Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions
Hong Wan, … , Mark B. Cannell, Clive Robinson
Hong Wan, … , Mark B. Cannell, Clive Robinson
Published July 1, 1999
Citation Information: J Clin Invest. 1999;104(1):123-133. https://doi.org/10.1172/JCI5844.
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Article

Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions

Abstract

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.

Authors

Hong Wan, Helen L. Winton, Christian Soeller, Euan R. Tovey, Dieter C. Gruenert, Philip J. Thompson, Geoffrey A. Stewart, Graham W. Taylor, David R. Garrod, Mark B. Cannell, Clive Robinson

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Figure 9

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Potential Der p 1 cleavage sites in claudin-1 extracellular loops. (a) D...
Potential Der p 1 cleavage sites in claudin-1 extracellular loops. (a) Digestion of 64KVFDSLLNLS74 (peptide IV) for 2 hours resulted in 4 major peptides. The HPLC/electrospray–selected ion chromatograms are shown in the left section. I: LNLNS; II: KVFDSL; III: KVFDSLLN; and V: KVFDSLLNL. Peptides II–V were associated with A260 ultraviolet absorbance. Unchanged peptide was the major species in the total ion current (TIC) (not shown). Mass spectra for the peptides are shown on the right. Each peptide generated an M+H+ ion as shown. Larger peptides (III–V) produced intense doubly charged ions (M+H22+, bracketed); the molecular ion regions of these spectra were magnified 2- to 4-fold for display. (b) Digestion of 138WYGNRIVQ144 (peptide VI) generated 2 major fragments, WYG (VII) and NRIVQ (VIII). Small amounts of other fragments were observed. The HPLC A280 ultraviolet absorbance chromatogram is shown together with electrospray mass chromatograms for the TIC and ion channels m/z 1,035, 629, and 425. Mass spectra for VI–VIII are shown at the right; doubly charged ions are bracketed; and the molecular ion region of VI has been magnified for display. (c) Schematic representation of putative cleavage sites within claudin-1. The shaded boxes superimposed on the extracellular domains show approximate locations of the cleavable segments depicted. Arrows indicate cleavage sites identified in peptides. Residue numbering from murine claudin-1.