Protease allergens as initiators–regulators of allergic inflammation

Abstract

Tremendous progress in the last few years has been made to explain how seemingly harmless environmental proteins from different origins can induce potent Th2-biased inflammatory responses. Convergent findings have shown the key roles of allergens displaying proteolytic activity in the initiation and progression of the allergic response. Through their propensity to activate IgE-independent inflammatory pathways, certain allergenic proteases are now considered as initiators for sensitization to themselves and to non-protease allergens. The protease allergens degrade junctional proteins of keratinocytes or airway epithelium to facilitate allergen delivery across the epithelial barrier and their subsequent uptake by antigen-presenting cells. Epithelial injuries mediated by these proteases together with their sensing by protease-activated receptors (PARs) elicit potent inflammatory responses resulting in the release of pro-Th2 cytokines (IL-6, IL-25, IL-1β, TSLP) and danger-associated molecular patterns (DAMPs; IL-33, ATP, uric acid). Recently, protease allergens were shown to cleave the protease sensor domain of IL-33 to produce a super-active form of the alarmin. At the same | 1149 SOH et al.

The origins and longevity of IgE responses as indicated by serological and cellular studies in mice and humans

“…This may occur under conditions that are sufficient to stimulate alarmin (IL‐25, IL‐33, and TSLP) production and activate an immune response, perhaps by damaging or activating epithelial cells, without triggering overt IFNγ production from resident myeloid cells, avoiding Th1 biasing of the immune response, so we would suggest a possible scenario where it is weakly immunogenic pathogen‐associated molecular pattern exposures that contributes to this form of sensitization, as has been indicated previously 89 . Other allergens, such as papain, Der p 1, and Der p 2 have auto‐adjuvanting properties due to their proteolytic activity, molecular mimicry of important innate immune pathway coreceptors such as MD2 or ability to activate pattern recognition receptors 90–94 . Birch pollen allergen extracts may even directly interact with the IL‐4Rα to promote sensitization 95 .…”

“…Damage to epithelial barriers caused by detergents and environmental pollutants is a tenet of the “epithelial barrier” hypothesis, seen as a major cause of multiple diseases, including those mediated by type 2 immunity and associated with IgE 99–101 . A recently identified subset of dendritic cells responsive to IL‐13 that promotes type 2 immunity may be key to IgE production after allergen exposure through a compromised epithelial barrier, 102 but alarmins, such as IL‐33 likely also play a role 91,96 . Similarly, a compromised intestinal epithelial barrier may also permit sensitization to otherwise well tolerated dietary proteins 103 .…”

Immunomodulatory properties of mesenchymal stem cells: A potential therapeutic strategy for allergic rhinitis

“…18,19 They also express various pattern recognition receptors, such as Toll-like receptors (TLRs) and C-type lectin receptors, which recognize allergens. 20 Mice with inactivated Tlr4 in the airway epithelium showed partial attenuation of HDM-mediated eosinophilic inflammation and IL-33 production. 21 Dectin-1 is expressed in epithelial cells and can mediate the recognition of inhaled Aspergillus fumigatus, among other allergens.…”

“…Epithelial cells are responsible for sensing allergens and regulating the allergic inflammatory response 18,19 . They also express various pattern recognition receptors, such as Toll‐like receptors (TLRs) and C‐type lectin receptors, which recognize allergens 20 . Mice with inactivated Tlr4 in the airway epithelium showed partial attenuation of HDM‐mediated eosinophilic inflammation and IL‐33 production 21 .…”

The epithelial barrier theory: development and exacerbation of allergic and other chronic inflammatory diseases

“…For example, early in the year, birch pollen allergen exposure is always overlapping with air pollutants in March in the Northern Hemisphere [ 65 ]. Proteases released by several aeroallergens target transmembrane adhesion proteins such as E-cadherin and transmembrane receptors, damage barrier permeability, facilitate allergen absorption and sensitization, and initiate inflammatory responses ( Table 1 ) [ 78 , 79 ]. Protease inhibitors could maintain lung homeostasis to stabilize the action of allergens and control apoptosis.…”