Allergic manifestations are increasingly common in infants and children. Accumulating evidence suggests that the ‘epidemic’ increase of childhood allergy may be associated with environmental factors such as stress. Although the impact of stress on the manifestation and exacerbation of allergy has been demonstrated, the underlying mechanisms of stress-induced exacerbation are still obscure. A growing number of studies have suggested an altered hypothalamus-pituitary-adrenal (HPA) axis function to stress in allergic children. It is speculated that a dysfunctional HPA axis in response to stress may facilitate and/or consolidate immunological aberrations and thus, may increase the risk for allergic sensitization and exacerbation especially under stressful conditions. In the present review the potential impact of a hyporesponsive as well as a hyperresponsive HPA axis on the onset and chronification of childhood allergy is summarized. Moreover, potential factors that may contribute to the development of an aberrant HPA axis responsiveness in allergy are discussed. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

<p>Allergic asthma is a chronic and complex disease of the airways characterized by dysregulated immune-inflammatory responses to aeroallergens and reversible airflow obstruction. The prevalence and economic burden of allergic asthma have increased substantially over the last five decades. Despite remarkable progress in our understanding of the immunobiology and pathophysiology of asthma, the ontogeny of the disease remains elusive. As a result, there is a lack of effective preventative strategies. Here, we used a murine model of allergic asthma to house dust mite (HDM), the most pervasive indoor aeroallergen worldwide to address issues pertaining to the development of allergic asthma. First, we provided a comprehensive computational view of the impact of dose and length of HDM exposure on both local and systemic allergic outcomes (Chapter 2). Parameters, such as thresholds of responsiveness, and non-linear relationships between allergen exposure, allergic sensitization and airway inflammation were identified. We, then, investigated molecular signatures implicated in the onset of allergic responses (Chapter 3). HDM exposure was associated with production of the epithelial-associated cytokines TSLP, IL-25 and IL-33. However, only IL-33 signaling was necessary for intact Th2 immunity to HDM, likely because of its superior ability to induce the critical co-stimulatory molecule OX40L on dendritic cells and expand innate lymphoid cells. Lastly, as individuals are most likely exposed to allergens concomitantly to other environmental immunogenic agents, we studied the impact of an initial immune perturbation on allergic responses to sub-threshold amounts of HDM (Chapter 4). We showed that transient expression of GM-CSF in the airway substantially lowers the threshold of allergen required to generate robust, HDM-specific Th2 immunity, likely through increasing IL-33 production from alveolar type II cells. These studies favor a paradigm whereby distinct molecular pathways can elicit type 2 immunity, intimating the need to classify asthma into distinct clinical subsets.</p> / Doctor of Philosophy (PhD)

Allergic manifestations are increasingly common in infants and children. Accumulating evidence suggests that the ‘epidemic’ increase of childhood allergy may be associated with environmental factors such as stress. Although the impact of stress on the manifestation and exacerbation of allergy has been demonstrated, the underlying mechanisms of stress-induced exacerbation are still obscure. A growing number of studies have suggested an altered hypothalamus-pituitary-adrenal (HPA) axis function to stress in allergic children. It is speculated that a dysfunctional HPA axis in response to stress may facilitate and/or consolidate immunological aberrations and thus, may increase the risk for allergic sensitization and exacerbation especially under stressful conditions. In the present review the potential impact of a hyporesponsive as well as a hyperresponsive HPA axis on the onset and chronification of childhood allergy is summarized. Moreover, potential factors that may contribute to the development of an aberrant HPA axis responsiveness in allergy are discussed. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

