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Proteolysis in Allergic Sensitization and Th2 Response

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2017) | Viewed by 68413

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Special Issue Editors

Prof. Dr. Fatima Ferreira

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Guest Editor

Division of Allergy and Immunology, Department of Biosciences, University of Salzburg, 5020 Salzburg, Austria
Interests: new diagnostic possibilities of allergies; innovative therapeutic approaches; allergens of birch and other selected trees; mugwort and ragweed pollen

Prof. Dr. Hans Brandstetter

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Guest Editor

Department of Molecular Biology, Division of Structural Biology and Bioinformatics, University of Salzburg, Hellbrunnerstrasse 34, A-5020 Salzburg, Austria
Interests: structure and mechanism of proteins in immunology and blood coagulation; antigen processing and presentation; cellular defense mechanisms; bacterial collagenases; allergen molecules; prostatic and epidermal kallikreins

Special Issue Information

Dear Colleagues,

There is convincing evidence that protease activity is linked to the capacity of certain allergens to induce sensitization and Th2 responses. It has been shown that the combined effects of serine- and cysteine-protease activities on epithelial barrier and on innate and adaptive immunity favor Th2 and IgE responses. A role of the protease activity of allergens on the function of adaptive immune cells has been demonstrated for the major house dust mite allergen, Der p 1, which cleaves the low-affinity IgE receptor CD23 on B-cells, thereby disrupting the negative feedback loop for IgE production. Der p 1 also cleaves CD25, the α-subunit of the T-cell IL-2 receptor, leading to inhibition of T-cell proliferation and production of IFN-γ, thus favoring Th2 responses. Several other pro-allergenic effects of Der p 1 on dendritic cells have been described, including decreased IL-12 production, inhibition of indoleamine-2,3-dioxygenase production, and cleavage of CD40 and DC-SIGN molecules.

Proteases in allergen sources have also been suggested to contribute to primary sensitization to allergens and to exacerbation of allergic disorders. Such non-allergen proteases were shown to compromise epithelial barrier function, to activate innate immune responses, and to facilitate allergen accessibility to dendritic cells. In addition, proteases have been shown to induce epithelial cells to produce thymic stromal lymphopoietin (TSLP), which triggers dendritic cells maturation.

This Special Issue, “Proteolysis in allergic sensitization and Th2 response”, aims to provide a summary of the field, to explore recent advances in protease-immune system interactions, and to discuss how proteolytic events may drive Th2 polarization and allergic sensitization/inflammation. We invite authors to submit original research and review articles related to any of these aspects.

Prof. Dr. Fatima Ferreira
Prof. Dr. Hans Brandstetter
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Allergens
Protease allergens
Proteolytic processing of allergens
Type 1 allergy
T helper 2 cell
Protease-activated receptors (PAR)
Allergen source-derived proteases
Innate immune cells
Allergic sensitization
Allergic inflammation
Epithelial barrier

Published Papers (12 papers)

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Research

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2026 KiB

Open AccessArticle

Two Distinct Conformations in Bet v 2 Determine Its Proteolytic Resistance to Cathepsin S

by Wai Tuck Soh, Peter Briza, Elfriede Dall, Claudia Asam, Mario Schubert, Sara Huber, Lorenz Aglas, Barbara Bohle, Fatima Ferreira and Hans Brandstetter

Int. J. Mol. Sci. 2017, 18(10), 2156; https://doi.org/10.3390/ijms18102156 - 16 Oct 2017

Cited by 6 | Viewed by 3688

Abstract

Birch pollen allergy affects more than 20% of the European allergic population. On a molecular level, birch pollen allergy can be linked to the two dominant allergens Bet v 1 and Bet v 2. Bet v 2 belongs to the profilin family, which is abundant in the plant kingdom. Importantly, the homologous plant profilins have a conserved cysteine motif with a currently unknown functional relevance. In particular, it is unknown whether the motif is relevant for disulfide formation and to what extent it would affect the profilins’ structural, functional and immunological properties. Here we present crystal structures of Bet v 2 in the reduced and the oxidized state, i.e., without and with a disulfide bridge. Despite overall structural similarity, the two structures distinctly differ at their termini which are stabilized to each other in the oxidized, i.e., disulfide-linked state. These structural differences translate into differences in their proteolytic resistance. Whereas the oxidized Bet v 2 is rather resistant towards the endolysosomal protease cathepsin S, it is rapidly degraded in the reduced form. By contrast, both Bet v 2 forms exhibit similar immunological properties as evidenced by their binding to IgE antibodies from birch pollen allergic patients and by their ability to trigger histamine release in a humanized rat basophilic leukemia cells (RBL) assay, independent of the presence or absence of the disulfide bridge. Taken together our findings suggest that the oxidized Bet v 2 conformation should be the relevant species, with a much longer retention time to trigger immune responses. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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Figure 1

