Pre-conception maternal helminth infection transfers via nursing long-lasting cellular immunity against helminths to offspring

Maternal immune transfer is the most significant source of protection from early-life infection, but whether maternal transfer of immunity by nursing permanently alters offspring immunity is poorly understood. Here, we identify maternal immune imprinting of offspring nursed by mothers who had a pre-conception helminth infection. Nursing of pups by helminth-exposed mothers transferred protective cellular immunity to these offspring against helminth infection. Enhanced control of infection was not dependent on maternal antibody. Protection associated with systemic development of protective type 2 immunity in T helper 2 (TH2) impaired IL-4R-/- offspring. This maternally acquired immunity was maintained into maturity and required transfer (via nursing) to the offspring of maternally derived TH2-competent CD4 T cells. Our data therefore reveal that maternal exposure to a globally prevalent source of infection before pregnancy provides long-term nursing-acquired immune benefits to offspring mediated by maternally derived pathogen-experienced lymphocytes. © 2019 by the Authors

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Non-pulmonary immune functions of surfactant proteins A and D

Surfactant proteins A (SP-A) and D (SP-D) are established as essential components of our innate immune system for protecting the lung from pathogens and allergens. They essentially exert their protective functions by regulating pulmonary homeostasis. Both proteins are however widely expressed throughout the body, including the female reproductive tract, urinary tract, gastrointestinal tract, the eye, ear, nasal compartment, central nervous system, the coronary artery and the skin. The functions of SP-A and SP-D at these sites are a relatively underinvestigated area, but it is emerging that both SP-A and SP-D contribute significantly to the regulation of inflammation and protection from infection at these sites. This review presents our current understanding of the roles of SP-A and SP-D in non-pulmonary sites.</p

Murine IL-4 is able to signal via chimeric human IL-4Rα/mouse γ-chain receptor

Human IL-4Rα binds to mouse γc resulting in a chimeric receptor specific for human IL-4 but not mouse IL-4, providing in principle an inducible hIL-4 system. We investigated the in vitro and in vivo characteristics of human IL-4Rα transgenic mice on a mouse IL-4Rα-deficient background (hIL-4Rα Tg/mIL-4Rα−/−). The integrity of lymphocyte-specific hIL-4Rα expression in hIL-4Rα Tg/mIL-4Rα−/− mice was demonstrated by FACS analysis. This was confirmed in functional studies as lymphocytes responded to recombinant hIL-4 but not mIL-4 or mIL-13 in proliferation and T helper differentiation assays, demonstrating species-specificity and inducibility of the chimeric receptor in vitro. We then infected transgenic mice with Nippostrongylus brasiliensis, known to induce a strong Type 2 response in wild-type mice. As expected hIL-4Rα Tg/mIL-4Rα−/− mice were unable to expel N. brasiliensis worms which confirms unresponsiveness in non-lymphocytes. However they developed a Th2 cytokine and IgE response in the absence of induction with hIL-4. These results suggested that lymphocyte-specific IL-4Rα responsiveness was still present in vivo. Neutralization of endogenous mIL-4 resulted in inhibition of N. brasiliensis-induced Th2 cytokine and total IgE production in hIL-4Rα Tg/mIL-4Rα−/− mice suggesting that mIL-4 was involved. Intercrossing hIL-4Rα Tg/mIL-4Rα−/− mice with mIL-4−/−/mIL-13−/− mice completely abrogated Type 2 responses in N. brasiliensis infections. Together, these data demonstrate that mIL-4 triggered the hIL-4Rα/mγc chimeric receptor in vivo

IL-4Ralpha responsive CD4+CD25−CD103+FoxP3− cells control Schistosoma mansoni egg-induced inflammation by secreted IL-10

IL-4Ralpha signalling drives Th2-type responses that mediate resistance to parasitic helminth infections. We generated a novel mouse model lacking IL-4Ralpha expression specifically on all T cells (iLckcreIl4ra−/lox) to investigate IL-4Ralpha-dependent T cell responses during Schistosoma mansoni egg-driven inflammation. These mice showed higher mortality during acute schistosomiasis compared with Il4ra−/lox controls and previously established CD4+ T cell specific IL-4Ralpha deficient mice (LckcreIl4ra−/lox). iLckcreIl4ra−/lox mice developed a liver restricted pathology associated with drastic reductions of both Th2/type 2 responses and alternative macrophage activation within the granulomas. Additionally, iLckcreIl4ra−/lox mice had (i) increased FoxP3+ Treg cell responses in the granulomas, which was explained by IL-4 mediated inhibition of FoxP3 induction, and (ii) reduction of antigen-specific production of IL-10 by CD4+CD103+FoxP3− cells. In a footpad model of S. mansoni egg-induced inflammation with subsequent IL-10 neutralisation and adoptive cell transfer experiments we found evidence that the increased inflammation in iLckcreIl4ra−/lox mice was due to the impaired development of IL-10-secreting CD4+CD25−CD103+FoxP3− cells. Together, these data demonstrate that IL-4Ralpha responsiveness by T cells promote IL-10-secreting CD4+CD25−CD103+FoxP3− cells and alternatively activated macrophages, which act in concert to control egg-induced inflammation

