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2.  Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway 
PLoS Pathogens  2016;12(5):e1005589.
Clinical and experimental studies have shown that estradiol (E2) confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c+ DCs in the vagina were the predominant APC population responsible for priming these Th17 responses, and a potent source of IL-6 and IL-1β, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored Th17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient Th1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4+ T cell anti-viral immunity by priming vaginal DCs to induce Th17 responses through an IL-1-dependent pathway.
Author Summary
Female sex hormones can affect susceptibility and immune responses to infections. While a number of previous studies, including our own, have shown that progesterone and progesterone-derived hormonal contraceptives increase susceptibility and impair immune responses, estradiol protects against sexually transmitted infections. The reason why estradiol is protective remains unknown. In this study, we investigated the effect of estradiol on dendritic cells, specialized immune cells that determine what type of anti-viral cellular immune responses will be mounted following infection with a sexually transmitted virus, HSV-2. Our studies show that estradiol influences dendritic cells in the vaginal tract of mice to initiate unique anti-viral T cell immunity that results in better protection against genital HSV-2 infection. This type of T cell response is unique to the vaginal tract and not found in any other mucosal lining of the body. This is the first study to show directly that estradiol, a female sex hormone, can determine how well the immune system will combat a sexually transmitted viral infection. The information from this study will be very important in understanding what type of immunity can protect women from sexually transmitted infections and how we can use this information to develop better vaccines.
doi:10.1371/journal.ppat.1005589
PMCID: PMC4858291  PMID: 27148737
3.  Therapeutic potential of anti-IL-6 therapies for granulocytic airway inflammation in asthma 
Background
Determining the cellular and molecular phenotypes of inflammation in asthma can identify patient populations that may best benefit from targeted therapies. Although elevated IL-6 and polymorphisms in IL-6 signalling are associated with lung dysfunction in asthma, it remains unknown if elevated IL-6 levels are associated with a specific cellular inflammatory phenotype, and how IL-6 blockade might impact such inflammatory responses.
Methods
Patients undergoing exacerbations of asthma were phenotyped according to their airway inflammatory characteristics (normal cell count, eosinophilic, neutrophilic, mixed granulocytic), sputum cytokine profiles, and lung function. Mice were exposed to the common allergen, house dust-mite (HDM), in the presence or absence of endogenous IL-6. The intensity and nature of lung inflammation, and levels of pro-granulocytic cytokines and chemokines under these conditions were analyzed.
Results
Elevated IL-6 was associated with a lower FEV1 in patients with mixed eosinophilic-neutrophilic bronchitis. In mice, allergen exposure increased lung IL-6 and IL-6 was produced by dendritic cells and alveolar macrophages. Loss-of-function of IL-6 signalling (knockout or antibody-mediated neutralization) abrogated elevations of eosinophil and neutrophil recruiting cytokines/chemokines and allergen-induced airway inflammation in mice.
Conclusions
We demonstrate the association of pleiotropic cellular airway inflammation with IL-6 using human and animal data. These data suggest that exacerbations of asthma, particularly those with a combined eosinophilic and neutrophilic bronchitis, may respond to therapies targeting the IL-6 pathway and therefore, provide a rational basis for initiation of clinical trials to evaluate this.
doi:10.1186/s13223-015-0081-1
PMCID: PMC4397814  PMID: 25878673
Airway inflammation; Asthma; Allergy; Bronchitis; Eosinophil; Neutrophil; Granulocyte; IL-6; IL-6R; House dust-mite (HDM)
4.  Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo 
The Journal of Experimental Medicine  2014;211(8):1657-1672.
Eosinophil degranulation of peroxidase promotes DC activation and mobilization from the intestine to LNs to induce Th2 immunity and food allergy.
