Oliver Brain

NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation

Nucleotide-binding oligomerization domain–containing-2 (NOD2) acts as a bacterial sensor in dendritic cells (DCs), but it is not clear how bacterial recognition links with antigen presentation after NOD2 stimulation. NOD2 variants are associated with Crohns disease, where breakdown in self-recognition of commensal bacteria leads to gastrointestinal inflammation. Here we show NOD2 triggering by muramyldipeptide induces autophagy in DCs. This effect requires receptor-interacting serine-threonine kinase-2 (RIPK-2), autophagy-related protein-5 (ATG5), ATG7 and ATG16L1 but not NLR family, pyrin domain containing-3 (NALP3).We show that NOD2-mediated autophagy is required for both bacterial handling and generation of major histocompatibility complex (MHC) class II antigen-specific CD4+ T cell responses in DCs. DCs from individuals with Crohns disease expressing Crohns disease—associated NOD2 or ATG16L1 risk variants are defective in autophagy induction, bacterial trafficking and antigen presentation. Our findings link two Crohns disease–associated susceptibility genes in a single functional pathway and reveal defects in this pathway in Crohns disease DCs that could lead to bacterial persistence via impaired lysosomal destruction and immune mediated clearance.

Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up

Background Endoscopic mucosal healing is an established treatment target for UC, yet the value of achieving histological remission remains unclear. Aims To evaluate histological remission compared to endoscopic mucosal healing for predicting patient outcomes in UC. Methods Blinded assessment of endoscopic and histological measures of disease activity was performed on patients with established UC at baseline. Concordance and prognostic values of endoscopic mucosal healing (defined by Baron score ≤1) and histological remission (defined by Truelove and Richards’ index) for predicting outcomes of corticosteroid use, hospitalisation and colectomy were determined over a median 6 years follow-up, including κ statistics and Cox regression multivariate analysis. Results 91 patients with UC were followed up for a median 72 months (IQR 54–75 months). Overall, concordance between endoscopic and histological remission was moderate (κ=0.56, 95% CI 0.36 to 0.77); 24% patients had persistent inflammation despite endoscopic remission. Histological remission predicted corticosteroid use and acute severe colitis requiring hospitalisation over the follow-up period (HR 0.42 (0.2 to 0.9), p=0.02; HR 0.21 (0.1 to 0.7), p=0.02; respectively), whereas endoscopic mucosal healing did not (HR 0.86, 95% CI 0.5 to 1.7, p0.65; HR 0.83 95% CI 0.3 to 2.4, p0.74; respectively). Conclusions Histological remission is a target distinct from endoscopic mucosal healing in UC and better predicts lower rates of corticosteroid use and acute severe colitis requiring hospitalisation, over a median of 6 years of follow-up. Our findings support the inclusion of histological indices in both UC clinical trials and practice, towards a target of ‘complete remission’.

Conventional drug therapy for inflammatory bowel disease

Abstract Most patients with inflammatory bowel diseases (IBD) are offered conventional medical therapy, because emerging therapies for IBD are regulated by health-care jurisdiction and often limited to academic centres. This review distils current evidence to provide a pragmatic approach to conventional IBD therapy, including aminosalicylates, corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, infliximab and adalimumab. It addresses drug efficacy, safety and salient practice points for optimal and appropriate practice.

Collagenous gastritis: reports and systematic review.

Collagenous gastritis is a rare disorder first described in 1989. After encountering two cases, we decided to review the literature and evaluate the collagen band. A systematic review of PubMed and EMBASE databases was performed. Twenty-eight cases have been previously described and two patterns of presentations are identifiable: children or young adults (median age 12 years, range 2-22 years) presenting with symptoms attributable to the gastritis (anaemia and pain); and older adults (median age 52 years, range 35-77 years) presenting with loose stools, often associated with collagenous colitis or coeliac disease. Our two cases (one child and one adult) matched this pattern. Immunostaining of the collagen band for collagens II, III, IV and VI, and tenascin showed that the band in our cases was predominantly tenascin. In conclusion, collagenous gastritis is a rare entity whose presentation depends on the age of the patient. An autoimmune aetiology seems possible given its associations. Treatment is empirical. The 30 cases now reported show that the disorder can relapse or persist for years.

Therapy of ulcerative colitis: state of the art.