Ascaris exposure and its association with lung function, asthma, and DNA methylation in Northern Europe

BackgroundAscaris infections, with a worldwide prevalence above 10%, can cause respiratory pathology. However, long-term effects on lung function in humans are largely unknown.ObjectiveWe investigated the associations of Ascaris exposure with lung function, asthma, and DNA methylation.MethodsSerum Ascaris IgG antibodies were measured in 671 adults aged 18 to 47 years (46% women) from Aarhus, Bergen, and Tartu RHINESSA study centers. Seropositivity was defined as IgG above the 90th percentile. Linear and logistic regressions were used to analyze Ascaris seropositivity as associated with lung function and asthma, adjusted for age, height, and smoking and clustered by center. DNA methylation in blood was profiled by a commercial methylation assay.ResultsAscaris seropositivity was associated with lower FEV1 (−247 mL; 95% CI, −460, −34) and higher odds for asthma (adjusted odds ratio, 5.84; 95% CI, 1.67, 20.37) among men but not women, also after further adjusting for house dust mite sensitivity, consistent across study centers. At a genome-wide level, Ascaris exposure was associated with 23 differentially methylated sites in men and 3 in women. We identified hypermethylation of the MYBPC1 gene, which can regulate airway muscle contraction. We also identified genes linked to asthma pathogenesis such as CRHR1 and GRK1, as well as a differentially methylated region in the PRSS22 gene linked to nematode infection.ConclusionAscaris exposure was associated with substantially lower lung function and increased asthma risk among men. Seropositive participants had sex-specific differences in DNA methylation compared to the unexposed, thus suggesting that exposure may lead to sex-specific epigenetic changes associated with lung pathology

Ascaris exposure and its association with lung function, asthma, and DNA methylation in Northern Europe

Background Ascaris infections, with a worldwide prevalence above 10%, can cause respiratory pathology. However, long-term effects on lung function in humans are largely unknown. Objective We investigated the associations of Ascaris exposure with lung function, asthma, and DNA methylation. Methods Serum Ascaris IgG antibodies were measured in 671 adults aged 18 to 47 years (46% women) from Aarhus, Bergen, and Tartu RHINESSA study centers. Seropositivity was defined as IgG above the 90th percentile. Linear and logistic regressions were used to analyze Ascaris seropositivity as associated with lung function and asthma, adjusted for age, height, and smoking and clustered by center. DNA methylation in blood was profiled by a commercial methylation assay. Results Ascaris seropositivity was associated with lower FEV1 (−247 mL; 95% CI, −460, −34) and higher odds for asthma (adjusted odds ratio, 5.84; 95% CI, 1.67, 20.37) among men but not women, also after further adjusting for house dust mite sensitivity, consistent across study centers. At a genome-wide level, Ascaris exposure was associated with 23 differentially methylated sites in men and 3 in women. We identified hypermethylation of the MYBPC1 gene, which can regulate airway muscle contraction. We also identified genes linked to asthma pathogenesis such as CRHR1 and GRK1, as well as a differentially methylated region in the PRSS22 gene linked to nematode infection. Conclusion Ascaris exposure was associated with substantially lower lung function and increased asthma risk among men. Seropositive participants had sex-specific differences in DNA methylation compared to the unexposed, thus suggesting that exposure may lead to sex-specific epigenetic changes associated with lung pathology

Zoonotic helminth exposure and risk of allergic diseases: A study of two generations in Norway

