Type-2-cell-mediated immunity, rich in eosinophils, basophils, mast cells, CD4+ T helper 2 (Th2) cells, and type 2 innate lymphoid cells (ILC2s), protects the host from helminth infection but also ...drives chronic allergic diseases like asthma and atopic dermatitis. Barrier epithelial cells (ECs) represent the very first line of defense and express pattern recognition receptors to recognize type-2-cell-mediated immune insults like proteolytic allergens or helminths. These ECs mount a prototypical response made up of chemokines, innate cytokines such as interleukin-1 (IL-1), IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), as well as the alarmins uric acid, ATP, HMGB1, and S100 proteins. These signals program dendritic cells (DCs) to mount Th2-cell-mediated immunity and in so doing boost ILC2, basophil, and mast cell function. Here we review the general mechanisms of how different stimuli trigger type-2-cell-mediated immunity at mucosal barriers and how this leads to protection or disease.
Although the role of hematopoietic cell subsets in initiating and maintaining a type 2 immune response has been extensively studied, the contribution of non-hematopoietic cells to this biology has only recently been appreciated. Hammad and Lambrecht review the literature on the specific role of barrier epithelial cells in this signature immune response.
In many asthmatics, chronic airway inflammation is driven by IL-4-, IL-5-, and IL-13-producing Th2 cells or ILC2s. Type 2 cytokines promote hallmark features of the disease such as eosinophilia, ...mucus hypersecretion, bronchial hyperresponsiveness (BHR), IgE production, and susceptibility to exacerbations. However, only half the asthmatics have this “type 2-high” signature, and “type 2-low” asthma is more associated with obesity, presence of neutrophils, and unresponsiveness to corticosteroids, the mainstay asthma therapy. Here, we review the underlying immunological basis of various asthma endotypes by discussing results obtained from animal studies as well as results generated in clinical studies targeting specific immune pathways.
Hammad and Lambrecht review the immunological basis of asthma endotypes by discussing results from animal studies that have unraveled molecular pathways and clinical studies targeting specific immune pathways using molecule-specific biologics.
The immunology of the hygiene hypothesis of allergy is complex and involves the loss of cellular and humoral immunoregulatory pathways as a result of the adoption of a Western lifestyle and the ...disappearance of chronic infectious diseases. The influence of diet and reduced microbiome diversity now forms the foundation of scientific thinking on how the allergy epidemic occurred, although clear mechanistic insights into the process in humans are still lacking. Here we propose that barrier epithelial cells are heavily influenced by environmental factors and by microbiome-derived danger signals and metabolites, and thus act as important rheostats for immunoregulation, particularly during early postnatal development. Preventive strategies based on this new knowledge could exploit the diversity of the microbial world and the way humans react to it, and possibly restore old symbiotic relationships that have been lost in recent times, without causing disease or requiring a return to an unhygienic life style.
The immunology of asthma Lambrecht, Bart N; Hammad, Hamida
Nature immunology,
01/2015, Volume:
16, Issue:
1
Journal Article
Peer reviewed
Asthma is a common disease that affects 300 million people worldwide. Given the large number of eosinophils in the airways of people with mild asthma, and verified by data from murine models, asthma ...was long considered the hallmark T helper type 2 (TH2) disease of the airways. It is now known that some asthmatic inflammation is neutrophilic, controlled by the TH17 subset of helper T cells, and that some eosinophilic inflammation is controlled by type 2 innate lymphoid cells (ILC2 cells) acting together with basophils. Here we discuss results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans and describe the extraordinary heterogeneity of asthma.
Allergic sensitization to inhaled antigens is common but poorly understood. Although lung epithelial cells were initially merely regarded as a passive barrier impeding allergen penetrance, we now ...realize that they recognize allergens through expression of pattern recognition receptors and mount an innate immune response driven by activation of nuclear factor κB. On allergen recognition, epithelial cells release cytokines, such as IL-1, IL-25, IL-33, thymic stromal lymphopoietin, and GM-CSF, and endogenous danger signals, such as high-mobility group box 1, uric acid, and ATP, that activate the dendritic cell network and other innate immune cells, such as basophils and type 2 innate lymphoid cells. Different allergens stimulate different aspects of this general scheme, and common environmental risk factors for sensitization, such as cigarette smoke and diesel particle exposure, do so as well. All of this is influenced by genetic polymorphisms affecting epithelial pattern recognition, barrier function, and cytokine production. Therefore, epithelial cells are crucial in determining the outcome of allergen inhalation.