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Open AccessArticle

Endolysosomal Degradation of Allergenic Ole e 1-Like Proteins: Analysis of Proteolytic Cleavage Sites Revealing T Cell Epitope-Containing Peptides

by Sabrina Wildner, Brigitta Elsässer, Teresa Stemeseder, Peter Briza, Wai Tuck Soh, Mayte Villalba, Jonas Lidholm, Hans Brandstetter and Gabriele Gadermaier

Int. J. Mol. Sci. 2017, 18(8), 1780; https://doi.org/10.3390/ijms18081780 - 16 Aug 2017

Cited by 10 | Viewed by 4660

Abstract

Knowledge of the susceptibility of proteins to endolysosomal proteases provides valuable information on immunogenicity. Though Ole e 1-like proteins are considered relevant allergens, little is known about their immunogenic properties and T cell epitopes. Thus, six representative molecules, i.e., Ole e 1, Fra e 1, Sal k 5, Che a 1, Phl p 11 and Pla l 1, were investigated. Endolysosomal degradation and peptide generation were simulated using microsomal fractions of JAWS II dendritic cells. Kinetics and peptide patterns were evaluated by gel electrophoresis and mass spectrometry. In silico MHC (major histocompatibility complex) class II binding prediction was performed with ProPred. Cleavage sites were assigned to the primary and secondary structure, and in silico docking experiments between the protease cathepsin S and Ole e 1 were performed. Different kinetics during endolysosomal degradation were observed while similar peptide profiles especially at the C-termini were detected. Typically, the identified peptide clusters comprised the previously-reported T cell epitopes of Ole e 1, consistent with an in silico analysis of the T cell epitopes. The results emphasize the importance of the fold on allergen processing, as also reflected by conserved cleavage sites located within the large flexible loop. In silico docking and mass spectrometry results suggest that one of the first Ole e 1 cleavages might occur at positions 107–108. Our results provided kinetic and structural information on endolysosomal processing of Ole e 1-like proteins. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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1216 KiB

Open AccessArticle

Multi-Approach Analysis for the Identification of Proteases within Birch Pollen

by Olivia E. McKenna, Gernot Posselt, Peter Briza, Peter Lackner, Armin O. Schmitt, Gabriele Gadermaier, Silja Wessler and Fatima Ferreira

Int. J. Mol. Sci. 2017, 18(7), 1433; https://doi.org/10.3390/ijms18071433 - 04 Jul 2017

Cited by 17 | Viewed by 4929

Abstract

Birch pollen allergy is highly prevalent, with up to 100 million reported cases worldwide. Proteases in such allergen sources have been suggested to contribute to primary sensitisation and exacerbation of allergic disorders. Until now the protease content of Betula verrucosa, a birch species endemic to the northern hemisphere has not been studied in detail. Hence, we aim to identify and characterise pollen and bacteria-derived proteases found within birch pollen. The pollen transcriptome was constructed via de novo transcriptome sequencing and analysis of the proteome was achieved via mass spectrometry; a cross-comparison of the two databases was then performed. A total of 42 individual proteases were identified at the proteomic level. Further clustering of proteases into their distinct catalytic classes revealed serine, cysteine, aspartic, threonine, and metallo-proteases. Further to this, protease activity of the pollen was quantified using a fluorescently-labelled casein substrate protease assay, as 0.61 ng/mg of pollen. A large number of bacterial strains were isolated from freshly collected birch pollen and zymographic gels with gelatinase and casein, enabled visualisation of proteolytic activity of the pollen and the collected bacterial strains. We report the successful discovery of pollen and bacteria-derived proteases of Betula verrucosa. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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1720 KiB

Open AccessArticle

Profiling the Extended Cleavage Specificity of the House Dust Mite Protease Allergens Der p 1, Der p 3 and Der p 6 for the Prediction of New Cell Surface Protein Substrates

by Alain Jacquet, Vincenzo Campisi, Martyna Szpakowska, Marie-Eve Dumez, Moreno Galleni and Andy Chevigné

Int. J. Mol. Sci. 2017, 18(7), 1373; https://doi.org/10.3390/ijms18071373 - 27 Jun 2017

