House Dust Mite Der p 1 Downregulates Defenses of the Lung by Inactivating Elastase Inhibitors

Abstract

House dust mites (HDM) are the most common source of aeroallergens and in genetic susceptible individuals can cause symptoms ranging from atopic dermatitis to bronchial asthma. Der p 1, a major target of the human immune responses to HDM, through its enzymatic properties can modulate the adaptive immune system by the cleavage of CD23 and CD25. The consequences of this would be to promote allergic inflammatory responses. Furthermore, by disrupting epithelial tight junctions Der p 1 facilitates the transport of allergen across the epithelium. Here, we report that Der p 1 has additional effects on the innate defense mechanisms of the lung, by inactivating in vitro and ex vivo the elastase inhibitors human (h) alpha1-proteinase inhibitor (h-A1-Pi), mouse (m-), (but not human [h])-SLPI and h-elafin. We confirm that Der p 1 contain both cysteine and serine proteinases, and extend this finding to demonstrate for the first time that h-elafin is particularly sensitive to the biological activity of the latter. Because these elastase inhibitors have antimicrobial, as well as antielastase activity, our results suggest that inactivation of these innate components of the lung defense system by Der p 1 may increase the susceptibility of patients with allergic inflammation to infection.

Crucial Commitment of Proteolytic Activity of a Purified Recombinant Major House Dust Mite Allergen Der p1 to Sensitization toward IgE and IgG Responses

“…We emphasize that complete inactivation of the proteolytic activity is critical for elimination of the in vivo IgE-eliciting activity on the basis of our observations that E-64 treatment was not able to erase IgE-eliciting activity when the reactions were conducted with lower concentrations of E-64 and rDer p 1 (our unpublished observations), which is considered to decrease the probability of molecular collisions between E-64 and Der p 1 and to decelerate the speed of formation of E-64-rDer p 1 complexes. The cysteine protease activity of the house dust mite group 1 allergens has been reported to cleave some cell surface molecules (22-24, 26 -28) and protease inhibitors (25,26,28,30) and to modulate functions of various types of cells (21,22,27,(31)(32)(33)(34)(35)(36)(37)(38)(39). E-64-treated rDer p 1 with no proteolytic activity is considered to lose such activities and, in the present study, actually exhibited a remarkable reduction in Ab-eliciting activity.…”

“…The cysteine protease activity of Der p 1 and Der f 1 has been suggested to be involved in the pathogenesis of allergies by facilitating the passage of their own and other allergens across the epithelium (21,22), cleaving and/or interacting with cell surface molecules and intrinsic protease inhibitors (23)(24)(25)(26)(27)(28)(29)(30), and modulating the function of various cells (23,27,(31)(32)(33)(34)(35)(36)(37)(38)(39). Herbert et al (21) speculated that cysteine protease activity of natural Der p 1 could be activated in vivo by glutathione in the airway on the basis of their in vitro observations.…”

Relationship between Propeptide pH Unfolding and Inhibitory Ability during ProDer p 1 Activation Mechanism

“…5 Several reports indicated that Der p 1 is able to increase bronchial permeability by disruption of the intercellular tight junctions and cleavage of the α1-antitrypsin serine protease inhibitor. 6,7 Furthermore, Der p 1 is capable of cleaving receptors, including the IgE low-affinity receptor (CD23) present at the surface of plasmocyte cells, the α-subunit of the interleukin-2 receptor (CD25) of T cells and the CD40 of dendritic cells. 5,[8][9][10][11] All these processes favor the development of the allergic response; thus, the development of specific Der p 1 inhibitors is of considerable interest.…”

Modulation of Allergenicity of Major House Dust Mite Allergens Der f 1 and Der p 1 by Interaction with an Endogenous Ligand

“…Cysteine protease activity of our preparations of rDer p 1 and rDer f 1 also crucially commits to the sensitization process in mice (37). Although Phillips et al (60) reported that Der p 1 stimulated purified human basophils to release IL-4, whether its cysteine protease activity is responsible for the basophil activation is unknown because their Der p 1 preparation also contained serine proteases other than Der p 1 (28,61). Whether the rDer f 1 and rDer p 1, which show cysteine protease activity but no serine protease activity (15), could stimulate basophils to produce Th2-inducing cytokines should be addressed in a future study.…”

“…It has been proposed that the proteolytic activity of Der f 1 and Der p 1 is involved in the pathogenesis of allergies and sensitization to the production of IgE by reducing physical and biochemical tissue barriers, cleaving various molecules, and modulating the functions of various cells (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). Cystatin A is the dominant biochemical skin barrier that eliminates the enzymatic activity of these mite cysteine proteases and prevents them from stimulating keratinocytes (31,40).…”