Helminthic dehydrogenase drives PGE2 and IL-10 production in monocytes to potentiate Treg induction.

Immunoregulation of inflammatory, infection-triggered processes in the brain constitutes a central mechanism to control devastating disease manifestations such as epilepsy. Observational studies implicate the viability of Taenia solium cysts as key factor determining severity of neurocysticercosis (NCC), the most common cause of epilepsy, especially in children, in Sub-Saharan Africa. Viable, in contrast to decaying, cysts mostly remain clinically silent by yet unknown mechanisms, potentially involving Tregs in controlling inflammation. Here, we show that glutamate dehydrogenase from viable cysts instructs tolerogenic monocytes to release IL-10 and the lipid mediator PGE2 . These act in concert, converting naive CD4+ T cells into CD127- CD25hi FoxP3+ CTLA-4+ Tregs, through the G protein-coupled receptors EP2 and EP4 and the IL-10 receptor. Moreover, while viable cyst products strongly upregulate IL-10 and PGE2 transcription in microglia, intravesicular fluid, released during cyst decay, induces pro-inflammatory microglia and TGF-ß as potential drivers of epilepsy. Inhibition of PGE2 synthesis and IL-10 signaling prevents Treg induction by viable cyst products. Harnessing the PGE2 -IL-10 axis and targeting TGF-ß signaling may offer an important therapeutic strategy in inflammatory epilepsy and NCC.

Neurocysticercosis and cognitive impairment among people with epilepsy in Taenia solium endemic regions of rural southern Tanzania: A hospital-based cross-sectional study in mental health clinics of selected sites in Tanzania.

BACKGROUND: Epilepsy poses a significant public health problem in many parts of the world. The majority of people with epilepsy (PWE) are from low-income and middle-income countries (LMICs). Taenia solium neurocysticercosis (NCC) is estimated to cause 30% of preventable epilepsy in PWE in areas of T. solium endemicity. This study was conducted to assess the prevalence of NCC in PWE, evaluate the presence of cognitive impairment in PWE and assess potentially contributing factors. METHODS: PWE were recruited within a mental health clinic-based cross-sectional study in rural Southern Tanzania. PWE underwent a detailed neurological examination, including mental state, and a blood sample was collected for T. solium cysticercosis (CC) serology testing. Patients who were serologically positive for CC and those detected to have prominent neurological deficits apart from epilepsy were invited to receive a cerebral computed tomography (CT) examination. RESULTS: Out of the 223 people with epilepsy (PWE) recruited, 221 underwent clinical examination. Among these, 26 (11.8 %) had cognitive impairment, and 2 had neurological signs or symptoms without cognitive impairment. Twenty-five of the 223 PWE (11.2 %) tested positive for CC, of which 4 had cognitive impairment. One hundred and ninety-eight (88.8 %) tested negative for CC, of which 22 had cognitive impairment. A total of 36 participants underwent CT scans, with 18 testing positive and 18 testing negative for CC. Of the 36 who had CT scans, 8 (22.2 %) were diagnosed with NCC; 7 were CC positive, and 1 was CC negative; only the latter had cognitive impairment. Multivariate logistic regression confirmed that cognitive impairment in PWE was 8.62 times higher for Kongwa participants than Chunya, with a statistically significant association (95 % CI: 1.75, 156; p = 0.037). Additionally, having and education was associated with a 91 % reduction in the odds of cognitive impairment (OR = 0.09) compared to no education, which was also statistically significant (95 % CI: 0.01, 0.33; p = 0.002). There was no association between cognitive impairment and NCC. CONCLUSION: Our study found a 22.2 % prevalence of NCC among PWE. Cognitive impairment was present in 11.8 % of PWE but was not significantly associated with NCC. Socioeconomic and educational factors may play a larger role in cognitive impairment among PWE.

Impact of Mannitol Bladder Distension in the Intraoperative Detection of Ureteral Kinking During Pelvic Floor Surgery.

