Inflammatory bowel disease (IBD), encompassing Crohn’s disease and ulcerative colitis, is a chronic intestinal inflammatory disorder characterized by diffuse accumulation of lymphocytes in the gut ...mucosa as a consequence of over-expression of endothelial adhesion molecules. The infiltrating lymphocytes have been identified as subsets of T cells, including T helper (Th)1 cells, Th17 cells, and regulatory T cells. The function of these lymphocyte subpopulations in the development of IBD is well-known, since they produce a number of pro-inflammatory cytokines, such as interferon-γ and interleukin-17A, which in turn activate mucosal proteases, thus leading to the development of intestinal lesions, i.e., ulcers, fistulas, abscesses, and strictures. However, the immune mechanisms underlying IBD are not yet fully understood, and knowledge about the function of newly discovered lymphocytes, including Th9 cells, innate lymphoid cells, mucosal-associated invariant T cells, and natural killer T cells, might add new pieces to the complex puzzle of IBD pathogenesis. This review summarizes the recent advances in the understanding of the role of mucosal lymphocytes in chronic intestinal inflammation and deals with the therapeutic potential of lymphocyte-targeting drugs in IBD patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Celiac disease is a chronic small bowel disorder caused by an abnormal immune response to an array of epitopes of wheat gluten and related proteins of rye and barley in genetically ...susceptible individuals who express the HLA-DQ2/-DQ8 haplotype. Gluten peptides are efficiently presented by celiac disease-specific HLA-DQ2- and HLA-DQ8-positive antigen presenting cells to CD4+ T-cells that, once activated, drive a T helper cell type 1 response leading to the development of the typical celiac lesion-villous atrophy, crypt hyperplasia and intraepithelial and lamina propria infiltration of inflammatory cells. Tissue transglutaminase (tTG) is a calcium dependent ubiquitous enzyme which catalyses posttranslational modification of proteins and is released from cells during inflammation. tTG is suggested to exert at least two crucial roles in celiac disease: as a deamidating enzyme, that can enhance the immunostimulatory effect of gluten, and as a target autoantigen in the immune response. Since glutamine-rich gliadin peptides are excellent substrates for tTG, and the resulting deamidated and thus negatively charged peptides have much higher affinity for the HLA-DQ2 and HLA-DQ8 molecules, the action of tTG is believed to be a key step in the pathogenesis of celiac disease. This review is focused on the function of tTG in celiac disease, although it also deals with novel advances in tTG-based therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The progressively growing knowledge of the pathophysiology of a number of immune-mediated gastrointestinal and liver disorders, including autoimmune atrophic gastritis, coeliac disease, autoimmune ...enteropathy, inflammatory bowel disease, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis and autoimmune pancreatitis, together with the improvement of their detection methods have increased the diagnostic power of serum antibodies. In some cases – coeliac disease and autoimmune atrophic gastritis – they have radically changed gastroenterologists’ diagnostic ability, while in others – autoimmune hepatitis, inflammatory bowel disease and autoimmune pancreatitis – their diagnostic performance is still inadequate. Of note, serum antibody misuse in clinical practice has raised a number of controversies, which may generate confusion in the diagnostic management of the aforementioned disorders. In this review, we critically re-evaluate the usefulness of serum antibodies as biomarkers of immune-mediated gastrointestinal and liver disorders, and discuss their pitfalls and merits.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
