Human eosinophils modulate peripheral blood mononuclear cell response to Schistosoma mansoni adult worm antigen in vitro.

High numbers of eosinophils are observed in parasitic infections and allergic diseases, where they are proposed to be terminally differentiated effector cells that play beneficial role in host defence, or cause harmful inflammatory response. Eosinophils have been associated with killing of schistosomulae in vitro, but there is growing evidence that eosinophils can play additional immuno-regulatory role. Here, we report results of a study that examines peripheral blood mononuclear cell (PBMC) cytokine responses to Schistosoma mansoni adult worm antigen (SWA) when stimulated alone or enriched with autologous eosinophils. Production of the Th-2 type cytokines interleukin (IL)-4, IL-5 and IL-13 was lower (P = 0·017, 0·018 and <0·001, respectively) in PBMC + eosinophil cultures than in PBMC-only cultures stimulated with SWA. Substantial levels of IL-13, IL-10, interferon gamma and tumour necrosis factor alpha were recorded in cultures of eosinophils, but none of these cytokines showed significant association with the observed eosinophil-induced drop in cytokine responses of PBMC. Transwell experiments suggested that the observed effect is due to soluble mediators that downmodulate production of Th-2 type cytokines. This study shows that eosinophils may down-modulate schistosome-specific Th-2 type cytokine responses in S. mansoni-infected individuals. The mechanism of this immune modulation remains to be elucidated.The study was a fellowship funded by Wellcome Trust, Makerere-UVRI Research Training Programme in Infection and Immunity (grant number 084344) and European Foundations Initiative for NTDs ‘EFINTD’ (grant ref 86 529). The study was carried out under co-infection studies programme lead by AME funded by Wellcome Trust (grant number 095778)

Critical role of the disintegrin metalloprotease ADAM-like Decysin-1 (ADAMDEC1) for intestinal immunity and inflammation

BACKGROUND AND AIMS: ADAM (A Disintegrin And Metalloproteinase) is a family of peptidase proteins, which have diverse roles in tissue homeostasis and immunity. Here, we study ADAM-like Decysin-1 (ADAMDEC1) a unique member of the ADAM family. ADAMDEC1 expression is restricted to the macrophage/dendritic cell populations of the gastrointestinal tract and secondary lymphoid tissue. The biological function of ADAMDEC1 is unknown but it has been hypothesised to play a role in immunity. The identification of reduced ADAMDEC1 expression in Crohn's disease patients has provided evidence of a potential role in bowel inflammation. METHODS: Adamdec1(-/-) mice were exposed to dextran sodium sulphate or infected orally with Citrobacter rodentium or Salmonella typhimurium The clinical response was monitored. RESULTS: The loss of Adamdec1 rendered mice more susceptible to the induction of bacterial and chemical induced colitis, as evidenced by increased neutrophil infiltration, greater IL-6 and IL-1β secretion, more weight loss and increased mortality. In the absence of Adamdec1, greater numbers of Citrobacter rodentium were found in the spleen, suggestive of a breakdown in mucosal immunity which resulted in bacteraemia. CONCLUSION: In summary, Adamdec1 protects the bowel from chemical and bacterial insults, failure of which may predispose to Crohn's disease

Effect of maternal Schistosoma mansoni infection and praziquantel treatment during pregnancy on Schistosoma mansoni infection and immune responsiveness among offspring at age five years.

INTRODUCTION: Offspring of Schistosoma mansoni-infected women in schistosomiasis-endemic areas may be sensitised in-utero. This may influence their immune responsiveness to schistosome infection and schistosomiasis-associated morbidity. Effects of praziquantel treatment of S. mansoni during pregnancy on risk of S. mansoni infection among offspring, and on their immune responsiveness when they become exposed to S. mansoni, are unknown. Here we examined effects of praziquantel treatment of S. mansoni during pregnancy on prevalence of S. mansoni and immune responsiveness among offspring at age five years. METHODS: In a trial in Uganda (ISRCTN32849447, http://www.controlled-trials.com/ISRCTN32849447/elliott), offspring of women treated with praziquantel or placebo during pregnancy were examined for S. mansoni infection and for cytokine and antibody responses to SWA and SEA, as well as for T cell expression of FoxP3, at age five years. RESULTS: Of the 1343 children examined, 32 (2.4%) had S. mansoni infection at age five years based on a single stool sample. Infection prevalence did not differ between children of treated or untreated mothers. Cytokine (IFNγ, IL-5, IL-10 and IL-13) and antibody (IgG1, Ig4 and IgE) responses to SWA and SEA, and FoxP3 expression, were higher among infected than uninfected children. Praziquantel treatment of S. mansoni during pregnancy had no effect on immune responses, with the exception of IL-10 responses to SWA, which was higher in offspring of women that received praziquantel during pregnancy than those who did not. CONCLUSION: We found no evidence that maternal S. mansoni infection and its treatment during pregnancy influence prevalence and intensity of S. mansoni infection or effector immune response to S. mansoni infection among offspring at age five years, but the observed effects on IL-10 responses to SWA suggest that maternal S. mansoni and its treatment during pregnancy may affect immunoregulatory responsiveness in childhood schistosomiasis. This might have implications for pathogenesis of the disease