INTRODUCTION AND HYPOTHESIS: Ureteral injuries are the most feared complications of gynecological surgery and therefore intraoperative recognition is of the utmost importance. Intraoperative cystoscopy represents the diagnostics of choice to investigate ureteral patency thanks to the direct visualization of ureteral flows after administration of infusion mediums. In this study, we aimed to compare the diagnostic performance of saline versus mannitol intraoperative cystoscopy in terms of false negatives in a large cohort of patients. METHODS: We retrospectively analyzed data of patients who underwent vaginal hysterectomy and high uterosacral ligament suspension for POP. Patients were divided in two groups based on the use of saline or mannitol medium for intraoperative cystoscopy. Postoperative daily control of serum creatinine was performed until discharge, as well as urinary tract imaging, in symptomatic patients. RESULTS: A total of 925 patients underwent vaginal hysterectomy followed by high USL suspension for POP. Saline and mannitol medium were used in 545 patients and 380 patients respectively. Postoperative ureteral injuries were identified in 12 patients, specifically in 2% of the saline group and in 0.3% of the mannitol group. CONCLUSIONS: The use of mannitol instead of saline as a bladder distension medium was able to significantly reduce the occurrence of postoperative ureteral sequelae.

A Novel Method for the Measurement of the Vaginal Wall Thickness by Transvaginal Ultrasound: A Study of Inter- and Intra-Observer Reliability.

Background and Objectives: A consensus regarding the optimal sonographic technique for measuring vaginal wall thickness (VWT) is still absent in the literature. This study aims to validate a new method for measuring VWT using a biplanar transvaginal ultrasound probe and assess both its intra-operator and inter-operator reproducibility. Material and Methods: This prospective study included patients with genitourinary syndrome of menopause-related symptoms. Women were scanned using a BK Medical Flex Focus 400 with the 65 × 5.5 mm linear longitudinal transducer of an endovaginal biplanar probe (BK Medical probe 8848, BK Ultrasound, Peabody, MA, USA). Vaginal wall thickness (VWT) measurements were acquired from the anterior and posterior vaginal wall at three levels. Results: An inter-observer analysis revealed good consistency between operators at every anatomical site, and the intra-class coefficient ranged from 0.931 to 0.987, indicating high reliability. An intra-observer analysis demonstrated robust consistency in vaginal wall thickness measurements, with an intra-class coefficient exceeding 0.9 for all anatomical sites. Conclusions: The measurement of vaginal wall thickness performed by transvaginal biplanar ultrasound was easy and demonstrated good intra- and inter-operator reliability.

High Uterosacral Ligaments Suspension for Post-Hysterectomy Vaginal Vault Prolapse Repair.

Background and Objectives: Uterosacral ligaments (USLs) suspension is a well-studied, safe, and long-lasting technique for central compartment correction. Preliminary clinical experiences showed encouraging data for this technique, also for post-hysterectomy vaginal vault prolapse surgical treatment. However, up-to-date evidence for post-hysterectomy vaginal vault prolapse repair through high uterosacral ligaments suspension is limited. Consequently, with this study, we aimed to assess the efficiency, complications frequency, and functional results of native-tissue repair through USLs in vaginal vault prolapse. Materials and Methods: This was a retrospective study. Women with symptomatic vaginal vault prolapse (≥stage 2) who underwent surgery with transvaginal native-tissue repair by high uterosacral ligaments were included. Patient characteristics, preoperative assessment, operative data, postoperative follow-up visits, and re-interventions were collected from the hospital's record files. High uterosacral ligament suspension was performed according to the technique previously described by Shull. A transverse apical colpotomy at the level of the post-hysterectomy scar was performed in order to enter the peritoneal cavity. USLs were identified and transfixed from ventral to dorsal with three absorbable sutures. Sutures were then passed through the vaginal apex and tightened to close the transverse colpotomy and suspend the vaginal cuff. At the end of the surgical time, a diagnostic cystoscopy was performed in order to evaluate ureteral bilateral patency. Using the POP-Q classification system, we considered an objective recurrence as the descensus of at least one compartment ≥ II stage, or the need for a subsequent surgery for POP. The complaint of bulging symptoms was considered the item to define a subjective recurrence. We employed PGI-I scores to assess patients' satisfaction. Results: Forty-seven consecutive patients corresponding to the given period were analyzed. No intraoperative complications were observed. We observed one postoperative hematoma that required surgical evacuation. Thirty-three patients completed a minimum of one-year follow-up (mean follow-up 21.7 ± 14.6 months). Objective cure rate was observed in 25 patients (75.8%). No patients required reintervention. The most frequent site of recurrence was the anterior compartment (21.2%), while apical compartment prolapse relapsed only in 6% of patients. An improvement in all POP-Q parameters was recorded except TVL which resulted in a mean 0.5 cm shorter. Subjective recurrence was referred by 4 (12.1%) patients. The mean satisfaction assessed by PGI-I score was 1.6 ± 0.8. Conclusion: This analysis demonstrated that native-tissue repair through high USL suspension is an effective and safe procedure for the treatment of post-hysterectomy vaginal vault prolapse. Objective, subjective, functional, and quality of life outcomes were satisfactory, with minimal complications.