Dendritic cells (DCs) are crucial for mounting allergic airway inflammation, but it is unclear which subset of DCs performs this task. By using CD64 and MAR-1 staining, we reliably separated CD11b+ ...monocyte-derived DCs (moDCs) from conventional DCs (cDCs) and studied antigen uptake, migration, and presentation assays of lung and lymph node (LN) DCs in response to inhaled house dust mite (HDM). Mainly CD11b+ cDCs but not CD103+ cDCs induced T helper 2 (Th2) cell immunity in HDM-specific T cells in vitro and asthma in vivo. Studies in Flt3l−/− mice, lacking all cDCs, revealed that moDCs were also sufficient to induce Th2 cell-mediated immunity but only when high-dose HDM was given. The main function of moDCs was the production of proinflammatory chemokines and allergen presentation in the lung during challenge. Thus, we have identified migratory CD11b+ cDCs as the principal subset inducing Th2 cell-mediated immunity in the LN, whereas moDCs orchestrate allergic inflammation in the lung.
▸ CD64 and MAR-1 are optimum markers for separating moDCs from cDCs ▸ CD11b+ cDCs, not CD103+ cDCs, induce Th2 cell priming in lung ▸ moDCs, not cDCs, are the source of proinflammatory chemokines ▸ moDCs are not the exclusive APC for Th1 cell induction
The novel coronavirus disease 2019 (COVID-19) pandemic is a global crisis, challenging healthcare systems worldwide. Many patients present with a remarkable disconnect in rest between profound ...hypoxemia yet without proportional signs of respiratory distress (i.e. happy hypoxemia) and rapid deterioration can occur. This particular clinical presentation in COVID-19 patients contrasts with the experience of physicians usually treating critically ill patients in respiratory failure and ensuring timely referral to the intensive care unit can, therefore, be challenging. A thorough understanding of the pathophysiological determinants of respiratory drive and hypoxemia may promote a more complete comprehension of a patient's clinical presentation and management. Preserved oxygen saturation despite low partial pressure of oxygen in arterial blood samples occur, due to leftward shift of the oxyhemoglobin dissociation curve induced by hypoxemia-driven hyperventilation as well as possible direct viral interactions with hemoglobin. Ventilation-perfusion mismatch, ranging from shunts to alveolar dead space ventilation, is the central hallmark and offers various therapeutic targets.
The Cytokines of Asthma Lambrecht, Bart N.; Hammad, Hamida; Fahy, John V.
Immunity (Cambridge, Mass.),
04/2019, Volume:
50, Issue:
4
Journal Article
Peer reviewed
Open access
Asthma is a chronic inflammatory airway disease associated with type 2 cytokines interleukin-4 (IL-4), IL-5, and IL-13, which promote airway eosinophilia, mucus overproduction, bronchial ...hyperresponsiveness (BHR), and immunogloubulin E (IgE) synthesis. However, only half of asthma patients exhibit signs of an exacerbated Type 2 response. “Type 2-low” asthma has different immune features: airway neutrophilia, obesity-related systemic inflammation, or in some cases, few signs of immune activation. Here, we review the cytokine networks driving asthma, placing these in cellular context and incorporating insights from cytokine-targeting therapies in the clinic. We discuss established and emerging paradigms in the context of the growing appreciation of disease heterogeneity and argue that the development of new and improved therapeutics will require understanding the diverse mechanisms underlying the spectrum of asthma pathologies.
Lambrecht et al. review pre-clinical and clinical data on the cytokine networks driving asthma and discuss established and emerging paradigms in the context of the growing appreciation of disease heterogeneity and results in the clinic.
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