Cited by 10 | Viewed by 4983

Abstract

House dust mite (HDM) protease allergens, through cleavages of critical surface proteins, drastically influence the initiation of the Th2 type immune responses. However, few human protein substrates for HDM proteases have been identified so far, mainly by applying time-consuming target-specific individual studies. Therefore, the identification of substrate repertoires for HDM proteases would represent an unprecedented key step toward a better understanding of the mechanism of HDM allergic response. In this study, phage display screenings using totally or partially randomized nonameric peptide substrate libraries were performed to characterize the extended substrate specificities (P₅–P₄′) of the HDM proteases Der p 1, Der p 3 and Der p 6. The bioinformatics interface PoPS (Prediction of Protease Specificity) was then applied to define the proteolytic specificity profile of each protease and to predict new protein substrates within the human cell surface proteome, with a special focus on immune receptors. Specificity profiling showed that the nature of residues in P₁ but also downstream the cleavage sites (P′ positions) are important for effective cleavages by all three HDM proteases. Strikingly, Der p 1 and Der p 3 display partially overlapping specificities. Analysis with PoPS interface predicted 50 new targets for the HDM proteases, including 21 cell surface receptors whose extracellular domains are potentially cleaved by Der p 1, Der p 3 and/or Der p 6. Twelve protein substrate candidates were confirmed by phage ELISA (enzyme linked immunosorbent assay). This extensive study of the natural protein substrate specificities of the HDM protease allergens unveils new cell surface target receptors for a better understanding on the role of these proteases in the HDM allergic response and paves the way for the design of specific protease inhibitors for future anti-allergic treatments. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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4904 KiB

Open AccessArticle

Comparing Proteolytic Fingerprints of Antigen-Presenting Cells during Allergen Processing

by Heidi Hofer, Tamara Weidinger, Peter Briza, Claudia Asam, Martin Wolf, Teresa E. Twaroch, Frank Stolz, Angela Neubauer, Elfriede Dall, Peter Hammerl, Alain Jacquet and Michael Wallner

Int. J. Mol. Sci. 2017, 18(6), 1225; https://doi.org/10.3390/ijms18061225 - 08 Jun 2017

Cited by 2 | Viewed by 4586

Abstract

Endolysosomal processing has a critical influence on immunogenicity as well as immune polarization of protein antigens. In industrialized countries, allergies affect around 25% of the population. For the rational design of protein-based allergy therapeutics for immunotherapy, a good knowledge of T cell-reactive regions on allergens is required. Thus, we sought to analyze endolysosomal degradation patterns of inhalant allergens. Four major allergens from ragweed, birch, as well as house dust mites were produced as recombinant proteins. Endolysosomal proteases were purified by differential centrifugation from dendritic cells, macrophages, and B cells, and combined with allergens for proteolytic processing. Thereafter, endolysosomal proteolysis was monitored by protein gel electrophoresis and mass spectrometry. We found that the overall proteolytic activity of specific endolysosomal fractions differed substantially, whereas the degradation patterns of the four model allergens obtained with the different proteases were extremely similar. Moreover, previously identified T cell epitopes were assigned to endolysosomal peptides and indeed showed a good overlap with known T cell epitopes for all four candidate allergens. Thus, we propose that the degradome assay can be used as a predictor to determine antigenic peptides as potential T cell epitopes, which will help in the rational design of protein-based allergy vaccine candidates. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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Open AccessArticle

Proteases of Dermatophagoides pteronyssinus

by Thomas A. Randall, Robert E. London, Michael C. Fitzgerald and Geoffrey A. Mueller

Int. J. Mol. Sci. 2017, 18(6), 1204; https://doi.org/10.3390/ijms18061204 - 06 Jun 2017

Cited by 12 | Viewed by 5076

Abstract

Since the discovery that Der p 1 is a cysteine protease, the role of proteolytic activity in allergic sensitization has been explored. There are many allergens with proteolytic activity; however, exposure from dust mites is not limited to allergens. In this paper, genomic, transcriptomic and proteomic data on Dermatophagoides pteronyssinus (DP) was mined for information regarding the complete degradome of this house dust mite. D. pteronyssinus has more proteases than the closely related Acari, Dermatophagoides farinae (DF) and Sarcoptes scabiei (SS). The group of proteases in D. pteronyssinus is found to be more highly transcribed than the norm for this species. The distribution of protease types is dominated by the cysteine proteases like Der p 1 that account for about half of protease transcription by abundance, and Der p 1 in particular accounts for 22% of the total protease transcripts. In an analysis of protease stability, the group of allergens (Der p 1, Der p 3, Der p 6, and Der p 9) is found to be more stable than the mean. It is also statistically demonstrated that the protease allergens are simultaneously more highly expressed and more stable than the group of D. pteronyssinus proteases being examined, consistent with common assumptions about allergens in general. There are several significant non-allergen outliers from the normal group of proteases with high expression and high stability that should be examined for IgE binding. This paper compiles the first holistic picture of the D. pteronyssinus degradome to which humans may be exposed. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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829 KiB

