Helminths in the gastrointestinal tract 1 as modulators of immunity and pathology

Helminth parasites are highly prevalent in many low- and middle-income countries, in which inflammatory bowel disease and other immunopathologies are less frequent than in the developed world. Many of the most common helminths establish in the gastrointestinal tract, and can exert counter-inflammatory influences on the host immune system. For these reasons, interest has arisen in how parasites may ameliorate intestinal inflammation and whether these organisms, or products they release, could offer future therapies for immune disorders. In this review, we discuss interactions between helminth parasites and the mucosal immune system, and progress made towards identifying mechanisms and molecular mediators through which it may be possible to attenuate pathology in the intestinal tract

Modulation of innate cells by helminth infection and helminth derived products

Helminth infection affects around a quarter of people worldwide, with no effective vaccines available. Future vaccines against helminth infection will require a more precise understanding of the cellular and molecular basis of protective immunity. In addition, it is notable that the prevalence of allergic and autoimmune diseases has increased, whilst that of helminths infections has reduced. This suggested that immune responses are dampened through direct immunomodulation by helminths infections or their excretory secretory products. Based on initial observations that Heligmosomoides polygyrus excretory secretory products (HES) can improve disease scores in a chronic T cell induced colitis, we explored the role of (HES) in an innate RAG-/- CD40 colitis. We found that HES did not affect inflammatory scores and disease activity in this model of colitis, however reduced the infiltration of inflammatory cells into the peritoneum. Immunity to intestinal helminth Nippostrongylus brasiliensis and H. polygyrus requires innate and adaptive mechanisms co-ordinated through the Type 2 IL-4R/STAT6-dependent pathway. We have now found that macrophage migration inhibitory factor (MIF) is also essential for development of immunity to infection. MIF-deficient mice are slower to expel N. brasiliensis, while in wildtype animals, the expression of MIF is upregulated in macrophages in response to infection. Cellular analyses in the MIF-deficient mice demonstrate reduced recruitment of innate lymphoid cells, eosinophils and alternatively activated macrophages. Type 2 epithelial responses were reduced in the mice showing reduced tuft cell hyperplasia and almost absent RELM-ß protein in goblet cells. In order to assess if this was a developmental abnormality, we administered 4-IPP, an inhibitor of MIF to infected wild type mice. Mice receiving 4-IPP were unable to expel parasites and demonstrated similar cellular and epithelial responses as the MIF-deficient mice. IL-25 has been shown to accelerate expulsion of N.brasiliensis via the recruitment of ILC2s. Administration of rIL-25 is able to completely rescue the MIF-deficient cellular and epithelial cell phenotype. The ligands for MIF are hypothesised to be CXCR2, CXCR4 and CD74. We demonstrate that ILCs and macrophages express CXCR4. CXCR2-deficiency did not result in the epithelial cell phenotype, therefore it is unlikely that MIF is acting via CXCR2 in the gut. A deficiency of CXCR2 however, altered the immune response to N. brasiliensis in the lung with reduced alternative activation of macrophages. In parallel, we assessed the immune responses in H. polygyrus. From previous work, we know that MIF-deficient mice are less able to expel H. polygyrus primary infection, and in addition, do not mount protective secondary immune responses or protective responses to immunisation with HES. We found no difference in the percentage of Foxp3 positive T regulatory cells or HES specific antibody levels. As in the N. brasiliensis model, MIF-deficient mice produced fewer alternatively activated macrophages confirming a defect in the innate immune compartment. A microarray had previously been performed comparing BALB/c and MIF5 deficient duodenum, finding genes arl2bp, phc2 and s100a8 being downregulated in the MIF-deficient mice. In order to assess the role of S100A8 deficiency in helminths infections, we infected s100a9-/- mice in which the A8/A9 complex cannot form. We found no difference in the primary or secondary clearance of H. polygyrus suggesting that S100A8 is not important in the pathogenesis of helminths infection. ARL2BP is known to be important for STAT3 nuclear retention. We assessed STAT6 and STAT3 phosphorylation and found no difference between the BALB/c and MIF-deficient mice in phosphorylation of STAT3/6. We conclude that in Type 2 infection, MIF plays an important role in the protective Type 2 response, potentially at two levels: firstly in activation of ILCs in a manner which is upstream of, and rescued by, IL-25; and secondly in promoting alternative activation of macrophages in synergy with IL-4

Improved patient selection for PEG insertion in England between 2007-2019

This is an accepted manuscript of an abstract presented at BSG Annual Meeting 2021, published by BMJ/British Society of Gastroenterology in Gut on 07/11/2021. The accepted version of the publication may differ from the final published version

Profile of Tofacitinib in the Treatment of Ulcerative Colitis: An Evidence-Based Review of Recent Data

Recent advances in the understanding of the pathophysiology of ulcerative colitis (UC) have led to the expansion of our therapeutic arsenal. Conventional treatment options, including aminosalicylates, corticosteroids, thiopurines, and calcineurin inhibitors, fail to control the disease in a significant proportion of patients. Approximately 25-50% of the patients treated with tumor necrosis factor antibodies (anti-TNFα) are primary and secondary non-responders to therapy. Tofacitinib is a novel orally administered small synthetic molecule that inhibits a homologous family of enzymes, termed Janus kinases that modulate multiple key cytokines involved in the pathogenesis of UC. Phase II and III trials showed promising results in UC, leading the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to approve its administration for the induction and maintenance of remission in moderate-to-severe UC. Herein, we review tofacitinib for the management of UC, its mechanism of action pharmacokinetic properties, efficacy, and safety

The communication of a secondary care diagnosis of autoimmune hepatitis to primary care practitioners: a population-based study

