Search

Background Exposure to respiratory allergens triggers airway hyperresponsiveness and inflammation characterized by the expansion of TH2 cells and the production of allergen specific IgE. Allergic asthma is characterized by an alteration in immune regulatory mechanisms leading to an imbalance between pro- and anti-inflammatory components of the immune system. Aims Recently B cells have been described as central regulators of exacerbated inflammation, notably in the case of autoimmunity. However, to what extent these cells can regulate airway inflammation and asthma remains to be elucidated. Materials & Methods We took advantage of a allergic asthma model in mice induced by percutaneous sensitization and respiratory challenge with an extract of house dust mite. Results In this study, we showed that the induction of allergic asthma alters the homeostasis of IL-10+ Bregs and favors the production of inflammatory cytokines by B cells. Deeper transcriptomic and phenotypic analysis of Bregs revealed that they were enriched in a CD9+ B cell subset. In asthmatic mice the adoptive transfer of CD9+ B cells normalized airway inflammation and lung function by inhibiting TH2- and TH17-driven inflammation in an IL-10-dependent manner, restoring a favorable immunological balance in lung tissues. Indeed we further showed that injection of CD9+ Bregs controls the expansion of lung effector T cells allowing the establishment of a favorable regulatory T cells/effector T cells ratio in lungs. Conclusion This finding strengthens the potential for Breg-targeted therapies in allergic asthma. [ABSTRACT FROM AUTHOR]

In this study we examined the effects of social intelligence, empathy, verbal ability and appearance-reality distinction on the level of peer acceptance, as well as the moderating role of gender. Participants were 98 five-year-old children (43 boys and 55 girls; mean age 5 years 3 months for boys and girls). Our results showed a main effect of social intelligence on peer acceptance, as well as several other effects that were moderated by gender: a significant and positive effect of verbal ability on social acceptance was found for boys; appearance-reality distinction was found to have a positive effect on social acceptance in the case of girls; and although empathy had a significant positive effect on social acceptance for both boys and girls, this effect was more pronounced among boys. Our results suggest that abilities promoting peer acceptance are different for boys and girls. [ABSTRACT FROM AUTHOR]

Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten-eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation., (© 2024. The Author(s).)

Objective: The ferritin heavy/heart chain (FTH) gene encodes the ferroxidase component of the iron (Fe) sequestering ferritin complex, which plays a central role in the regulation of cellular Fe metabolism. Here we tested the hypothesis that ferritin regulates organismal Fe metabolism in a manner that impacts energy balance and thermal homeostasis., Methods: We developed a mouse strain, referred herein as Fth R26 fl/fl , expressing a tamoxifen-inducible Cre recombinase under the control of the Rosa26 (R26) promoter and carrying two LoxP (fl) sites: one at the 5'end of the Fth promoter and another the 3' end of the first Fth exon. Tamoxifen administration induces global deletion of Fth in adult Fth R26Δ/Δ mice, testing whether FTH is required for maintenance of organismal homeostasis., Results: Under standard nutritional Fe supply, Fth deletion in adult Fth R26Δ/Δ mice led to a profound deregulation of organismal Fe metabolism, oxidative stress, inflammation, and multi-organ damage, culminating in death. Unexpectedly, Fth deletion was also associated with a profound atrophy of white and brown adipose tissue as well as with collapse of energy expenditure and thermogenesis. This was attributed mechanistically to mitochondrial dysfunction, as assessed in the liver and in adipose tissue., Conclusion: The FTH component of ferritin acts as a master regulator of organismal Fe homeostasis, coupling nutritional Fe supply to organismal redox homeostasis, energy expenditure and thermoregulation., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Pathogenic organisms exert a negative impact on host health, revealed by the clinical signs of infectious diseases. Immunity limits the severity of infectious diseases through resistance mechanisms that sense and target pathogens for containment, killing, or expulsion. These resistance mechanisms are viewed as the prevailing function of immunity. Under pathophysiologic conditions, however, immunity arises in response to infections that carry health and fitness costs to the host. Therefore, additional defense mechanisms are required to limit these costs, before immunity becomes operational as well as thereafter to avoid immunopathology. These are tissue damage control mechanisms that adjust the metabolic output of host tissues to different forms of stress and damage associated with infection. Disease tolerance is the term used to define this defense strategy, which does not exert a direct impact on pathogens but is essential to limit the health and fitness costs of infection. Under this argument, we propose that disease tolerance is an inherent component of immunity.

