The tolerogenic modulation of dendritic cells in Crohn’s disease

Crohn’s disease is a chronic relapsing remitting inflammatory disease of the gut. The aetiology is multifactorial, and incompletely understood. The immune system plays a key role as evidenced by animal and human studies, as well as the predominance of immune-targeting treatments amongst the Crohn’s disease therapeutic arsenal. Defects in the adaptive immune system in Crohn’s have been well described, and there is an increasing body of evidence that the innate immune system, including dendritic cells (DCs) may be involved as well. Vitamin D is of interest as a potential adjunctive therapy in IBD, and its potential mechanisms of action are incompletely understood. In this thesis, we utilised flow cytometry, ELISA, electron microscopy and PCR to explore the interactions between DCs, anti-TNF treatment and vitamin D in Crohn’s disease. We found abnormalities in circulating DCs in Crohn’s disease, especially in the expression of homing markers, and in the production of inflammatory cytokines. Expression of homing markers were discriminatory for both location of disease and degree of inflammation. There were abnormalities in the less well studied plasmacytoid DC (pDC) population. Abnormalities in intracellular DC production of inflammatory cytokines were mirrored by serum cytokine concentrations. The phenotype and function of circulating DCs was seen to alter after ex vivo treatment with anti-TNF. Anti-TNF therapy was associated with a switch away from gut-homing circulating DC phenotype towards skin homing, and with a decrease in on-going DC production of intracellular cytokines such as TNFa and IL-6. These findings may provide further mechanisms of action of anti-TNF treatment as well as an explanation for its high rates of dermatological complications. Vitamin D was seen to alter DC homing profile in both in vitro and ex vivo studies to non-skin homing, and in addition augmented down-regulation of TNFa production by DCs. This could have potential clinical applications.Open Acces

The Effect of Vitamin D on Intestinal Inflammation and Faecal Microbiota in Patients with Ulcerative Colitis

This work was supported by the European Crohn’s and Colitis Organisation Fellowship awarded to Dr Mayur Garg, and St Mark’s Foundation Research Grant 2015 awarded to Prof Ailsa Hart and Dr Mayur Garg.Peer reviewedPostprin

Paleobiology Database User Guide Version 1.0

The Paleobiology Database is an online, non-governmental, non-profit public resource for paleontological data. It is organized and operated by a multi-disciplinary, multi-institutional, international group of paleobiological researchers. This volume is designed to be a comprehensive guide for Paleobiology Database users, both General and Contributory. It covers most database uses from data retrieval and mapping to data contribution of all types. It contains numerous examples to illustrate database use as well as definitions of terms and additional links to numerous other sources. We hope that this user guide will help all users access the great volume of data in the Paleobiology Database and lead others to start and continue to add data to the system

Deficient resident memory T-cell and Cd8 T-cell response to commensals in inflammatory bowel disease

Background Aims: The intestinal microbiota is closely associated with resident memory lymphocytes in mucosal tissue. We sought to understand how acquired cellular and humoral immunity to the microbiota differ in health versus inflammatory bowel disease (IBD). Methods Resident memory T-cells (Trm) in colonic biopsies and local antibody responses to intraepithelial microbes were analyzed. Systemic antigen-specific immune T- and B-cell memory to a panel of commensal microbes was assessed. Results Systemically, healthy blood showed CD4 and occasional CD8 memory T-cell responses to selected intestinal bacteria but few memory B-cell responses. In IBD, CD8 memory T-cell responses decreased although B-cell responses and circulating plasmablasts increased. Possibly secondary to loss of systemic CD8 T-cell responses in IBD, dramatically reduced numbers of mucosal CD8+ Trm and γδ T-cells were observed. IgA responses to intraepithelial bacteria were increased. Colonic Trm expressed CD39 and CD73 ectonucleotidases, characteristic of regulatory T-cells. Cytokines/factors required for Trm differentiation were identified, and in vitro-generated Trm expressed regulatory T-cell function via CD39. Cognate interaction between T-cells and dendritic cells induced T-bet expression in dendritic cells, a key mechanism in regulating cell-mediated mucosal responses. Conclusions A previously unrecognized imbalance exists between cellular and humoral immunity to the microbiota in IBD, with loss of mucosal T-cell-mediated barrier immunity and uncontrolled antibody responses. Regulatory function of Trm may explain their association with intestinal health. Promoting Trm and their interaction with dendritic cells rather than immunosuppression may reinforce tissue immunity, improve barrier function and prevent B-cell dysfunction in microbiota-associated disease and IBD etiology

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

BackgroundAnterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability.MethodsWe did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367.FindingsBetween Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications.InterpretationSurgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management