Purpose of review Advances in conventional therapy, novel targets and therapeutic goals are the highlights of treatment for ulcerative colitis in the last year. There have also been disappointments. This review summarizes the highs and lows, with an emphasis on strategy as opposed to seeking the newest treatment option. Recent findings In conventional therapy, once daily therapy for 5-aminosalicylic acid is generally sufficient. Furthermore, a new 5-aminosalicylic acid (mesalamine MMX) has been released that effectively induces and maintains remission. There have been reappraisals of immunomodulators and further evaluation of (yes, now conventional!) infliximab for ulcerative colitis. Opportunistic infections, long-term outcomes and the burden of disease are being characterized. New therapeutic targets included an antibody against T cells (anti-CD3), but trials on visilizumab for acute severe colitis have been suspended. T-cell costimulation, phosphatidylcholine to promote barrier function, new anti-tumour necrosis factor agents, B-cell (anti-CD20) depletion and complementary therapies represent new therapeutic horizons. International agreement is needed on activity indices, definitions of remission, therapeutic goals (including mucosal healing) and outcomes that matter to patients, so that trials can be compared. Summary Advances will take time to alter mainstream practice, but 2007–2008 is the year of organized strategies, with European, American and British guidelines on ulcerative colitis published or in press. These should be the platform for better outcomes for patients.

NOD2-mediated autophagy and Crohn disease

Autophagy is important in immune cells as a means of disposing of pathogens and in connecting with the antigen presentation machinery to facilitate immune priming and initiation of a correctly targeted adaptive immune response. While Toll-like receptors (TLRs) are known to regulate autophagy in this context, the extent to which other pattern recognition receptors (PRRs) are involved has been unclear. NOD2 is an intracellular PRR of the Nod-like receptor (NLR) family that is notable in that variants in the ligand recognition domain are associated with Crohn disease (CD). Our recent study shows NOD2 activates autophagy in a manner requiring ATG16L1, another CD susceptibility gene. NOD2 autophagy induction is required for bacterial handling and MHC class II antigen presentation in human dendritic cells (DCs). CD patients DCs expressing CD risk variant NOD2 or ATG16L1 display reduced autophagy induction after NOD2 triggering resulting in reduced bacterial killing and defective antigen presentation. Aberrant bacterial handling and immune priming could act as a trigger for inflammation in CD.

Functional consequences of mutations in the autophagy genes in the pathogenesis of Crohn's disease

&NA; Genome‐wide association studies have highlighted a number of genes involved in autophagy, which are of potential importance in the pathogenesis of Crohns disease (CD). The associated polymorphisms in ATG16L1 and IRGM have been confirmed, and functional studies have begun to shed light on how they link to CD pathogenesis. In this review we consider the most salient aspects of this rapidly expanding field. (Inflamm Bowel Dis 2011;)

Spectral fusion for estimating respiratory rate from the ECG

A new method for extracting respiratory signals from the electrocardiogram (ECG) is proposed. The method performs AR spectral analysis on heart rate variability and beat morphology information extracted from the ECG and identifies the closest matched frequencies which then provide an estimate of the respiration frequency. Fusing frequency information from different sources reliably rejects noise and movement-induced artefact and is promising for application to ambulatory hospital data. The performance of the method was validated on two databases of simultaneously recorded ECG and reference respiration signals. The spectral fusion technique is found to correctly estimate respiratory rate 90% of the time in the case of non-ambulatory data and 86% of the time in the case of ambulatory data with a root mean square error of 0.92 and 1.40 breaths per minute, respectively.

Pattern recognition receptor mediated downregulation of microRNA-650 fine-tunes MxA expression in dendritic cells infected with influenza A virus

MicroRNAs are important posttranscriptional regulators of gene expression, which have been shown to fine‐tune innate immune responses downstream of pattern recognition receptor (PRR) signaling. This study identifies miR‐650 as a novel PRR‐responsive microRNA that is downregulated upon stimulation of primary human monocyte‐derived dendritic cells (MDDCs) with a variety of different microbe‐associated molecular patterns. A comprehensive target search combining in silico analysis, transcriptional profiling, and reporter assays reveals that miR‐650 regulates several well‐known interferon‐stimulated genes, including IFIT2 and MXA. In particular, downregulation of miR‐650 in influenza A infected MDDCs enhances the expression of MxA and may therefore contribute to the establishment of an antiviral state. Together these findings reveal a novel link between miR‐650 and the innate immune response in human MDDCs.

1003 - New Faecal Calprotectin Cut-Off Points for Remission and Active Disease Defined by Uceis and Nancy Indices in Ulcerative Colitis

Disease activity assessment is an essential part of clinical management in UC, most accurately evaluated by endoscopy and biopsy, since patient symptoms may not reliably reflect activity. Published cut-offs for faecal calprotectin (FCal) in UC are largely based on prediction of relapse, rather than prediction of endoscopic or histopathologic activity.