Eosinophils natively inhabit the small intestine, but a functional role for them there has remained elusive. Here, we show that eosinophil-deficient mice were protected from induction of Th2-mediated peanut food allergy and anaphylaxis, and Th2 priming was restored by reconstitution with il4+/+ or il4−/− eosinophils. Eosinophils controlled CD103+ dendritic cell (DC) activation and migration from the intestine to draining lymph nodes, events necessary for Th2 priming. Eosinophil activation in vitro and in vivo led to degranulation of eosinophil peroxidase, a granule protein whose enzymatic activity promoted DC activation in mice and humans in vitro, and intestinal and extraintestinal mouse DC activation and mobilization to lymph nodes in vivo. Further, eosinophil peroxidase enhanced responses to ovalbumin seen after immunization. Thus, eosinophils can be critical contributors to the intestinal immune system, and granule-mediated shaping of DC responses can promote both intestinal and extraintestinal adaptive immunity.
doi:10.1084/jem.20131800
PMCID: PMC4113937  PMID: 25071163
5.  A GM-CSF/IL-33 Pathway Facilitates Allergic Airway Responses to Sub-Threshold House Dust Mite Exposure 
PLoS ONE  2014;9(2):e88714.
Allergic asthma is a chronic immune-inflammatory disease of the airways. Despite aeroallergen exposure being universal, allergic asthma affects only a fraction of individuals. This is likely related, at least in part, to the extent of allergen exposure. Regarding house dust mite (HDM), we previously identified the threshold required to elicit allergic responses in BALB/c mice. Here, we investigated the impact of an initial immune perturbation on the response to sub-threshold HDM exposure. We show that transient GM-CSF expression in the lung facilitated robust eosinophilic inflammation, long-lasting antigen-specific Th2 responses, mucus production and airway hyperresponsiveness. This was associated with increased IL-33 levels and activated CD11b+ DCs expressing OX40L. GM-CSF-driven allergic responses were significantly blunted in IL-33-deficient mice. IL-33 was localized on alveolar type II cells and in vitro stimulation of human epithelial cells with GM-CSF enhanced intracellular IL-33 independently of IL-1α. Likewise, GM-CSF administration in vivo resulted in increased levels of IL-33 but not IL-1α. These findings suggest that exposures to environmental agents associated with GM-CSF production, including airway infections and pollutants, may decrease the threshold of allergen responsiveness and, hence, increase the susceptibility to develop allergic asthma through a GM-CSF/IL-33/OX40L pathway.
doi:10.1371/journal.pone.0088714
PMCID: PMC3925157  PMID: 24551140
6.  In Vivo-to-In Silico Iterations to Investigate Aeroallergen-Host Interactions 
PLoS ONE  2008;3(6):e2426.
Background
Allergic asthma is a complex process arising out of the interaction between the immune system and aeroallergens. Yet, the relationship between aeroallergen exposure, allergic sensitization and disease remains unclear. This knowledge is essential to gain further insight into the origin and evolution of allergic diseases. The objective of this research is to develop a computational view of the interaction between aeroallergens and the host by investigating the impact of dose and length of aeroallergen exposure on allergic sensitization and allergic disease outcomes, mainly airway inflammation and to a lesser extent lung dysfunction and airway remodeling.
Methods and Principal Findings
BALB/C mice were exposed intranasally to a range of concentrations of the most pervasive aeroallergen worldwide, house dust mite (HDM), for up to a quarter of their lifespan (20 weeks). Actual biological data delineating the kinetics, nature and extent of responses for local (airway inflammation) and systemic (HDM-specific immunoglobulins) events were obtained. Mathematical equations for each outcome were developed, evaluated, refined through several iterations involving in vivo experimentation, and validated. The models accurately predicted the original biological data and simulated an extensive array of previously unknown responses, eliciting two- and three-dimensional models. Our data demonstrate the non-linearity of the relationship between aeroallergen exposure and either allergic sensitization or airway inflammation, identify thresholds, behaviours and maximal responsiveness for each outcome, and examine inter-variable relationships.
Conclusions
This research provides a novel way to visualize allergic responses in vivo and establishes a basic experimental platform upon which additional variables and perturbations can be incorporated into the system.
doi:10.1371/journal.pone.0002426
PMCID: PMC2409221  PMID: 18545674

Results 1-6 (6)