INTRODUCTION
The fundamental causes of adult allergic diseases and especially asthma are now widely regarded as having an inflammatory basis. Studies over the past two decades have elucidated the intricate interplay between the innate and adaptive immune systems in allergic inflammation that comprise antigen presenting cells, T helper (TH) 2 cells, IgE-producing B cells, eosinophils, mast cells and basophils, the cytokines IL-4, IL-5, and IL-13 and many other cells and molecules. Whereas the contributions of adaptive immune responses to allergic disease have been emphasized in the past, the last few years have seen crucial advances in how innate immune cells and molecular pathways contribute to allergy and asthma. Simultaneously with these advances, important progress has been made in our understanding of how the environment, and especially pathogenic organisms derived from the built environment, initiate allergic inflammation and disease. We review here the important recent advances made in these key areas, emphasizing the allergen-related signals that drive allergic responses.
KEY POINTS
•Chronic allergic diseases are increasingly recognized as beginning innately through the activation of AECs and group 2 innate lymphoid cells that secrete the cytokines TSLP, IL-25, IL-33, IL-4, and IL-13.
•Newly recognized innate immune receptors with potential to regulate allergic inflammation and disease include TLR4, PAR-2, and DP2.
•Diverse pathogens, including fungi and bacteria, can promote allergic inflammation through the release of proteinases and other factors.
•Proteinases mediate allergic inflammation and disease in part by cleaving the clotting factor fibrinogen, a fibrinogen cleavage product of which then induces innate allergic inflammation and antifungal immunity through TLR4.
•Environmental factors with antiallergic activity include lipopolysaccharide, which signals through TLR4 to activate the ubiquitin modifying factor A20 and parasites, such as helminths and the protozoan T. gondii.
FungiFungi are frequently associated with allergic disease and extracts from fungi are a common method of inducing asthma in animal models. In the past 2 years, significant progress into understanding the mechanism of fungi-mediated allergic disease has been made. A protease allergen extracted from the fungus Aspergillus fumigatus was shown to penetrate airway epithelium and submucosa to trigger airway hyperresponsiveness by degrading the extra-cellular matrix of the ASM [30▪]. Furthermore, inhaled fungal proteinase has been found to cleave fibrinogen in the airway to provoke allergic disease and antifungal immune responses. These responses were mediated in part by AECs and macrophages and were dependent on TLR4 [25]. An additional study adds significantly to the growing body of literature indicating that severe allergic airway diseases, including steroid-refractory chronic rhinosinusitis (CRS), allergic fungal rhinosinusitis, and severe asthma, are fungal infectious diseases. Porter et al. [31] demonstrated in a cohort of patients undergoing endoscopic sinus surgery that fungi are culturable from the sinus lavage fluid obtained from the majority of patients with allergic airway disease (CRS with nasal polyps, many also having asthma), but in less than 20% of patients without CRS undergoing the identical procedure [31]. They also showed that the majority of patients with allergic airway disease demonstrate fungus-specific TH2 responses, whereas no patient without allergic disease demonstrated similar responses. These findings together suggest that CRS with or without asthma is because of the noninvasive growth of fungi along the airway mucosal surface (airway mycosis) and that clearance of such fungi might be palliative in these conditions. This is further supported by studies demonstrating that many live fungi are alone sufficient to reproduce all salient features of asthma in mice [32].
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863991/
The fundamental causes of adult allergic diseases and especially asthma are now widely regarded as having an inflammatory basis. Studies over the past two decades have elucidated the intricate interplay between the innate and adaptive immune systems in allergic inflammation that comprise antigen presenting cells, T helper (TH) 2 cells, IgE-producing B cells, eosinophils, mast cells and basophils, the cytokines IL-4, IL-5, and IL-13 and many other cells and molecules. Whereas the contributions of adaptive immune responses to allergic disease have been emphasized in the past, the last few years have seen crucial advances in how innate immune cells and molecular pathways contribute to allergy and asthma. Simultaneously with these advances, important progress has been made in our understanding of how the environment, and especially pathogenic organisms derived from the built environment, initiate allergic inflammation and disease. We review here the important recent advances made in these key areas, emphasizing the allergen-related signals that drive allergic responses.
KEY POINTS
•Chronic allergic diseases are increasingly recognized as beginning innately through the activation of AECs and group 2 innate lymphoid cells that secrete the cytokines TSLP, IL-25, IL-33, IL-4, and IL-13.
•Newly recognized innate immune receptors with potential to regulate allergic inflammation and disease include TLR4, PAR-2, and DP2.
•Diverse pathogens, including fungi and bacteria, can promote allergic inflammation through the release of proteinases and other factors.
•Proteinases mediate allergic inflammation and disease in part by cleaving the clotting factor fibrinogen, a fibrinogen cleavage product of which then induces innate allergic inflammation and antifungal immunity through TLR4.
•Environmental factors with antiallergic activity include lipopolysaccharide, which signals through TLR4 to activate the ubiquitin modifying factor A20 and parasites, such as helminths and the protozoan T. gondii.
FungiFungi are frequently associated with allergic disease and extracts from fungi are a common method of inducing asthma in animal models. In the past 2 years, significant progress into understanding the mechanism of fungi-mediated allergic disease has been made. A protease allergen extracted from the fungus Aspergillus fumigatus was shown to penetrate airway epithelium and submucosa to trigger airway hyperresponsiveness by degrading the extra-cellular matrix of the ASM [30▪]. Furthermore, inhaled fungal proteinase has been found to cleave fibrinogen in the airway to provoke allergic disease and antifungal immune responses. These responses were mediated in part by AECs and macrophages and were dependent on TLR4 [25]. An additional study adds significantly to the growing body of literature indicating that severe allergic airway diseases, including steroid-refractory chronic rhinosinusitis (CRS), allergic fungal rhinosinusitis, and severe asthma, are fungal infectious diseases. Porter et al. [31] demonstrated in a cohort of patients undergoing endoscopic sinus surgery that fungi are culturable from the sinus lavage fluid obtained from the majority of patients with allergic airway disease (CRS with nasal polyps, many also having asthma), but in less than 20% of patients without CRS undergoing the identical procedure [31]. They also showed that the majority of patients with allergic airway disease demonstrate fungus-specific TH2 responses, whereas no patient without allergic disease demonstrated similar responses. These findings together suggest that CRS with or without asthma is because of the noninvasive growth of fungi along the airway mucosal surface (airway mycosis) and that clearance of such fungi might be palliative in these conditions. This is further supported by studies demonstrating that many live fungi are alone sufficient to reproduce all salient features of asthma in mice [32].
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863991/