leading a shift to other inflammatory pathways and targets, including those of both the innate and adaptive immune systems, and targets linking both systems including anti-leukocyte trafficking agents-integrins and adhesion molecules. This review briefly describes the molecular basis of immune based gastrointestinal inflammation in IBD, and then describes how several current and future biologic agents work to manipulate these pathways, and their clinical success to date.

关键词： Biomarker   Biopsies   Crohn's disease   IBD genetics   Inflammatory bowel disease   Long non-coding RNAs   Plasma   Ulcerative colitis  

摘要： Inflammatory bowel diseases (IBDs) are multifactorial autoimmune diseases with growing prevalence but the interaction between genetic, environmental and immunologic factors in their development is complex and remains obscure. There is great need to understand their pathogenetic mechanisms and evolve diagnostic and therapeutic tools. Long non-coding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides that are known to interfere in gene regulation but their roles and functions have not yet been fully understood. While they are widely investigated in cancers, little is known about their contribution in other diseases. There is growing evidence that lncRNAs play critical role in regulation of immune system and that they interfere in the pathogenetic mechanisms of autoimmune diseases, like IBDs. Recent studies have identified lncRNAs in the proximity of IBD-associated genes and single nucleotide polymorphisms within IBD-associated lncRNAs as well. Furthermore, blood samples and pinch biopsies were also analyzed and a plethora of lncRNAs are found to be deregulated in Crohn's disease (CD), Ulcerative colitis (UC) or both. (Especially in UC samples the lncRNAs INFG-AS1 and BC012900 were found to be significantly up-regulated. Similarly, ANRIL, a 1ncRNA that nest different disease associated SNPs, is significantly down-regulated in inflamed IBD tissue.) This review aims at recording for the first time recent data about lncRNAs found to be deregulated in IBDs and discussing suggestive pathogenetic mechanisms and future use of lncRNAs as biomarkers. (C) 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

关键词： INTERLEUKIN-10   INFLAMMATORY bowel diseases   IMMUNODEFICIENCY   ULCERATIVE colitis   CROHN'S disease  

摘要： Inflammatory bowel disease (IBD) can be divided into Crohn disease, ulcerative colitis and inflammatory bowel disease unclassified (IBDU). In most patients, these disorders present in adolescence or early adulthood. Patients with infantile IBD can have an associated underlying immunodeficiency disorder caused by a mutation in interleukin (IL)-10 or its receptor. We describe a child presenting with intractable bloody diarrhoea since 2weeks of age and with severe nappy ulceration, who was ultimately diagnosed as having inflammatory bowel disease (IBD) due to an immunodeficiency in the IL-10 receptor. This report highlights the importance of considering this rare immunodeficiency in patients with infantile IBD presenting with severe perianal disease to a dermatologist.

关键词： Intestinal Diseases   Daily   Numerical controls   Gastrointestinal Tract   Abdominal Pain   Headache   Migraine Disorders   Pain  

摘要： BackgroundInflammatory bowel diseases (IBD) are systemic, chronic inflammatory conditions that predominately affect the gastrointestinal tract and can induce abdominal pain. Besides, many IBD patients complain about headaches in daily practice. The objective was to assess the prevalence of headaches, including migraines and pain with neuropathic characteristics (NC), in IBD patients compared to historical controls from the general population. MethodsOverall, 203 consecutive tertiary-care centre patients completed validated self-administered questionnaires and benefitted from a clinical evaluation performed by an IBD physician at the same time. ResultsIn our cohort, 75% of the patients experienced pain in the previous 3months. Migraine prevalence was two-fold higher in IBD patients compared to the general population (41% vs. 21.3%, p<0.001). Migraine was associated with a younger age, female gender and higher depression scores. Although migraine impact was very important for 30% of the patients (61/203), specific acute therapeutics were prescribed in only 22% of cases (18/83). Chronic pain with NC was more frequent than in the general population (11.3% vs. 6.9%, p=0.012) and was strongly associated with the presence of extra-intestinal manifestations (p<0.001). Abdominal pain concerned 19% of the patients during the previous week and was, as expected, associated with disease activity. ConclusionsMigraine prevalence is strongly increased in IBD patients followed in tertiary care. A systematic screening for migraine should be done by IBD physicians in daily practice to provide adequate therapeutics. Further studies are needed to confirm whether migraine should be classified as IBD extra-intestinal manifestations. SignificanceMigraine prevalence was two-fold higher in IBD patients compared to the general population, was generally poorly treated and a systematic screening for migraine should be done by IBD physicians in daily practice to provide adequate therapeutics.