Graviton Vertices and the Mapping of Anomalous Correlators to Momentum Space for a General Conformal Field Theory

We investigate the mapping of conformal correlators and of their anomalies from configuration to momentum space for general dimensions, focusing on the anomalous correlators $TOO$, $TVV$ - involving the energy-momentum tensor $(T)$ with a vector $(V)$ or a scalar operator ($O$) - and the 3-graviton vertex $TTT$. We compute the $TOO$, $TVV$ and $TTT$ one-loop vertex functions in dimensional regularization for free field theories involving conformal scalar, fermion and vector fields. Since there are only one or two independent tensor structures solving all the conformal Ward identities for the $TOO$ or $TVV$ vertex functions respectively, and three independent tensor structures for the $TTT$ vertex, and the coefficients of these tensors are known for free fields, it is possible to identify the corresponding tensors in momentum space from the computation of the correlators for free fields. This works in general $d$ dimensions for $TOO$ and $TVV$ correlators, but only in 4 dimensions for $TTT$, since vector fields are conformal only in $d=4$. In this way the general solution of the Ward identities including anomalous ones for these correlators in (Euclidean) position space, found by Osborn and Petkou is mapped to the ordinary diagrammatic one in momentum space. We give simplified expressions of all these correlators in configuration space which are explicitly Fourier integrable and provide a diagrammatic interpretation of all the contact terms arising when two or more of the points coincide. We discuss how the anomalies arise in each approach [...]Comment: 57 pages, 7 figures. Refs adde

Complementary activation of peripheral natural killer cell immunity in nasopharyngeal carcinoma

NK cells and αβ- and γδ-CTL play important roles in cellular immunity against tumors. We previously demonstrated that NPC patients have a quantitative and qualitative deficit in γδ-CTL and EBV-specific αβ-CTL when compared to normal subjects and NPC long-term survivors. In this study we report further observations of a complementary activation of peripheral NK cells in NPC patients. The NK cells in these patients, compared to those of healthy subjects and NPC survivors, were preferentially activated in response to the stimulation of myeloma cell line XG-7 and expanded in the presence of exogenous IL-2. The production of IFN-γ was lowest in the patient group, whereas IL-12, IL-15 and TNF-α were produced in higher levels in patients than in the donors and survivors. The cytolytic effect of the NK cells against NPC cells in the patient group was also higher than that of the donors and survivors. Furthermore, the patients at later stages of NPC had lower γδ-CTL activity but higher NK cytotoxicity towards NPC targets, with higher production of IL-12, IL-15 and TNF-α but lower production of IFN-γ than in patients at earlier stages. This might be part of a triggered compensatory re-activation of the innate immunity, believed to be mediated through various cytokines and chemokines when adaptive T cell immunity is breached. Together, these data suggest complementary roles of innate and adaptive immune response in tumor immunity where NK cells, γδ- and αβ-CTL compensate for the deficits of one another at different stages of tumor invasion. © 2006 Japanese Cancer Association.published_or_final_versio

Managerial Work in a Practice-Embodying Institution - The role of calling, the virtue of constancy

What can be learned from a small scale study of managerial work in a highly marginal and under-researched working community? This paper uses the ‘goods-virtues-practices-institutions’ framework to examine the managerial work of owner-directors of traditional circuses. Inspired by MacIntyre’s arguments for the necessity of a narrative understanding of the virtues, interviews explored how British and Irish circus directors accounted for their working lives. A purposive sample was used to select subjects who had owned and managed traditional touring circuses for at least 15 years, a period in which the economic and reputational fortunes of traditional circuses have suffered badly. This sample enabled the research to examine the self-understanding of people who had, at least on the face of it, exhibited the virtue of constancy. The research contributes to our understanding of the role of the virtues in organizations by presenting evidence of an intimate relationship between the virtue of constancy and a ‘calling’ work orientation. This enhances our understanding of the virtues that are required if management is exercised as a domain-related practice

Molecular identification of papillomavirus in ducks

Papillomaviruses infect many vertebrates, including birds. Persistent infections by some strains can cause malignant proliferation of cells (i.e. cancer), though more typically infections cause benign tumours, or may be completely subclinical. Sometimes extensive, persistent tumours are recorded– notably in chaffinches and humans. In 2016, a novel papillomavirus genotype was characterized from a duck faecal microbiome, in Bhopal, India; the sixth papillomavirus genotype from birds. Prompted by this finding, we screened 160 cloacal swabs and 968 faecal samples collected from 299 ducks sampled at Ottenby Bird Observatory, Sweden in 2015, using a newly designed real-time PCR. Twenty one samples (1.9%) from six individuals (2%) were positive. Eighteen sequences were identical to the published genotype, duck papillomavirus 1. One additional novel genotype was recovered from three samples. Both genotypes were recovered from a wild strain domestic mallard that was infected for more than 60 days with each genotype. All positive individuals were adult (P = 0.004). Significantly more positive samples were detected from swabs than faecal samples (P < 0.0001). Sample type data suggests transmission may be via direct contact, and only infrequently, via the oral-faecal route. Infection in only adult birds supports the hypothesis that this virus is sexually transmitted, though more work is required to verify this.Thanks to duck trappers at Ottenby Bird Observatory for support and sample collection, and to Abbtesaim Jawad for DNA extraction. This work was supported by the Crafoord Foundation Sweden (grants number 20160971 and 20170671). This is contribution no. 306 from Ottenby Bird Observatory