Background Autoimmune Hepatitis is a chronic liver disease which affects young people and can result in liver failure leading to death or transplantation yet there is a lack of information on the incidence and prevalence of this disease and its natural history in the UK. A means of obtaining this information is via the use of clinical databases formed of electronic primary care records. How reliably the diagnosis is coded in such records is however unknown. The aim of this study therefore was to assess the proportion of consultant hepatologist diagnoses of Autoimmune Hepatitis which were accurately recorded in General Practice computerised records. Methods Our study population were patients with Autoimmune Hepatitis diagnosed by consultant hepatologists in the Queens Medical Centre, Nottingham University Hospitals (UK) between 2004 and 2009. We wrote to the general practitioners of these patients to obtain the percentage of patients who had a valid READ code specific for Autoimmune Hepatitis. Results We examined the electronic records of 51 patients who had biopsy evidence and a possible diagnosis of Autoimmune Hepatitis. Forty two of these patients had a confirmed clinical diagnosis of Autoimmune Hepatitis by a consultant hepatologist: we contacted the General Practitioners of these patients obtaining a response rate of 90.5% (39/42 GPs). 37/39 of these GPs responded with coding information and 89% of these patients (33/37) used Read code J638.00 (Autoimmune Hepatitis) to record a diagnosis. Conclusions The diagnosis of Autoimmune Hepatitis made by a Consultant Hepatologist is accurately communicated to and electronically recorded by primary care in the UK. As a large proportion of cases of Autoimmune Hepatitis are recorded in primary care, this minimises the risk of introducing selection bias and therefore selecting cases using these data will be a valid method of conducting population based studies on Autoimmune Hepatitis

Macrophage migration inhibitory factor (MIF) is essential for Type 2 effector cell immunity to an intestinal helminth parasite

Immunity to intestinal helminths is known to require both innate and adaptive components of the immune system activated alongthe Type 2 IL-4R/STAT6-dependent pathway. We have found that macrophage migration inhibitory factor (MIF) is essential for thedevelopment of effective immunity to the intestinal helminth Heligmosomoides polygyrus, even following vaccination which inducessterile immunity in wild-type mice. A chemical inhibitor of MIF, 4-IPP, was similarly found to compromise anti-parasite immunity.Cellular analyses found that the adaptive arm of the immune response, including IgG1 antibody responses and Th2-derivedcytokines, was intact and that Foxp3+ T regulatory cell responses were unaltered in the absence of MIF. However, MIF was found tobe an essential cytokine for innate cells, with ablated eosinophilia and ILC2 responses, and delayed recruitment and activation ofmacrophages to the M2 phenotype (expressing Arginase 1, Chil3, and RΕLM‐alpha) upon infection of MIF‐deficient mice; amacrophage deficit was also seen in wild-type BALB/c mice exposed to 4-IPP. Gene expression analysis of intestinal and lymph nodetissues from MIF-deficient and -sufficient infected mice indicated significantly reduced levels of Arl2bp, encoding a factor involved innuclear localization of STAT3. We further found that STAT3-deficient macrophages expressed less Arginase-1, and that mice lackingSTAT3 in the myeloid compartment (LysMCrexSTAT3fl/fl) were unable to reject a secondary infection with H. polygyrus. We thusconclude that in the context of a Type 2 infection, MIF plays a critical role in polarizing macrophages into the protectivealternatively-activated phenotype, and that STAT3 signaling may make a previously unrecognized contribution to immunity tohelminths

The communication of a secondary care diagnosis of autoimmune hepatitis to primary care practitioners: a population-based study

Abstract Background: Autoimmune Hepatitis is a chronic liver disease which affects young people and can result in liver failure leading to death or transplantation yet there is a lack of information on the incidence and prevalence of this disease and its natural history in the UK

Improving 30-day mortality following percutaneous endoscopic gastrostomy tube placement in England from 2007 to 2019: a retrospective national cohort analysis of 87,862 patients

This is an accepted manuscript of an article published by Elsevier on 04/07/2022, available online: https://doi.org/10.1016/j.gie.2022.06.031 The accepted version of the publication may differ from the final published version.Background and aims Percutaneous endoscopic gastrostomy (PEG) has been associated with poor case selection and high mortality. We examined indications, 30-day mortality and 7-day complications in a national cohort undergoing PEG insertion. Methods Adults undergoing first PEG insertion from 2007–2019 were identified in Hospital Episode Statistics. The indications and complications were identified using ICD-10 codes. Multivariable logistic regression modelling examined factors associated with mortality. Results 87,682 patients identified; 58% male; median age 69 (IQR 57-79) years. The number of patients with dementia or stroke as PEG indication fell from 2007 to 2019 : dementia - 147 to 28, p<0.001; stroke - 2851 to 1781, p<0.001. Median interval from stroke admission to PEG insertion increased from 21 (IQR 12-36) to 28 (13-45) days, p<0.001. Aspiration pneumonia within 7 days of PEG fell from 10.2% to 8.6%, p 0.04. 30 day mortality fell from 13.2% to 5.3% (p<0.001) and factors associated included: increasing age (≥ 82 years quintile odds ratio 4.44 (95% CI 4.01-4.92)); PEG insertion during emergency admission (2.10 (1.97-2.25)); Charlson comorbidity score ≥ 5 (1.67 (1.53-1.82)); and dementia (1.46 (1.26-1.71)).Female sex (0.81 (0.77-0.85)), least deprived quintile (0.88 (0.81-0.95)), and more recent years of PEG insertion (2019, 0.44 (0.39-0.51)) were negatively associated with mortality. Conclusions 30 day mortality following PEG insertion has fallen 60% over 13 years. Dementia or stroke as a PEG indication fell and the time interval from stroke to PEG insertion increased. These findings may be attributable to improved patient selection and timing for PEG insertion