Changes in Pelvic Floor Ultrasonographic Features after Flat Magnetic Stimulation in Women with Chronic Pelvic Pain and Levator Ani Muscle Hypertonicity.

Background and Objectives: Chronic pelvic pain (CPP) represents a major public health problem for women with a significant impact on their quality of life. In many cases of CPP, due to gynecological causes-such as endometriosis and vulvodynia-improper pelvic floor muscle relaxation can be identified. Treatment of CPP with pelvic floor hypertonicity (PFH) usually involves a multimodal approach. Traditional magnetic stimulation has been proposed as medical technology to manage muscle hypertonicity and pelvic pain conditions through nerve stimulation, neuromodulation, and muscle relaxation. New Flat Magnetic Stimulation (FMS)-which involves homogeneous rather than curved electromagnetic fields-has the potential to induce sacral S2-S4 roots neuromodulation, muscle decontraction, and blood circulation improvement. However, the benefits of this new technology on chronic pelvic pain symptoms and biometrical muscular parameters are poorly known. In this study, we want to evaluate the modification of the sonographic aspect of the levator ani muscle before and after treatment with Flat Magnetic Stimulation in women with chronic pelvic pain and levator ani hypertonicity, along with symptoms evolution. Materials and Methods: A prospective observational study was carried out in a tertiary-level Urogynaecology department and included women with CPP and PFH. Approval from the local Ethics Committee was obtained before the start of the study (protocol code: MAGCHAIR). At the baseline, the intensity of pelvic pain was measured using a 10 cm visual analog scale (VAS), and patients were asked to evaluate their pelvic floor symptoms severity by answering the question, "How much do your pelvic floor symptoms bother you?" on a 5-answer Likert scale. Transperineal ultrasound (TPU) was performed to assess anorectal angle (ARA) and levator ani muscle minimal plane distance (LAMD). Treatment involved Flat Magnetic Stimulation alone or with concomitant local or systemic pharmacological therapy, depending on the patient's preferences. FMS was delivered with the DR ARNOLD system (DEKA M.E.L.A. Calenzano, Italy). After the treatment, patients were asked again to score the intensity of pelvic pain using the 10 cm visual analog scale (VAS) and to evaluate the severity of their pelvic floor symptoms on the 5-answer Likert scale. Patients underwent TPU to assess anorectal angle (ARA) and levator ani muscle minimal plane distance (LAMD). Results: In total, 11 patients completed baseline evaluation, treatment, and postoperative evaluation in the period of interest. All patients underwent eight sessions of Flat Magnetic Stimulation according to the protocol. Adjuvant pharmacological treatment was used in five (45.5%) patients. Specifically, we observed a significant increase in both ARA and LAMD comparing baseline and post-treatment measurements (p < 0.001). Quality of life scale scores at baseline and after treatment demonstrated a significant improvement in both tools (p < 0.0001). Conclusions: Flat Magnetic Stimulation, with or without adjuvant pharmacological treatment, demonstrated safety and efficacy in reducing pelvic floor hypertonicity, resulting in improvement in symptoms' severity and sonographic parameters of muscular spasm.

Flat Magnetic Stimulation for Urge Urinary Incontinence.

