The proteolytic activity of the major dust mite allergen Der p 1 conditions dendritic cells to produce less interleukin‐12: allergen‐induced Th2 bias determined at the dendritic cell level

Ghaemmaghami, Amir M.; Gough, Lucy; Sewell, Herb F.; Shakib, F

doi:10.1046/j.1365-2745.2002.01504.x

Cited by 139 publications

(137 citation statements)

References 24 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…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to erase IgE-eliciting activity when the reactions were conducted with lower concentrations of E-64 and rDer p 1 (our unpublished observations), which is considered to decrease the probability of molecular collisions between E-64 and Der p 1 and to decelerate the speed of formation of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.…”

Section: Discussionmentioning

confidence: 63%

“…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.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 63%

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

View full text Add to dashboard Cite

show abstract

“…There was a reduction in IL-12 levels in the supernatant of Per a 10 stimulated BMDCs and in BALF of Per a 10 immunized mice. Previous studies have demonstrated the role of CD40 cleavage in IL-12 production [29,30]. The mRNA levels of IL-12p40 were unaltered between PBS group and active Per a 10 immunized group.…”

mentioning

confidence: 79%

Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

2015

View full text Add to dashboard Cite

Proteases are implicated in exacerbation of allergic diseases. In this study, the role of proteolytic activity of Per a 10 was evaluated on Th2 polarization. Intranasal administration of Per a 10 in mice led to allergic airway inflammation as seen by higher IgE levels, cellular infiltration, IL-17A, and Th2 cytokines, whereas, inactive ( )Per a 10 showed attenuated response. There was an increased OX40L expression on lung and lymph node dendritic cells in Per a 10 immunized group and on Per a 10 stimulated BMDCs. Reduction in CD40 expression without any change at transcript level in lungs of Per a 10 immunized mice suggested CD40 cleavage. BMDCs pulsed with Per a 10 showed reduced CD40 expression with lower IL-12p70 secretion as compared to heat inactivated Per a 10. IL-23, TNF-α, and IL-6 levels were significantly higher in Per a 10 stimulated BMDCs supernatant. In DC-T cell coculture studies, Per a 10 pulsed BMDCs showed higher levels of IL-4 and IL-13 that were reduced on blocking of either IL-23 or OX40L. In conclusion, the data suggests a critical role of protease activity of Per a 10 in promoting Th2 polarization by increasing IL-23 secretion and OX40L expression on dendritic cells.Keywords: CD40 r Cytokines r Dendritic cell r OX40L r Protease allergen Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionProteases are known to play an important role in manifestation of diseases like cancer, coagulopathies, respiratory inflammatory diseases, rheumatoid arthritis, and degenerative diseases [1][2][3]. Proteases from sources like house dust mite (Der p 1, Der p 3, Der p 6, Der p 9, Der f 1) and fungi (Asp f 13, Pen c 1, Pen c 13, Epi p 1) have been characterized as potent allergens [4]. Protease allergens act by proteolytic cleavage of an array of cell surface molecules and are known to modulate the functions of a variety of cell types including both immune and structural cells [5]. Proteolytic allergens from house dust mite are known to exacerbate allergic immune responses by selective cleavage of CD23, CD25, DC-SIGN, and DC-SIGNR on surface of immune cells Correspondence: Dr. Naveen Arora e-mail: naveen@igib.res.in; navdelhi@hotmail.com [6,7]. Further, cleavage and subsequent activation of PAR receptors by proteases lead to increased secretion of chemokines, proinflammatory, and pro Th2 cytokines from airway epithelial cells [8,9]. Studies have reported impaired epithelial barrier function as the feature of allergic diseases like asthma and atopic dermatitis [10]. The enzymatic activity of proteases has been reported to compromise epithelial barrier directly by cleaving tight junction proteins ZO-1 and occludin thereby increasing epithelial permeability [11,12]. Proteases can also act as adjuvants to bystander allergens present in the same microenvironment [13,14].Cockroaches have emerged as an important source of indoor allergens worldwide and cockroach extract is shown to be rich in proteases [15]. Previously, Per a 10, a serine protea...

show abstract

“…We used the Der p 1 Ag from the house dust mite as a relevant Ag. Some studies report that Der p 1 is capable of modulating DC to induce a Th2 response because of an intrinsic enzymatic activity of the molecule (25)(26)(27). To exclude such interference with our experiments, purified Der p 1 without protection of the reactive thiol group was used.…”

Section: Discussionmentioning

confidence: 99%

The Toll-Like Receptor-2/6 Agonist Macrophage-Activating Lipopeptide-2 Cooperates with IFN-γ to Reverse the Th2 Skew in an In Vitro Allergy Model

Weigt

Mühlradt²,

Larbig

et al. 2004

The Journal of Immunology

View full text Add to dashboard Cite

Dendritic cells (DC) are the most potent APCs with the capacity to induce, modulate, or shut down immune function. These features make them potentially useful for treating diseases associated with misled immunologic responses. Therefore, it was the aim of this study to reverse the allergen-dependent Th2 reaction responsible for allergic symptoms by modulating DC function. This issue was addressed in an in vitro test system consisting of human monocyte-derived allergen-pulsed DC from allergics cocultured with autologous lymphocytes. A Th2 reaction judged by the amplification of IL-4 and the down-regulation of IFN-γ was induced by pulsing DC with the relevant allergen. To modulate this reaction, the Toll-like receptor 2/6 engaging mycoplasmal lipopetide macrophage-activating lipopeptide 2 kDa was combined with IFN-γ to stimulate allergen-pulsed DC. Such treatment resulted in a 500-fold increase in IFN-γ production in the supernatant of cocultured autologous lymphocytes, while the Th2 marker IL-4 was not affected. This phenomenon was associated with an increase in proliferation and the number of IFN-γ-producing lymphocytes. Phenotype and function of thus treated DC remained stable. These data indicate that a former allergen-dependent Th2 reaction can be reversed toward a Th1-type response by an appropriate treatment of DC.

show abstract

The proteolytic activity of the major dust mite allergen Der p 1 conditions dendritic cells to produce less interleukin‐12: allergen‐induced Th2 bias determined at the dendritic cell level

Abstract: Collectively, our data provide compelling evidence for the role of the proteolytic activity of Der p 1 in directing DCs to induce Th2 subset development.

Cited by 139 publications

References 24 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

Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

The Toll-Like Receptor-2/6 Agonist Macrophage-Activating Lipopeptide-2 Cooperates with IFN-γ to Reverse the Th2 Skew in an In Vitro Allergy Model

Contact Info

Product

Resources

About