Open AccessArticle

Identification of Proteases and Protease Inhibitors in Allergenic and Non-Allergenic Pollen

by Barbara Höllbacher, Armin O. Schmitt, Heidi Hofer, Fatima Ferreira and Peter Lackner

Int. J. Mol. Sci. 2017, 18(6), 1199; https://doi.org/10.3390/ijms18061199 - 05 Jun 2017

Cited by 16 | Viewed by 5327

Abstract

Pollen is one of the most common causes of allergy worldwide, making the study of their molecular composition crucial for the advancement of allergy research. Despite substantial efforts in this field, it is not yet clear why some plant pollens strongly provoke allergies while others do not. However, proteases and protease inhibitors from allergen sources are known to play an important role in the development of pollen allergies. In this study, we aim to uncover differences in the transcriptional pattern of proteases and protease inhibitors in Betula verrucosa and Pinus sylvestris pollen as models for high and low allergenic potential, respectively. We applied RNA sequencing to Betula verrucosa and Pinus sylvestris pollen. After de-novo assembly we derived general functional profiles of the protein coding transcripts. By utilization of domain based functional annotation we identified potential proteases and protease inhibitors and compared their expression in the two types of pollen. Functional profiles are highly similar between Betula verrucosa and Pinus sylvestris pollen. Both pollen contain proteases and inhibitors from 53 and 7 Pfam families, respectively. Some of the members comprised within those families are implicated in facilitating allergen entry, while others are known allergens themselves. Our work revealed several candidate proteins which, with further investigation, represent exciting new leads in elucidating the process behind allergic sensitization. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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2436 KiB

Open AccessArticle

Conformational Flexibility Differentiates Naturally Occurring Bet v 1 Isoforms

by Sarina Grutsch, Julian E. Fuchs, Linda Ahammer, Anna S. Kamenik, Klaus R. Liedl and Martin Tollinger

Int. J. Mol. Sci. 2017, 18(6), 1192; https://doi.org/10.3390/ijms18061192 - 03 Jun 2017

Cited by 15 | Viewed by 5485

Abstract

The protein Bet v 1 represents the main cause for allergic reactions to birch pollen in Europe and North America. Structurally homologous isoforms of Bet v 1 can have different properties regarding allergic sensitization and Th2 polarization, most likely due to differential susceptibility to proteolytic cleavage. Using NMR relaxation experiments and molecular dynamics simulations, we demonstrate that the initial proteolytic cleavage sites in two naturally occurring Bet v 1 isoforms, Bet v 1.0101 (Bet v 1a) and Bet v 1.0102 (Bet v 1d), are conformationally flexible. Inaccessible cleavage sites in helices and strands are highly flexible on the microsecond-millisecond time scale, whereas those located in loops display faster nanosecond-microsecond flexibility. The data consistently show that Bet v 1.0102 is more flexible and conformationally heterogeneous than Bet v 1.0101. Moreover, NMR hydrogen-deuterium exchange measurements reveal that the backbone amides in Bet v 1.0102 are significantly more solvent exposed, in agreement with this isoform’s higher susceptibility to proteolytic cleavage. The differential conformational flexibility of Bet v 1 isoforms, along with the transient exposure of inaccessible sites to the protein surface, may be linked to proteolytic susceptibility, representing a potential structure-based rationale for the observed differences in Th2 polarization and allergic sensitization. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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4109 KiB

Open AccessArticle

The Lys-Asp-Tyr Triad within the Mite Allergen Der p 1 Propeptide Is a Critical Structural Element for the pH-Dependent Initiation of the Protease Maturation

by Andy Chevigné, Vincenzo Campizi, Martyna Szpakowska, David Bourry, Marie-Eve Dumez, José C. Martins, André Matagne, Moreno Galleni and Alain Jacquet

Int. J. Mol. Sci. 2017, 18(5), 1087; https://doi.org/10.3390/ijms18051087 - 20 May 2017

