Proteolytic activity of the house dust mite allergen Der p 1 enhances allergenicity in a mouse inhalation model

Gough, Lucy; Campbell, Emma M.; Bayley, Deborah; Heeke, Gino Van; Shakib, F

doi:10.1046/j.1365-2222.2003.01716.x

Cited by 71 publications

(60 citation statements)

References 17 publications

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“…To our surprise, E-64-treated rDer p 1 induced remarkably little production of both IgE and IgGs despite the maintenance of the global structure and conformational B cell epitopes. This finding is important because it strongly suggests that the IgE-and IgG-eliciting activity of rDer p 1 is dependent on its cysteine protease activity differing from the partial reduction in the IgE-eliciting activity of natural Der p 1 caused by E-64 treatment without affecting IgG production (40,41).…”

Section: Discussionmentioning

confidence: 96%

“…However, which molecule(s) and/or which cell type(s) are the most critical targets of the cysteine protease activity of Der p 1 and Der f 1 for pathogenesis of allergy and where Der p 1 and Der f 1 become active and work effectively are not well investigated. Two research groups reported an enhancement of IgE production (40,41) and induction of Th2 responses (42) by the proteolytic activity of Der p 1 in mice, respectively. Gough et al (40,41) reported that treatment of Der p 1 with an irreversible cysteine protease-specific inhibitor, E-64, partially reduced the IgE-eliciting activity of the allergen without affecting production of IgG in mice.…”

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confidence: 99%

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

Kikuchi

Takai²,

Kuhara³

et al. 2006

The Journal of Immunology

102

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The major proteolytic allergen derived from the house dust mite Dermatophagoides pteronyssinus, Der p1, is one of the most clinically relevant allergens worldwide. In the present study, we evaluate the contribution of the proteolytic activity and structure of a highly purified rDer p 1 to immune responses. Mice were i.p. immunized with three forms of rDer p 1 adsorbed to Alum: one enzymatically active, one treated with an irreversible cysteine protease-specific inhibitor, E-64, and one heat denatured. Immunization with E-64-treated or heat-denatured rDer p 1 elicited much less production of serum total IgE and not only rDer p 1-specific IgE but also IgGs compared with immunization with active rDer p 1. Assays for Ab-binding and its inhibition and structural analyses indicated that E-64-treated rDer p 1 retained its global structure and conformational B cell epitopes. A proliferative response and production of IL-5 by spleen cells restimulated with rDer p 1 were observed on immunization with the active rDer p 1 but not E-64-treated rDer p 1. The cells from mice immunized with heat-denatured rDer p 1 exhibited the highest levels of proliferation and production of IL-5 and IFN-γ. The results indicate that the proteolytic activity of the highly purified rDer p 1 crucially commits to the sensitization process, including both IgE and IgG responses. Additionally, we demonstrated immunogenic differences by functional or structural manipulations of the rDer p 1. The findings have implications for sensitization to this relevant allergen in humans and for the design of modified allergen-vaccines for future allergen-specific immunotherapy.

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

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

Kikuchi

Takai²,

Kuhara³

et al. 2006

The Journal of Immunology

102

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“…Occludin, a protein component of intercellular tight junctions, is another substrate of Der p 1 (29), thus allowing the destruction of the integrity of tight junctions between epithelial cells. The importance of the enzyme activity of Der p 1 in inducing allergy has also been demonstrated in vivo, where intranasal administration of proteolytically active Der p 1 to sensitized mice leads to enhanced inflammatory cellular infiltration of the lungs and systemic production of IgE, in comparison to inactive Der p 1, which has no effect (30).…”

mentioning

confidence: 96%

Major House Dust Mite Allergens Dermatophagoides pteronyssinus 1 and Dermatophagoides farinae 1 Degrade and Inactivate Lung Surfactant Proteins A and D

Deb

Shakib

Reid

et al. 2007

Journal of Biological Chemistry

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“…The cysteine and serine protease allergens from the dust mite have been examined for their ability to stimulate allergic immune responses in animal models (18,19), the cockroach serine protease Per a 10 induces allergic airway inflammation in a mouse model (20), and an alkaline serine protease from Aspergillus sp. has synergistic effects on the immune response induced by a major Aspergillus fumigatus allergen, Asp f 2, in mice (21).…”

Section: * This Work Was Supported In Part By the Program For Excellementioning

confidence: 99%

The Protease Allergen Pen c 13 Induces Allergic Airway Inflammation and Changes in Epithelial Barrier Integrity and Function in a Murine Model

Chen

Chuang

et al. 2011

Journal of Biological Chemistry

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Fungal allergens are associated with the development of asthma, and some have been characterized as proteases. Here, we established an animal model of allergic airway inflammation in response to continuous exposure to proteolytically active Pen c 13, a major allergen secreted by Penicillium citrinum. In functional analyses, Pen c 13 exposure led to increased airway hyperresponsiveness, significant inflammatory cell infiltration, mucus overproduction, and collagen deposition in the lung, dramatically elevated serum levels of total IgE and Pen c 13-specific IgE and IgG1, and increased production of the Th2 cytokines IL-4, IL-5, and IL-13 by splenocytes stimulated in vitro with Pen c 13. To examine the mechanisms involved in the regulation of allergenicity by Pen c 13, we performed two-dimensional fluorescence difference gel electrophoresis analysis combined with nano-LC-MS/MS, followed by bioinformatics analysis to identify potential targets that associated with allergic inflammation, which suggested that galectin-3 and laminin might be involved in novel pathogenic mechanisms. Finally, we focused on junctional proteins between cells, because, in addition to opening of the epithelial barrier by environmental proteases possibly being the initial step in the development of asthma, these proteins are also associated with actin rearrangement. Taken together, our findings indicate that Pen c 13 exposure causes junctional structure alterations and actin cytoskeletal rearrangements, resulting in increased permeability and airway structural changes. These effects probably change the lung microenvironment and foster the development of allergic sensitization.

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Proteolytic activity of the house dust mite allergen Der p 1 enhances allergenicity in a mouse inhalation model

Abstract: These data underline the important role of the proteolytic activity of Der p 1 in driving the allergic response in the lungs.

Cited by 71 publications

References 17 publications

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

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

Major House Dust Mite Allergens Dermatophagoides pteronyssinus 1 and Dermatophagoides farinae 1 Degrade and Inactivate Lung Surfactant Proteins A and D

The Protease Allergen Pen c 13 Induces Allergic Airway Inflammation and Changes in Epithelial Barrier Integrity and Function in a Murine Model

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