Malaria, the disease caused by Plasmodium spp. infection, remains a major global cause of morbidity and mortality. Host protection from malaria relies on immune-driven resistance mechanisms that kill Plasmodium However, these mechanisms are not sufficient per se to avoid the development of severe forms of disease. This is accomplished instead via the establishment of disease tolerance to malaria, a defense strategy that does not target Plasmodium directly. Here we demonstrate that the establishment of disease tolerance to malaria relies on a tissue damage-control mechanism that operates specifically in renal proximal tubule epithelial cells (RPTEC). This protective response relies on the induction of heme oxygenase-1 ( HMOX1 ; HO-1) and ferritin H chain ( FTH ) via a mechanism that involves the transcription-factor nuclear-factor E2-related factor-2 ( NRF2 ). As it accumulates in plasma and urine during the blood stage of Plasmodium infection, labile heme is detoxified in RPTEC by HO-1 and FTH, preventing the development of acute kidney injury, a clinical hallmark of severe malaria., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Background: The molecular mechanisms responsible for airway smooth muscle cells' (aSMCs) contraction and proliferation in airway hyperresponsiveness (AHR) associated with asthma are still largely unknown. The small GTPases of the Rho family (RhoA, Rac1, and Cdc42) play a central role in SMC functions including migration, proliferation, and contraction., Objective: The objective of this study was to identify the role of Rac1 in aSMC contraction and to investigate its involvement in AHR associated with allergic asthma., Methods: To define the role of Rac1 in aSMC, ex and in vitro analyses of bronchial reactivity were performed on bronchi from smooth muscle (SM)-specific Rac1 knockout mice and human individuals. In addition, this murine model was exposed to allergens (ovalbumin or house dust mite extract) to decipher in vivo the implication of Rac1 in AHR., Results: The specific SMC deletion or pharmacological inhibition of Rac1 in mice prevented the bronchoconstrictor response to methacholine. In human bronchi, a similar role of Rac1 was observed during bronchoconstriction. We further demonstrated that Rac1 activation is responsible for bronchoconstrictor-induced increase in intracellular Ca 2+ concentration and contraction both in murine and in human bronchial aSMCs, through its association with phospholipase C β2 and the stimulation of inositol 1,4,5-trisphosphate production. In vivo, Rac1 deletion in SMCs or pharmacological Rac1 inhibition by nebulization of NSC23766 prevented AHR in murine models of allergic asthma. Moreover, nebulization of NSC23766 decreased eosinophil and neutrophil populations in bronchoalveolar lavages from mice with asthma., Conclusions: Our data reveal an unexpected and essential role of Rac1 in the regulation of intracellular Ca 2+ and contraction of aSMCs, and the development of AHR. Rac1 thus appears as an attractive therapeutic target in asthma, with a combined beneficial action on both bronchoconstriction and pulmonary inflammation., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

A maternal authoritarian style has been related to the development of physical aggression during childhood and later future social problems; however, not too many studies have detected other than individual or family factors that may buffer this maternal effect. This work examines whether daycare center attendance may moderate the relationships between a mother authoritarian style and physical aggression. The study sample was 72 (40 girls) kindergarten children from Spain. Parents were asked to complete two questionnaires focused on individual family characteristics and parenting styles. At age 5, children physical aggression was assessed by direct observation at playtime; aggression scores at 6 was obtained by a peer-rated questionnaire. A least squared multiple regression was performed after controlling for children's level of physical aggression at 5, child sex and siblings. A positive contribution of maternal authoritarian style on physical aggression was detected. Daycare center attendance appears to attenuate the effect of the mother's authoritarian style on physical aggression, only in boys.

Mesenchymal stem cell (MSC) immunosuppressive functions make them attractive candidates for anti-inflammatory therapy in allergic asthma. However, the mechanisms by which they ensure therapeutic effects remain to be elucidated. In an acute mouse model of house dust mite (Der f)-induced asthma, one i.v. MSC injection was sufficient to normalize and stabilize lung function in Der f-sensitized mice as compared to control mice. MSC injection decreased in vivo airway responsiveness and decreased ex vivo carbachol-induced bronchial contraction, maintaining bronchial expression of the inhibitory type 2 muscarinic receptor. To evaluate in vivo MSC survival, MSCs were labeled with PKH26 fluorescent marker prior to i.v. injection, and 1 to 10 days later total lungs were digested to obtain single-cell suspensions. 91.5 ± 2.3% and 86.6 ± 6.3% of the recovered PKH26(+) lung cells expressed specific macrophage markers in control and Der f mice, respectively, suggesting that macrophages had phagocyted in vivo the injected MSCs. Interestingly, only PKH26(+) macrophages expressed M2 phenotype, while the innate PKH26(-) macrophages expressed M1 phenotype. Finally, the remaining 0.5% PKH26(+) MSCs expressed 10- to 100-fold more COX-2 than before injection, suggesting in vivo MSC phenotype modification. Together, the results of this study indicate that MSCs attenuate asthma by being phagocyted by lung macrophages, which in turn acquire a M2 suppressive phenotype. Stem Cells 2016;34:1836-1845., (© 2016 AlphaMed Press.)