Background and Objectives: Strategies for overactive bladder syndrome (OAB) management involve, among others, strengthening the bladder outlet to suppress urgency and neuromodulating the sacral roots. Magnetic stimulation (MS) is a technology that involves an extracorporeal device that is able to provide an electromagnetic field specifically designed to interact with pelvic floor neuromuscular tissue. The resulting tissue electrical activity induces contraction of the pelvic muscle and neuromodulation of the S2-S4 sacral roots. Flat Magnetic Stimulation (FMS) is a relevant advancement involving homogeneous electromagnetic fields, which are able to optimize the effect on the entire pelvic area. However, the benefits of this new technology for OAB syndrome are poorly known. Consequently, the aim of our study is to analyze the outcomes and quality of life (QoL) impact of FMS with Dr. Arnold (DEKA, Calenzano, Italy) in women suffering from OAB syndrome associated with urinary incontinence. Materials and Methods: This prospective study included patients with OAB, urge urinary incontinence, and no ongoing OAB treatments. At baseline (T0), the Incontinence Impact Questionnaire (IIQ-7), the Female Sexual Function Index (FSFI-19), and the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) were collected. Patients underwent 8 FMS sessions of 25 min each in one month. At the termination of the therapy (T1), women repeated the ICIQ-UI SF, FSFI-19, and IIQ-7 tools. Moreover, the Patient Global Impression of Improvement (PGI-I) questionnaire was collected to evaluate the cure rate. Results: Our study enrolled a total of 57 consecutive patients. Most women had at least one second- or third-line treatment before FMS, while the remaining naive patients had contraindications to pharmacological treatments. No women reported adverse effects during the treatment. After the treatment, we observed a decrease in the IIQ-7 (p < 0.001) and ICIQ-UI SF scores (p < 0.001) and an improvement in sexual function (p < 0.001) evaluated with FSFI-19. According to PGI-I scores, 42 (73.7%) women referred to some kind of improvement, scoring ≤ 3 points. Specifically, 8.7% of patients considered themselves very much improved, 29.8% much improved, 35.1% minimally improved, and 26.3% found no changes. FMS was effective in treating OAB symptoms without any adverse effects. The mechanism is supposed to be related to suppressing the initiation of micturition. This makes FMS a promising device for treating naive and refractory urge urinary incontinence. Conclusions: The new FMS represents a promising non-pharmacological option for the treatment of naive and refractory OAB.

Infection Control Measures and Prevalence of SARS-CoV-2 IgG among 4,554 University Hospital Employees, Munich, Germany.

Hospital staff are at high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease (COVID-19) pandemic. This cross-sectional study aimed to determine the prevalence of SARS-CoV-2 infection in hospital staff at the University Hospital rechts der Isar in Munich, Germany, and identify modulating factors. Overall seroprevalence of SARS-CoV-2-IgG in 4,554 participants was 2.4%. Staff engaged in direct patient care, including those working in COVID-19 units, had a similar probability of being seropositive as non-patient-facing staff. Increased probability of infection was observed in staff reporting interactions with SARS-CoV-2‒infected coworkers or private contacts or exposure to COVID-19 patients without appropriate personal protective equipment. Analysis of spatiotemporal trajectories identified that distinct hotspots for SARS-CoV-2‒positive staff and patients only partially overlap. Patient-facing work in a healthcare facility during the SARS-CoV-2 pandemic might be safe as long as adequate personal protective equipment is used and infection prevention practices are followed inside and outside the hospital.

Fetomaternal immune cross talk modifies T-cell priming through sustained changes to DC function.

BACKGROUND: Prenatal exposure to infections can modify immune development. These environmental disturbances during early life potentially alter the incidence of inflammatory disorders as well as priming of immune responses. Infection with the helminth Schistosoma mansoni is widely studied for its ability to alter immune responsiveness and is associated with variations in coinfection, allergy, and vaccine efficacy in endemic populations. OBJECTIVE: Exposure to maternal schistosomiasis during early life, even without transmission of infection, can result in priming effects on offspring immune responses to bystander antigenic challenges as related to allergic responsiveness and vaccination, with this article seeking to further clarify the effects and underlying immunologic imprinting. METHODS: Here, we have combined a model of chronic maternal schistosomiasis infection with a thorough analysis of subsequent offspring immune responses to allergy and vaccination models, including viral challenge and steady-state changes to immune cell compartments. RESULTS: We have demonstrated that maternal schistosomiasis alters CD4+ responses during allergic sensitization and challenge in a skewed IL-4/B-cell-dominant response to antigenic challenge associated with limited inflammatory response. Beyond that, we have uncovered previously unidentified alterations to CD8+ T-cell responses during immunization that are dependent on vaccine formulation and have functional impact on the efficacy of vaccination against viral infection in a murine hepatitis B virus model. CONCLUSION: In addition to steady-state modifications to CD4+ T-cell polarization and B-cell priming, we have traced these modified CD8+ responses to an altered dendritic cell phenotype sustained into adulthood, providing evidence for complex priming effects imparted by infection via fetomaternal cross talk.