Background Animal and human studies indicate that definitive host helminth infections may confer protection from allergies. However, zoonotic helminths, such as Toxocara species (spp.), have been associated with increased allergies. Objective We describe the prevalence of Toxocara spp. and Ascaris spp. seropositivity and associations with allergic diseases and sensitization, in 2 generations in Bergen, Norway. Methods Serum levels of total IgG4, anti-Toxocara spp. IgG4 and Ascaris spp. IgG4 were established by ELISA in 2 cohorts: parents born 1945-1972 (n = 171) and their offspring born 1969-2003 (n = 264). Allergic outcomes and covariates were recorded through interviews and clinical examinations including serum IgEs and skin prick tests. Results Anti-Ascaris spp. IgG4 was detected in 29.2% of parents and 10.3% of offspring, and anti-Toxocara spp. IgG4 in 17.5% and 8.0% of parents and offspring, respectively. Among offspring, anti-Toxocara spp. IgG4 was associated with pet keeping before age 15 (OR = 6.15; 95% CI = 1.37-27.5) and increasing BMI (1.16[1.06-1.25] per kg/m2). Toxocara spp. seropositivity was associated with wheeze (2.97[1.45- 7.76]), hayfever (4.03[1.63-9.95]), eczema (2.89[1.08-7.76]) and cat sensitization (5.65[1.92-16.6]) among offspring, but was not associated with allergic outcomes among parents. Adjustment for childhood or current pet keeping did not alter associations with allergies. Parental Toxocara spp. seropositivity was associated with increased offspring allergies following a sex-specific pattern. Conclusions & Clinical Relevance Zoonotic helminth exposure in Norway was less frequent in offspring than parents; however, Toxocara spp. seropositivity was associated with increased risk of allergic manifestations in the offspring generation, but not among parents. Changes in response to helminth exposure may provide insights into the increase in allergy incidence in affluent countries

Zoonotic helminth exposure and risk of allergic diseases: a study of two generations in Norway

Background: Animal and human studies indicate that definitive host helminth infections may confer protection from allergies. However, zoonotic helminths, such as Toxocara species (spp.), have been associated with increased allergies. Objective: We describe the prevalence of Toxocara spp. and Ascaris spp. seropositivity, and associations with allergic diseases and sensitisation, in two generations in Bergen, Norway. Methods: Serum levels of total IgG4, anti-Toxocara spp. IgG4 and Ascaris spp. IgG4 were established by ELISA in two cohorts; parents born 1945-1972 (n=171) and their offspring born 1969-2003 (n=264). Allergic outcomes and covariates were recorded through interviews and clinical examinations including serum IgEs and skin prick tests. Results: Anti-Ascaris spp. IgG4 was detected in 29.2% of parents and 10.3% of offspring, and anti-Toxocara spp. IgG4 in 17.5% and 8.0% of parents and offspring, respectively. Among offspring anti-Toxocara spp. IgG4 was associated with pet keeping before age 15 (OR=6.15; 95% CI=1.37-27.5) and increasing BMI (1.16[1.06-1.25] per kg/m2). Toxocara spp. seropositivity was associated with wheeze (2.97[1.45- 7.76]), hay fever (4.03[1.63-9.95]), eczema (2.89[1.08-7.76]) and cat sensitization (5.65[1.92-16.6]) among offspring, but was not associated with allergic outcomes among parents. Adjustment for childhood or current pet keeping did not alter associations with allergies. Parental Toxocara spp. seropositivity was associated with increased offspring allergies following a sex-specific pattern. Conclusions &amp; Clinical Relevance: Zoonotic helminth exposure in Norway was less frequent in offspring than parents; however, Toxocara spp. seropositivity was associated with increased risk of allergic manifestations in the offspring generation, but not among parents. Changes in response to helminth exposure may provide insights into the increase in allergy incidence in affluent countries

Expression of IL-4 receptor α on smooth muscle cells is not necessary for development of experimental allergic asthma

Background\ud \ud Airflow in the lungs of patients with allergic asthma is impaired by excessive mucus production and airway smooth muscle contractions. Elevated levels of the cytokines IL-4 and IL-13 are associated with this pathology. In vitro studies have suggested that IL-4 receptor α (IL-4Rα) signaling on smooth muscle cells is critical for airway inflammation and airway hyperresponsiveness.\ud Objective\ud \ud To define the contribution of IL-4 and IL-13 to the onset of asthmatic pathology, the role of their key receptor IL-4Rα in smooth muscle cells was examined in vivo.\ud Methods\ud \ud By using transgenic smooth muscle myosin heavy chaincreIL-4Rα-/lox mice deficient in IL-4Rα in smooth muscle cells, in vivo effects of impaired IL-4Rα signaling in smooth muscle cells on the outcome of asthmatic disease were investigated for the first time. Allergic asthma was introduced in mice by repeated sensitization with ovalbumin/aluminum hydroxide on days 0, 7, and 14, followed by intranasal allergen challenge on days 21 to 23. Mice were investigated for the presence of airway hyperresponsiveness, airway inflammation, allergen-specific antibody production, Th2-type cytokine responses, and lung pathology.\ud Results\ud \ud Airway hyperresponsiveness, airway inflammation, mucus production, Th2 cytokine production, and specific antibody responses were unaffected in smooth muscle myosin heavy chaincreIL-4Rα-/lox mice compared with control animals.\ud Conclusion\ud \ud The impairment of IL-4Rα on smooth muscle cells had no effect on major etiologic markers of allergic asthma. These findings suggest that IL-4Rα responsiveness in airway smooth muscle cells during the early phase of allergic asthma is not, as suggested, necessary for the outcome of the disease