House dust mite Der p 1 downregulates defenses of the lung by inactivating elastase inhibitors.
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.
Brown
Alan
A
School of Pharmaceutical Sciences, University of Nottingham, United Kingdom.
Farmer
Kinley
K
MacDonald
Louise
L
Kalsheker
Noor
N
Pritchard
Dave
D
Haslett
Chris
C
Lamb
Jonathan
J
Sallenave
J-M
JM
D000208:Acute Disease; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000494:pharmacology*; D060829:Arthropod Proteins; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D003545:Cysteine / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006967:Hypersensitivity; D007249:Inflammation; D007700:Kinetics; D008168:Lung / Q000378:metabolism*; D008171:Lung Diseases / Q000378:metabolism; D051379:Mice; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000494:pharmacology; D017455:Receptors, IgE / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D053481:Secretory Leukocyte Peptidase Inhibitor; D013379:Substrate Specificity; D013997:Time Factors
D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; D004791:Enzyme Inhibitors; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D017455:Receptors, IgE; D015375:Receptors, Interleukin-2; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse; D010196:Pancreatic Elastase; D003546:Cysteine Endopeptidases; C451162:Dermatophagoides pteronyssinus antigen p 1; D003545:Cysteine