IL‐13 has been implicated in the pathogenesis of ulcerative colitis (UC), and may have a role in animal models of gut fibrosis. We studied the involvement of IL‐13 in inflammation and fibrosis in UC ...and Crohn's disease (CD). Intestinal biopsies and anti‐CD3/CD28‐ or anti‐CD2/CD28‐stimulated lamina propria mononuclear cells from UC and CD patients and control subjects were cultured, and IL‐13, IL‐4, IL‐5, IL‐17A and IFN‐γ production was measured. Mucosal IL‐13‐producing cells were characterised by flow cytometry. Gut explants from strictured CD, non‐strictured CD and healthy donors were cultured ex vivo, and secreted IL‐13, IL‐1β and collagen were measured. IL‐13 production by mucosal explants and activated lamina propria mononuclear cells did not differ between CD, UC and control subjects, and was at least a log lower than IFN‐γ and IL‐17A. IL‐13‐producing cells, and in particular natural killer T cells, were uniformly low in all groups. IL‐4 and IL‐5 were undetectable in culture supernatants. Explants of CD strictures produced low amounts of IL‐13, whereas IL‐1β and collagen were elevated. We could not confirm that UC or strictured CD are associated with elevated IL‐13 production. These data suggest that an anti‐IL‐13 Ab would not be an appropriate therapeutic strategy in inflammatory bowel disease.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In the last decades, Endoscopic ultrasound (EUS) has rapidly grown and evolved from being mainly a diagnostic procedure, to being an interventional and therapeutic tool in several pathological ...clinical scenarios. With the progressive growth in technical expertise and dedicated devices, interventional endoscopic ultrasound procedures (IEUSP) have shown high rates of technical and clinical success, together with a relatively safe profile. However, the description and the standardization of different and specific types of adverse events (AEs) are still scarce in literature, and, consequently, even less the management of AEs. The aim of this study is to critical review and to describe AEs related to each of the main IEUSP, and to provide an overview on the possible management strategies of endoscopic complications. Future studies and guidelines are surely required to reach a better standardization of different AEs and their best management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Intestinal fibrosis with stricture formation is a complication of CD (Crohn's disease) that may mandate surgical resection. Accurate biomarkers that reflect the relative contribution of fibrosis to ...an individual stricture are an unmet need in managing patients with CD. The miRNA-29 (miR-29) family has been implicated in cardiac, hepatic and pulmonary fibrosis. In the present study, we investigated the expression of miR-29a, miR-29b and miR-29c in mucosa overlying a stricture in CD patients (SCD) paired with mucosa from non-strictured areas (NSCD). There was significant down-regulation of the miR-29 family in mucosa overlying SCD compared with mucosa overlying NSCD. miR-29b showed the largest fold-decrease and was selected for functional analysis. Overexpression of miR-29b in CD fibroblasts led to a down-regulation of collagen I and III transcripts and collagen III protein, but did not alter MMP (matrix metalloproteinase)-3, MMP-12 and TIMP (tissue inhibitor of metalloproteinase)-1 production. TGF (transforming growth factor)-β1 up-regulated collagen I and III transcripts and collagen III protein as a consequence of the down-regulation of miR-29b, and TGF-β1-induced collagen expression was reversed by exogenous overexpression of miR-29b. Furthermore, serum levels of miR-29 were lower in patients with stricturing disease compared with those without. These findings implicate the miR-29 family in the pathogenesis of intestinal fibrosis in CD and provide impetus for the further evaluation of the miR-29 family as biomarkers.
Pancreatic fluid collections (PFCs) are well-known complications of acute pancreatitis. The overinfection of these collections leads to a worsening of the prognosis with an increase in the morbidity ...and mortality rate. The primary strategy for managing infected pancreatic necrosis (IPN) or symptomatic PFCs is a minimally invasive step-up approach, with endosonography-guided (EUS-guided) transmural drainage and debridement as the preferred and less invasive method. Different stents are available to drain PFCs: self-expandable metal stents (SEMSs), double pigtail stents (DPPSs), or lumen-apposing metal stents (LAMSs). In particular, LAMSs are useful when direct endoscopic necrosectomy is needed, as they allow easy access to the necrotic cavity; however, the rate of adverse events is not negligible, and to date, the superiority over DPPSs is still debated. Moreover, the timing for necrosectomy, the drainage technique, and the concurrent medical management are still debated. In this review, we focus attention on indications, timing, techniques, complications, and particularly on aspects that remain under debate concerning the EUS-guided drainage of PFCs.