Graft inflammation impairs the induction of solid organ transplant tolerance and enhances acute and chronic rejection. Elucidating the mechanisms by which inflammation is induced after organ transplantation could lead to novel therapeutics to improve transplant outcomes. In this Review we describe endogenous substances--damage-associated molecular patterns (DAMPs)--that are released after allograft reperfusion and induce inflammation. We also describe innate immune signalling pathways that are activated after solid organ transplantation, with a focus on Toll-like receptors (TLRs) and their signal adaptor, MYD88. Experimental and clinical studies have yielded a large body of evidence that TLRs and MYD88 are instrumental in initiating allograft inflammation and promoting the development of acute and chronic rejection. Ongoing clinical studies are testing TLR inhibition strategies in solid organ transplantation, although avoiding compromising host defence to pathogens is a key challenge. Further elucidation of the mechanisms by which sterile inflammation is induced, maintained and amplified within the allograft has the potential to lead to novel anti-inflammatory treatments that could improve outcomes for solid organ transplant recipients.

Objectives: This study explored the developmental trajectory of aggressive behavior from age 8 to age 10 in school-aged children, taking into account possible sex differences, as well as the involvement of certain hormones., Methods: Participants were 90 children (49 boys and 41 girls) from four schools. At the beginning of the study, the children were 8-year old and were in 3rd grade of primary school. The second data collection phase was carried out two years later (at age 10) when the children were in 5th grade (primary). Their aggressive behavior was measured by the Direct and Indirect Aggression Scale, an instrument which uses peer rating. Hormone levels, testosterone, cortisol and estradiol were analyzed using an enzymoimmunoassay technique in saliva samples., Results: The results revealed a difference in aggressive behavior between the ages of 8 and 10, in boys only, who were found to be more aggressive at age 10. A regression analysis revealed that cortisol and estradiol contributed to explaining the changes observed in aggressive behavior in boys. Boys whose cortisol levels rose most between the ages of 8 and 10 were also those whose aggressive behavior increased most during the same timeframe. Moreover, boys whose estradiol levels rose most between the ages of 8 and 10 were also those whose aggressive behavior decreased most during the same timeframe., Conclusions: Our results highlight the importance of studying aggressive behavior from a longitudinal perspective, taking into account sex differences and biological measures., (© 2015 Wiley Periodicals, Inc.)

Background: Brain injuries (BI) induce a state of systemic immunosuppression, leading to a high risk of pneumonia. In this pilot study, we investigated the status of B cell compartment in BI patients., Methods: A prospective observational study was performed in 2 intensive care units in a university hospital. Blood samples were collected in 14 patients at day 1 and day 7 after acute BI. The phenotype and the ability of B cells to secrete IL-10 were compared to 11 healthy volunteers (HV)., Results: Among the circulating lymphocytes, the frequency of B cells was significantly higher in BI patients compared to HV (p<0.001). B cells from BI patients displayed an activated profil on day 7 after BI, reflected by a significantly higher proportion of CD27(+) memory (p=0.01) and CD27(+) IgD(-) switched memory B cells (p=0.02), as well as a significantly higher blood level of IgA (p=0.001) and IgM (p<0.001) as compared to day 1. The frequency of IL-10 secreting B cells (IL-10(+) B cells) on day 1 and day 7 was significantly lower in BI patients compared to HV (p<0.05). Interestingly, we observed that all BI patients with high frequency of IL-10(+) B cells on day 1 displayed an episode of pneumonia, and had a longer duration of mechanical ventilation and ICU stay compared to BI patients with low proportion of IL-10(+) B cells., Conclusion: This study provides an extensive description of the phenotype and function of B cells in BI patients. Our results suggest that IL-10(+) B cells could play a major role in immunosuppression after BI., (Copyright © 2015 Elsevier Ltd. All rights reserved.)