Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions.
House dust mite (HDM) allergens are important factors in the increasing prevalence of asthma. The lung epithelium forms a barrier that allergens must cross before they can cause sensitization. However, the mechanisms involved are unknown. Here we show that the cysteine proteinase allergen Der p 1 from fecal pellets of the HDM Dermatophagoides pteronyssinus causes disruption of intercellular tight junctions (TJs), which are the principal components of the epithelial paracellular permeability barrier. In confluent airway epithelial cells, Der p 1 led to cleavage of the TJ adhesion protein occludin. Cleavage was attenuated by antipain, but not by inhibitors of serine, aspartic, or matrix metalloproteinases. Putative Der p 1 cleavage sites were found in peptides from an extracellular domain of occludin and in the TJ adhesion protein claudin-1. TJ breakdown nonspecifically increased epithelial permeability, allowing Der p 1 to cross the epithelial barrier. Thus, transepithelial movement of Der p 1 to dendritic antigen-presenting cells via the paracellular pathway may be promoted by the allergen's own proteolytic activity. These results suggest that opening of TJs by environmental proteinases may be the initial step in the development of asthma to a variety of allergens.
Department of Pharmacology and Clinical Pharmacology, St. George's Hospital Medical School, London SW17 0RE, United Kingdom.
H
H
Wan
H L
HL
Winton
C
C
Soeller
E R
ER
Tovey
D C
DC
Gruenert
P J
PJ
Thompson
G A
GA
Stewart
G W
GW
Taylor
D R
DR
Garrod
M B
MB
Cannell
C
C
Robinson
D000485:Allergens / Q000378:metabolism*; D000818:Animals; D039741:Antigens, Dermatophagoides; D000976:Antipain / Q000494:pharmacology; D001692:Biological Transport; D002460:Cell Line; D002478:Cells, Cultured; D062445:Claudin-1; D003546:Cysteine Endopeptidases / Q000494:pharmacology*; D003896:Desmosomes / Q000648:ultrastructure; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007668:Kidney; D008565:Membrane Proteins / Q000378:metabolism; D008925:Mites / Q000276:immunology*; D062793:Occludin; D010446:Peptide Fragments / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D012221:Rhinitis, Allergic, Perennial / Q000209:etiology / Q000276:immunology; D013379:Substrate Specificity; D019108:Tight Junctions / Q000187:drug effects* / Q000648:ultrastructure
D000485:Allergens; D039741:Antigens, Dermatophagoides; C568108:CLDN1 protein, human; D062445:Claudin-1; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D010446:Peptide Fragments; D000976:Antipain; D003546:Cysteine Endopeptidases