Cited by 6 | Viewed by 5102

Abstract

The major house dust mite allergen, Der p 1, is a papain-like cysteine protease expressed as an inactive precursor, proDer p 1, carrying an N-terminal propeptide with a unique structure. The maturation of the zymogen into an enzymatically-active form of Der p 1 is a multistep autocatalytic process initiated under acidic conditions through conformational changes of the propeptide, leading to the loss of its inhibitory ability and its subsequent gradual cleavage. The aims of this study were to characterize the residues present in the Der p 1 propeptide involved in the initiation of the zymogen maturation process, but also to assess the impact of acidic pH on the propeptide structure, the activity of Der p 1 and the fate of the propeptide. Using various complementary enzymatic and structural approaches, we demonstrated that a structural triad K17p-D51p-Y19p within the N-terminal domain of the propeptide is essential for its stabilization and the sensing of pH changes. Particularly, the protonation of D51p under acidic conditions unfolds the propeptide through disruption of the K17p-D51p salt bridge, reduces its inhibition capacity and unmasks the buried residues K17p and Y19p constituting the first maturation cleavage site of the zymogen. Our results also evidenced that this triad acts in a cooperative manner with other propeptide pH-responsive elements, including residues E56p and E80p, to promote the propeptide unfolding and/or to facilitate its proteolysis. Furthermore, we showed that acidic conditions modify Der p 1 proteolytic specificity and confirmed that the formation of the first intermediate represents the limiting step of the in vitro Der p 1 maturation process. Altogether, our results provide new insights into the early events of the mechanism of proDer p 1 maturation and identify a unique structural triad acting as a stabilizing and a pH-sensing regulatory element. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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Review

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2307 KiB

Open AccessReview

Dendritic Cells and Their Role in Allergy: Uptake, Proteolytic Processing and Presentation of Allergens

by Piotr Humeniuk, Pawel Dubiela and Karin Hoffmann-Sommergruber

Int. J. Mol. Sci. 2017, 18(7), 1491; https://doi.org/10.3390/ijms18071491 - 11 Jul 2017

Cited by 51 | Viewed by 7492

Abstract

Dendritic cells (DCs) are the most important antigen presenting cells to activate naïve T cells, which results in the case of Type 1 allergies in a Type 2 helper T cell (Th2)-driven specific immune response towards allergens. So far, a number of different subsets of specialized DCs in different organs have been identified. In the recent past methods to study the interaction of DCs with allergenic proteins, their different uptake and processing mechanisms followed by the presentation to T cells were developed. The following review aims to summarize the most important characteristics of DC subsets in the context of allergic diseases, and highlights the recent findings. These detailed studies can contribute to a better understanding of the pathomechanisms of allergic diseases and contribute to the identification of key factors to be addressed for therapeutic interventions. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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1776 KiB

Open AccessReview

Allergens with Protease Activity from House Dust Mites

by Manuel Reithofer and Beatrice Jahn-Schmid

Int. J. Mol. Sci. 2017, 18(7), 1368; https://doi.org/10.3390/ijms18071368 - 27 Jun 2017

Cited by 72 | Viewed by 10038

Abstract

Globally, house dust mites (HDM) are one of the main sources of allergens causing Type I allergy, which has a high risk of progressing into a severe disabling disease manifestation such as allergic asthma. The strong protease activities of a number of these allergens are thought to be involved in several steps of the pathophysiology of this allergic disease. It has been a common notion that protease activity may be one of the properties that confers allergenicity to proteins. In this review we summarize and discuss the roles of the different HDM proteases in the development of Type I allergy. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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891 KiB

Open AccessReview

Oxidative Stress: Promoter of Allergic Sensitization to Protease Allergens?

by Leonie S. Van Rijt, Lara Utsch, René Lutter and Ronald Van Ree

Int. J. Mol. Sci. 2017, 18(6), 1112; https://doi.org/10.3390/ijms18061112 - 23 May 2017

Cited by 30 | Viewed by 6023

Abstract

Allergies arise from aberrant T helper type 2 responses to allergens. Several respiratory allergens possess proteolytic activity, which has been recognized to act as an adjuvant for the development of a Th2 response. Allergen source-derived proteases can activate the protease-activated receptor-2, have specific effects on immune cells by cleaving cell membrane-bound regulatory molecules, and can disrupt tight junctions. The protease activity can induce a non-allergen-specific inflammatory response in the airways, which will set the stage for an allergen-specific Th2 response. In this review, we will discuss the evidence for the induction of oxidative stress as an underlying mechanism in Th2 sensitization to proteolytic allergens. We will discuss recent data linking the proteolytic activity of an allergen to its potential to induce oxidative stress and how this can facilitate allergic sensitization. Based on experimental data, we propose that a less proficient anti-oxidant response to allergen-induced oxidative stress contributes to the susceptibility to allergic sensitization. Besides the effect of oxidative stress on the immune response, we will also discuss how oxidative stress can increase the immunogenicity of an allergen by chemical modification. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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