L’asthme est répandu chez 250 millions de personnes dans le monde, dont la majorité souffre d’asthme allergique à médiation IgE. La diaphonie neuro-immune a récemment fait l’objet d’études approfondies. La présente thèse comprend des études sur des modèles de souris, y compris nos travaux publiés portant sur l’interaction neurone sensoriel-cellule B, un manuscrit soumis sur l’interaction neurones pruricepteurs vagaux-basophiles, ainsi que nos méthodes de recherche publiées sous forme de chapitre de livre. Dans le chapitre 1, nous avons démontré que la perte de fonction des neurones sensoriels atténuait l’inflammation allergique des voies respiratoires induite par les acariens et l’activation des cellules IgE+ B. Les données in vitro suggèrent que l’activation des lymphocytes B et la production d’anticorps étaient améliorées par la substance P. Dans le chapitre 2, nous avons démontré que les neurones sensoriels vagaux répondent aux pruritogènes, à l’analogue du LPA xy-17, à la β-alanine et à la chloroquine, suggérant que le pruricepteur-comme le comportement de certains neurones sensoriels vagaux, comme le prédisent les récents résultats de séquençage d’ARN unicellulaire. Plus important encore, nous avons démontré que l’oncostatine M est produite par les basophiles sous stimulation basée sur FcεRI et peut sensibiliser plusieurs populations sensorielles vagales, y compris les sous-ensembles jugulaires TRPV1+Tac1+ et MrgprA3+. Enfin, dans le chapitre 3, nous illustrons les méthodes détaillées d’étude des neurones sensoriels vagaux, y compris les approches génétiques et pharmacologiques de perte de fonction, et l’analyse transcriptomique des neurones sensoriels vagaux issus du tri cellulaire activé par fluorescence (FACS). Prises ensemble, nos données suggèrent que les neurones sensoriels peptidergiques participent à l’établissement de l’immunité humorale et que les neurones pruricepteurs vagaux répondent aux médiateurs inflammatoires allergiques, y compris la cytokine amplificatrice des démangeaisons, l’oncostatine M, produite par les basophiles activés par FcεRI. Des études supplémentaires sont nécessaires pour déchiffrer le rôle des neurones pruricepteurs vagaux dans la transmission du signal du tronc cérébral, l’inflammation périphérique et la mécanique pulmonaire globale de l’asthme. / Asthma is prevalent among 250 million people globally, the majority of which feature IgE-mediated allergic asthma. The neuro-immune crosstalk has been under intense study recently. The present thesis comprises studies of mouse models, including our published work focusing on sensory neuron-B cell interaction, a submitted manuscript on vagal pruriceptor neurons-basophil interaction, as well as our research methods published as a book chapter. In chapter 1, we demonstrated that loss of function of sensory neurons dampened house dust mite-induced allergic airway inflammation, IgE+ B cell activation. In vitro data suggests that the B cell activation and antibody production were enhanced by substance P. In chapter 2, we demonstrated that vagal sensory neurons respond to pruritogens, the LPA analog xy-17, β-alanine, and chloroquine, suggesting the pruriceptor-like behavior of some vagal sensory neurons, as predicted by recent singlecell RNA sequencing results. Most importantly, we demonstrated that oncostatin M is produced by basophils under FcεRI-based stimulation, and can sensitize multiple vagal sensory populations, including the jugular TRPV1+Tac1+ and MrgprA3+ subsets. Finally, in chapter 3, we illustrate the detailed methods for studying vagal sensory neurons, including the genetic and pharmacological loss-of-function approaches, and transcriptomic analysis of vagal sensory neurons yield from fluorescence-activated cell sorting (FACS). Taken together, our data suggests that peptidergic sensory neurons participate in the humoral immunity establishment and vagal pruriceptor neurons respond to allergic inflammatory mediators, including the itch-amplifying cytokine, oncostatin M, produced by FcεRI-activated basophils. Further studies are needed to decipher the role of vagal pruriceptor neurons in brainstem signal transmission, peripheral inflammation, and overall asthmatic lung mechanics.

Plasmacytoid dendritic cells (pDCs) regulate innate and adaptive immunity. Neurotrophins and their receptors control the function of neuronal tissue. In addition, they have been demonstrated to be part of the immune response but little is known about the effector immune cells involved. We report, for the first time, the expression and immune-regulatory function of the low affinity neurotrophin receptor p75 neurotrophin receptor (p75NTR) by the antigen-presenting pDCs, mediated by toll-like receptor (TLR) 9 activation and differential phosphorylation of interferon regulatory factor 3 and 7. The modulation of p75NTR on pDCs significantly influences disease progression of asthma in an ovalbumin-induced mouse model mediated by the TLR9 signaling pathway. p75NTR activation of pDCs from patients with asthma increased allergen-specific T cell proliferation and cytokine secretion in nerve growth factor concentration-dependent manner. Further, p75NTR activation of pDCs delayed the onset of autoimmune diabetes in RIP-CD80GP mice and aggravated graft-versus-host disease in a xenotransplantation model. Thus, p75NTR signaling on pDCs constitutes a new and critical mechanism connecting neurotrophin signaling and immune response regulation with great therapeutic potential for a variety of immune disorders.

Plasmacytoid dendritic cells (pDCs) regulate innate and adaptive immunity. Neurotrophins and their receptors control the function of neuronal tissue. In addition, they have been demonstrated to be part of the immune response but little is known about the effector immune cells involved. We report, for the first time, the expression and immune-regulatory function of the low affinity neurotrophin receptor p75 neurotrophin receptor (p75NTR) by the antigen-presenting pDCs, mediated by toll-like receptor (TLR) 9 activation and differential phosphorylation of interferon regulatory factor 3 and 7. The modulation of p75NTR on pDCs significantly influences disease progression of asthma in an ovalbumin-induced mouse model mediated by the TLR9 signaling pathway. p75NTR activation of pDCs from patients with asthma increased allergen-specific T cell proliferation and cytokine secretion in nerve growth factor concentration-dependent manner. Further, p75NTR activation of pDCs delayed the onset of autoimmune diabetes in RIP-CD80GP mice and aggravated graft-versus-host disease in a xenotransplantation model. Thus, p75NTR signaling on pDCs constitutes a new and critical mechanism connecting neurotrophin signaling and immune response regulation with great therapeutic potential for a variety of immune disorders.