关键词： Microscopic colitis   Lymphocytic colitis   Collagenous colitis   Inflammatory bowel disease   Lamina propria mononuclear cells   T lymphocytes   Mucosal immunity  

摘要： An association between microscopic colitis (MC), i.e., lymphocytic colitis (LC) and collagenous colitis (CC), and inflammatory bowel diseases (IBD) has been noticed. A subset of MC cases may evolve into IBD, and IBD in remission may present as MC in a histologic pattern. Moreover, MC and IBD may coexist in different regions of the bowel. A link between MC and IBD in their pathogenesis is, therefore, suggested. Abnormal mucosal immunity is likely the key. We reviewed 2324 MC cases in Calgary over 14 years and identified 20 cases evolved into IBD (IBD transformers). 13 of them were further investigated for colonic mucosal lamina propria mononuclear cells (LPMNCs), as opposed to 22 cases whose MC resolved. On their index colonic biopsy immunohistochemistry was performed to detect major T cell subsets characterized by key cytokines and master transcription factors (IFN gamma and T-bet for Th1/Tc1, GATA-3 for Th2/Tc2, IL-17 and RORc for Th17/Tc17, FoxP3 for Treg/Tcreg) as well as TNF alpha(+) cells (partly representing Th1). LPMNCs positive for each marker were counted (average number per high-power field). IBD transformers had increased IFN gamma(+), T-bet(+), TNF-alpha(+), and GATA-3(+) LPMNCs compared to the MC-resolved cases. The LC-to-IBD subgroup had increased IFN gamma(+) and GATA-3(+) cells compared to the LC-resolved subgroup. The CC-to-IBD subgroup had increased T-bet(+), TNF-alpha(+), and GATA-3(+) cells compared to the CC-resolved subgroup. Among MC-resolved patients, more TNF-alpha(+) and RORc(+) cells were seen in LC than in CC. Th1/Tc1- and TNF alpha-producing cells, and likely a subset of Th2/Tc2 cells as well, may be involved in the MC-to-IBD transformation.

关键词： Severe acute colitis   Inflammatory bowel disease   Biological therapy   Medical treatment   Subtotal colectomy  

摘要： The aim of medical treatment of severe acute colitis (SAC) complicating inflammatory bowel disease (IBD) is to avoid surgery, but in 20 to 50% of the cases, colectomy remains necessary. This study aimed to determine the impact of the different lines of medical therapy (i.e., steroids, anti-TNF, or ciclosporin) on postoperative course after laparoscopic subtotal colectomy for SAC complicating IBD. All the patients who underwent laparoscopic subtotal colectomy for SAC were included and divided into two groups: those who presented with postoperative morbidity (group A) and those with an uneventful postoperative course (group B). Preoperative physical, endoscopic and radiological data, and medical treatments were compared between groups. From 2006 to 2015, 65 consecutive patients (32 males, median age = 35 [17-87] years) operated for SAC were included. Postoperative morbidity occurred in 19 patients (29%, group A) and was mainly represented by surgical morbidity (n = 15), including ileus (n = 9), stoma-related complications (n = 5), and intra-abdominal abscess (n = 4). Lichtiger score, endoscopic and radiological evaluations were similar between groups. Patients with morbidity had more frequently presented two previous episodes of SAC (26%) than those without (7%, p = 0.04). Duration of anti-TNF treatment was more frequently longer than 2 months in group A (67%) than that in group B (14%, p = 0.04). No significant differences between groups were noted regarding other preoperative medical treatments and number of lines therapy. This study suggests that postoperative course after laparoscopic subtotal colectomy for SAC is affected by prolonged preoperative anti-TNF therapy, and in the case of recurrent SAC.

关键词： Computational biology and bioinformatics   Inflammatory bowel disease  

摘要： A major challenge in inflammatory bowel disease (IBD) is the integration of diverse IBD data sets to construct predictive models of IBD. We present a predictive model of the immune component of IBD that informs causal relationships among loci previously linked to IBD through genome-wide association studies (GWAS) using functional and regulatory annotations that relate to the cells, tissues, and pathophysiology of IBD. Our model consists of individual networks constructed using molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease. We performed key driver analysis to identify genes predicted to modulate network regulatory states associated with IBD, prioritizing and prospectively validating 12 of the top key drivers experimentally. This validated key driver set not only introduces new regulators of processes central to IBD but also provides the integrated circuits of genetic, molecular, and clinical traits that can be directly queried to interrogate and refine the regulatory framework defining IBD.