All thresholds of maternal hyperglycaemia from the WHO 2013 criteria for gestational diabetes identify women with a higher genetic risk for type 2 diabetes

This is the final version. Available from F1000Research via the DOI in this record.Data availability Underlying data Data is not freely available due to it consisting of potentially identifiable information, and as such is held securely to protect the interests of research participants in line with the guidance from the relevant ethics committees. However, the ethics committees will allow data analysed and generated in this study to be available to researchers through open collaboration. For access to the data used in this study please contact Dr Rachel Freathy ([email protected]) and Professor William Lowe Jr ([email protected]) in relation to HAPO and Dr Rachel Freathy and Professor Fidelma Dunne ([email protected]) in relation to Atlantic DIP. Requests will be reviewed as soon as possible on receipt and will be facilitated with an agreement to ensure that data is transferred and held securely and results of new analyses shared with the relevant study investigators. The websites describing the studies and other data available are https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000096.v4.p1 for HAPO and http://atlanticdipireland.com/for Atlantic DIP. Extended data Figshare: Extended data Wellcome Open Research 16097.pdf. https://doi.org/10.6084/m9.figshare.14180033 The file contains an extended data table with sensitivity analyses adjusting the genetic scores for maternal pre-pregnancy BMI and age and a figure with a directed acyclic graph (DAG) showing how the relationships between the genetic scores and GDM diagnostic category are not driven by maternal pre-pregnancy BMI or age.Background: Using genetic scores for fasting plasma glucose (FPG GS) and type 2 diabetes (T2D GS), we investigated whether the fasting, 1-hour and 2-hour glucose thresholds from the WHO 2013 criteria for gestational diabetes (GDM) have different implications for genetic susceptibility to raised fasting glucose and type 2 diabetes in women from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) and Atlantic Diabetes in Pregnancy (DIP) studies. Methods: Cases were divided into three subgroups: (i) FPG ≥5.1 mmol/L only, n=222; (ii) 1-hour glucose post 75 g oral glucose load ≥10 mmol/L only, n=154 (iii) 2-hour glucose ≥8.5 mmol/L only, n=73; and (iv) both FPG ≥5.1 mmol/L and either of a 1-hour glucose ≥10 mmol/L or 2-hour glucose ≥8.5 mmol/L, n=172. We compared the FPG and T2D GS of these groups with controls (n=3,091) in HAPO and DIP separately. Results: In HAPO and DIP, the mean FPG GS in women with a FPG ≥5.1 mmol/L, either on its own or with 1-hour glucose ≥10 mmol/L or 2-hour glucose ≥8.5 mmol/L, was higher than controls (all P <0.01). Mean T2D GS in women with a raised FPG alone or with either a raised 1-hour or 2-hour glucose was higher than controls (all P <0.05). GDM defined by 1-hour or 2-hour hyperglycaemia only was also associated with a higher T2D GS than controls (all P <0.05). Conclusions: The different diagnostic categories that are part of the WHO 2013 criteria for GDM identify women with a genetic predisposition to type 2 diabetes as well as a risk for adverse pregnancy outcomes.Wellcome TrustNational Institute for Health ResearchEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Human Genome Research InstituteNational Institute of Diabetes and Digestive and Kidney DiseasesAmerican Diabetes AssociationIreland Health Research Boar

Proteomic Identification of IPSE/alpha-1 as a Major Hepatotoxin Secreted by Schistosoma mansoni Eggs

The flatworm disease, schistosomiasis, is a major public health problem in sub-Saharan Africa, South America and East Asia. A hallmark of infection with Schistosoma mansoni is the immune response to parasite eggs trapped in the liver and other organs. This response involves an infiltration of cells that surround the parasite egg forming a “granuloma.” In mice deprived of T-cells, this granulomatous response is lacking, and toxic products released by eggs quickly cause liver damage and death. Thus the granulomata protect the host from toxic egg products. Only one hepatotoxic molecule, omega-1, has been described to date. We set out to identify other S. mansoni egg hepatotoxins using liver cells grown in culture. We first showed that live eggs, their secretions, and pure omega-1 are toxic. Using a physical separation technique to prepare fractions from whole egg secretions, we identified the presence of IPSE/alpha-1, a protein that is known to strongly influence the immune system. We showed that IPSE/alpha-1 is also hepatotoxic, and that toxicity of both omega-1 and IPSE/alpha-1 can be prevented by first mixing the proteins with specific neutralizing antibodies. Both proteins constitute the majority of hepatotoxicity released by eggs