Anastomotic defects are deleterious complications after either oncologic or bariatric surgery, leading to high morbidity and mortality. Besides surgical revision in early stages or instable patients, ...endoscopic treatment has become the mainstay. To date, many options for endoscopic treatment in this setting exist, including fully covered metal stent placement, endoscopic vacuum therapy (EVT), endoscopic internal drainage with pigtail placement (EID), leak closure with through the scope or over the scope clips, endoluminal suturing, fibrin glue sealing and a combination of all these techniques. Current evidence is mostly based on retrospective single and multicenter studies. No guidelines exist in this important field. Treatment options have to be chosen upon each case individually, taking into account clinical and anatomic criteria, such as timing, size, infectious wound complications and hemodynamic stability. Local expertise and availability of treatment devices need to be taken into account whenever choosing a treatment strategy. This review aimed to present current treatment options in terms of effectiveness, advantages and disadvantages in order to guide the clinician for his decision making. Additionally, we aimed to provide a treatment algorithm.
Direct-acting antivirals (DAAs) revolutionized the treatment of chronic HCV-related disease achieving high rates of sustained virological response (SVR), even in advanced cirrhosis, with modest ...contraindications and a low rate of adverse events. However, the risk of hepatocellular carcinoma (HCC) persists due to the underlying chronic liver disease, both in patients with and without history of HCC. Although some initial studies reported a presumptive high risk of HCC development after DAA therapy, more recent observational studies denied this hypothesis. The residual risk for HCC occurrence after HCV eradication seems being progressively reduced with time after SVR. Data on recurrence of HCC after DAA exposure in patients with previously treated carcinoma initially reported conflicting results too, this being also due to methodological issues in analysis of retrospective multicenter studies. Anyway, current evidence support the use of DAAs in HCV-HCC treated patients, without any higher risk of tumor recurrence linked to antiviral therapy. Less effort has been made to evaluate the efficacy of DAA therapy in patients with untreated active HCC and it has been questioned whether a lower rate of SVR would be obtained among patients with active HCC. Studies conducted in this perspective concluded that HCC status does not influence the likelihood to obtain SVR with DAAs, making DAAs appropriate in HCC-active patients. As far as survival is concerned, recent studies conducted in cirrhotic HCV-related early-stage HCC found that DAAs improved overall survival, a benefit probably due to the reduction of hepatic decompensation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Autoimmune atrophic gastritis (AAG) is a chronic disease that can progress to gastric cancer (GC). To better understand AAG pathology, this proteomics study investigated gastric proteins ...whose expression levels are altered in this disease and also in GC.
Methods
Using two-dimensional difference gel electrophoresis (2D-DIGE), we compared protein maps of gastric corpus biopsies from AAG patients and controls. Differentially abundant spots (|fold change|≥ 1.5,
P
< 0.01) were selected and identified by LC–MS/MS. The spots were further assessed in gastric antrum biopsies from AAG patients (without and with
Helicobacter pylori
infection) and from GC patients and unaffected first-degree relatives of GC patients.
Results
2D-DIGE identified 67 differentially abundant spots, with 28 more and 39 less abundant in AAG-corpus than controls. LC–MS/MS identified these as 53 distinct proteins. The most significant (adjusted
P
< 0.01) biological process associated with the less abundant proteins was “tricarboxylic acid cycle”. Of the 67 spots, 57 were similarly differentially abundant in AAG-antrum biopsies irrespective of
H. pylori
infection status. The differential abundance was also observed in GC biopsies for 14 of 28 more abundant and 35 of 39 less abundant spots, and in normal gastric biopsies of relatives of GC patients for 6 and 25 spots, respectively. Immunoblotting confirmed the different expression levels of two more abundant proteins (
PDIA3, GSTP
gene products) and four less abundant proteins (
ATP5F1A, PGA3, SDHB, PGC
).
Conclusion
This study identified a proteomics signature of AAG. Many differential proteins were shared by GC and may be involved in the progression of AAG to GC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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