Dectin-1/2-induced autocrine PGE2 signaling licenses dendritic cells to prime Th2 responses.

The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from Schistosoma mansoni, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE2), which subsequently-in an autocrine manner-induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE2 synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 1 and 2 (COX-1 and COX-2). In addition, this pathway was activated independently of the actions of omega-1 (ω-1), a previously described Th2-priming glycoprotein present in SEA. These findings were supported by in vivo murine data showing that ω-1-independent Th2 priming by SEA was mediated by Dectin-2 and Syk signaling in DCs. Finally, we found that Dectin-2-/-, and to a lesser extent Dectin-1-/- mice, displayed impaired Th2 responses and reduced egg-driven granuloma formation following S. mansoni infection, highlighting the physiological importance of this pathway in Th2 polarization during a helminth infection. In summary, we identified a novel pathway in DCs involving Dectin-1/2-Syk-PGE2-OX40L through which Th2 immune responses are induced.

Fetal growth restriction in a cohort of migrants in Germany.

BACKGROUND: Migrant women may have an increased risk of adverse birth outcomes. This study analyses the occurrence of low birth weight, preterm birth and intrauterine growth restriction / fetal growth restriction (IUGR/FGR) in pregnant migrants. METHOD: Cross-sectional study of 82 mother-child pairs of pregnant migrants attending medical care in Germany. RESULTS: The Median age was 27 years, 49% of patients were of oriental-asian ethnicity and median year of migration was 2015. At least one previous pregnancy was reported in 76% of patients, in 40% the delivery mode was caesarian section. Median gestational age was 39.7 weeks. Preterm birth occurred in 6.1% of pregnancies. Median gestational age for preterm birth was 32.3 weeks. Low birth weight (< 2500 g) occurred in 6.1%. Birth weights below the 10th percentile of birth weight for gestational age were observed in 8.5% of the total cohort. CONCLUSIONS: Compared to German data no increased occurrence of low birth weight, preterm birth or IUGR/FGR was found. We note that the rate of caesarian section births was higher than in the general population for reasons yet to be identified. The authors propose stratification according to migration status for the national documentation of birth outcomes in Germany.

Dynamic, Helminth-Induced Immune Modulation Influences the Outcome of Acute and Chronic Hepatitis B Virus Infection.

BACKGROUND: Chronic hepatitis B develops more frequently in countries with high prevalence of helminth infections. The crosstalk between these 2 major liver-residing pathogens, Schistosoma mansoni and hepatitis B virus (HBV), is barely understood. METHODS: We used state-of-the-art models for both acute and chronic HBV infection to study the pathogen-crosstalk during the different immune phases of schistosome infection. RESULTS: Although liver pathology caused by schistosome infection was not affected by either acute or chronic HBV infection, S mansoni infection influenced HBV infection outcomes in a phase-dependent manner. Interferon (IFN)-γ secreting, HBV- and schistosome-specific CD8 T cells acted in synergy to reduce HBV-induced pathology during the TH1 phase and chronic phase of schistosomiasis. Consequently, HBV was completely rescued in IFN-γ-deficient or in TH2 phase coinfected mice demonstrating the key role of this cytokine. It is interesting to note that secondary helminth infection on the basis of persistent (chronic) HBV infection increased HBV-specific T-cell frequency and resulted in suppression of virus replication but failed to fully restore T-cell function and eliminate HBV. CONCLUSIONS: Thus, schistosome-induced IFN-γ had a prominent antiviral effect that outcompeted immunosuppressive effects of TH2 cytokines, whereas HBV coinfection did not alter schistosome pathogenicity.

Maternal helminth infections and the shaping of offspring immunity.

Helminth infections leave a long-lasting immunological footprint on their hosts. Clinical studies have provided first evidence that maternal helminth infections can result in an altered immune profile in their offspring which can potentially shape how they respond to conditions throughout life. This can relate to changes in offspring induction of immune responses against other diseases. However, whether these changes result in actual changes in offspring ability to control disease is unclear. Our understanding of which immune mechanisms are altered and how they are changed is limited. In this review, we highlight what we know from human and mouse studies about this important context of helminth exposure. Moreover, we discuss how mechanisms such as antibody transfer, antigen exposure, maternal cell uptake, chimerism and epigenetics are all likely to be functional contributors to the striking changes that are seen in offspring born or nursed by helminth exposed mothers.

Chronic schistosomiasis during pregnancy epigenetically reprograms T-cell differentiation in offspring of infected mothers.

Schistosomiasis is a nontransplacental helminth infection. Chronic infection during pregnancy suppresses allergic airway responses in offspring. We addressed the question whether in utero exposure to chronic schistosome infection (Reg phase) in mice affects B-cell and T-cell development. Therefore, we focused our analyses on T-cell differentiation capacity induced by epigenetic changes in promoter regions of signature cytokines in offspring. Here, we show that naïve T cells from offspring of schistosome infected female mice had a strong capacity to differentiate into TH 1 cells, whereas TH 2 differentiation was impaired. In accordance, reduced levels of histone acetylation of the IL-4 promoter regions were observed in naïve T cells. To conclude, our mouse model revealed distinct epigenetic changes within the naïve T-cell compartment affecting TH 2 and TH 1 cell differentiation in offspring of mothers with chronic helminth infection. These findings could eventually help understand how helminths alter T-cell driven immune responses induced by allergens, bacterial or viral infections, as well as vaccines.

Usefulness of 1,3 Beta-D-Glucan Detection in non-HIV Immunocompromised Mechanical Ventilated Critically Ill Patients with ARDS and Suspected Pneumocystis jirovecii Pneumonia.

INTRODUCTION: Pneumocystis jirovecii pneumonia (PCP) is a major cause of disease in immunocompromised individuals. Diagnosis is typically obtained by microscopy and/or PCR. For ambiguous PCR results, we evaluated the new biomarker 1,3-Beta-D-Glucan (BDG). METHODS: BDG serum levels were assessed and correlated to PCR results in immunosuppressed patients with ARDS. RESULTS: 11 (22%) out of 50 patients had suspected PCP. APACHE II (26 vs. 24; p < 0.002), SOFA score (16 vs. 14; p < 0.010) and mortality rate (34 vs. 69% p < 0.004; 34 vs. 80% p < 0.003) were significantly altered in patients with positive (pPCR) and slightly positive (spPCR) PCJ PCR as compared to patients with no-PCP (nPCP). BDG levels were significantly lower in patients with nPCP (86; 30-315 pg/ml) than in patients with pPCR (589; 356-1000 pg/ml; p < 0.001) and spPCP (398; 297-516 pg/ml; p < 0.004) referring to the cutoff in this study for PCP of 275 pg/ml. An overall sensitivity (S) of 92% (95% CI 86-96%) and specificity (SP) of 84% (95% CI 79-85%) for PCP were found for the BDG Fungitell assay. In detail, S of 98% (95% CI 94-100%) and SP of 86% (95% CI 82-92%) for pPCP and S of 98% (95% CI 96-100%) and SP of 88% (95% CI 86-96%) for spPCO were found. CONCLUSION: Serum BDG levels were strongly elevated in PCP, and the negative predictive value is high. BDG could be used as a preliminary test for patients with suspected PCP, especially in patients with slightly positive PCR results.

Microbes and asthma: Opportunities for intervention.

The worldwide incidence and prevalence of asthma continues to increase. Asthma is now understood as an umbrella term for different phenotypes or endotypes, which arise through different pathophysiologic pathways. Understanding the many factors contributing to development of the disease is important for the identification of novel therapeutic targets for the treatment of certain asthma phenotypes. The hygiene hypothesis has been formulated to explain the increasing prevalence of allergic disease, including asthma. This hypothesis postulates that decreased exposure at a young age to certain infectious agents as a result of improved hygiene, increased antibiotic use and vaccination, and changes in lifestyle and dietary habits is associated with changes in the immune system, which predispose subjects to allergy. Many microbes, during their coevolution with human subjects, developed mechanisms to manipulate the human immune system and to increase their chances of survival. Improving models of asthma, as well as choosing adequate end points in clinical trials, will lead to a more complete understanding of the underlying mechanisms, thus providing an opportunity to devise primary and secondary interventions at the same time as identifying new molecular targets for treatment. This article reports the discussion and conclusion of a workshop under the auspices of the Netherlands Lung Foundation to extend our understanding of how modulation of the immune system by bacterial, parasitic, and viral infections might affect the development of asthma and to map out future lines of investigation.

T cell-derived IL-4/IL-13 protects mice against fatal Schistosoma mansoni infection independently of basophils.

Schistosomiasis is a severe and chronic disease caused by the parasitic trematode Schistosoma mansoni after deposition of eggs in the liver and intestines. The immune response to S. mansoni eggs is characterized by increased Th2 cells, eosinophilia, and high serum IgE levels. Granulomas are formed around the eggs to protect the organs against tissue damage caused by toxic products that are secreted from the eggs. Egg-derived components have further been shown to activate the IgE-mediated release of IL-4 and IL-13 from basophils, suggesting that basophils could be involved in protection against a fatal course of infection. Using T cell-specific IL-4/IL-13-deficient mice and basophil-deficient Mcpt8Cre mice, we determined the contribution of Th2 cells and basophils for protective immunity against S. mansoni egg-induced pathology during the patent stage of infection. Our results demonstrate that T cell-derived IL-4/IL-13 was essential for granuloma formation, IgE production, basophilia, differentiation of alternatively activated macrophages, and protection against fatal infection. Although basophils were recruited into liver granulomas, they appeared to be dispensable as a source of IL-4/IL-13 both for differentiation of Th2 cells and for prevention of weight loss and mortality.

Helicobacter pylori-induced IL-1ß secretion in innate immune cells is regulated by the NLRP3 inflammasome and requires the cag pathogenicity island.

Infection with the gram-negative bacterium Helicobacter pylori is the most prevalent chronic bacterial infection, affecting ∼50% of the world's population, and is the main risk factor of gastric cancer. The proinflammatory cytokine IL-1ß plays a crucial role in the development of gastric tumors and polymorphisms in the IL-1 gene cluster leading to increased IL-1ß production have been associated with increased risk for gastric cancer. To be active, pro-IL-1ß must be cleaved by the inflammasome, an intracellular multiprotein complex implicated in physiological and pathological inflammation. Recently, H. pylori was postulated to activate the inflammasome in murine bone marrow-derived dendritic cells; however, the molecular mechanisms as well as the bacterial virulence factor acting as signal 2 activating the inflammasome remain elusive. In this study, we analyzed the inflammasome complex regulating IL-1ß upon H. pylori infection as well as the molecular mechanisms involved. Our results indicate that H. pylori-induced IL-1ß secretion is mediated by activation of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 inflammasome. We also show that reactive oxygen species, potassium efflux, and lysosomal destabilization are the main cellular mechanisms responsible of nucleotide-binding oligomerization domain family, pyrin domain-containing 3 inflammasome activation upon H. pylori infection, and identify vacuolating cytotoxin A and cag pathogenicity island as the bacterial virulence determinants involved. Moreover, in vivo experiments indicate an important role for the inflammasome in the onset and establishment of H. pylori infection and in the subsequent inflammatory response of the host.

Fetal-maternal alignment of regulatory T cells correlates with IL-10 and Bcl-2 upregulation in pregnancy.

Transplacental immune regulation refers to the concept that during pregnancy, significant cross-talk occurs between the maternal and fetal immune system with potential long-term effects for both the mother and child. In this study, we made the surprising observation that there is a strong correlation of peripheral blood regulatory T (Treg) cells between the mother and the fetus. In contrast, there is no significant Treg cell correlation between paternal fetal dyads (pairs), suggesting that the specific context of pregnancy, rather than the genetic parental similarity to the fetus, is responsible for this correlation. Gene microarray analysis of Treg cells identified a typical IL-10-dependent signature in maternal and fetal Treg cells. In addition, a direct correlation of serum IL-10 protein levels between maternal fetal dyads was observed. Furthermore, we show that maternal serum IL-10 levels correlate with serum estradiol and estriol, implicating hormonal involvement in this alignment. Interestingly, we show that Treg cells possess higher expression of IL-10 receptor α and that Treg cell IL-10 receptor α expression directly correlates with their Bcl-2 expression. Indeed, in vitro data in both humans and mice demonstrate that IL-10 upregulates Bcl-2 specifically in Treg cells but not non-Treg cells. Our results provide evidence for transplacental regulation of cellular immunity and suggest that IL-10 may influence Treg cell homeostasis through its effect on Treg cell Bcl-2 expression. These novel findings have important implications on immune tolerance in pregnancy and beyond in areas of autoimmunity, allergy, and transplantation.