Antigenic Determinants of Der p 1: Specificity and Cross-Reactivity Associated with IgE Antibody Recognition

Glesner, Jill; Vailes, Lisa D.; Schlachter, Caleb R.; Mank, Nicholas; Minor, Władek; Osinski, T.; Chruszcz, M.; Chapman, Martin D.; Pomés, Anna

doi:10.4049/jimmunol.1600072

Cited by 24 publications

(31 citation statements)

References 31 publications

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“…The CDRs contain the amino acids that form the paratope. The H CDR3 is sufficient for most antibody specificities ( 66 ), although exceptions have been found ( 67 ). In a few cases, additional residues outside the CDR, located in the “framework” of the antibody, can also contribute to antibody binding.…”

Section: Structures Of Allergen-antibody Complexes By X-ray Crystallomentioning

confidence: 99%

“…Once the IgG epitope was identified, site-directed mutagenesis of the allergen residues involved in antibody recognition was performed, followed by IgE antibody binding analysis of the mutants, to identify IgE antibody binding sites. This approach resulted in the design and production of allergen mutants with decreased capacity to bind IgE, which are being investigated as future candidates for immunotherapy ( 51 , 58 , 67 , 73 ).…”

Section: Structures Of Allergen-antibody Complexes By X-ray Crystallomentioning

confidence: 99%

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Structural Aspects of the Allergen-Antibody Interaction

2020

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The development of allergic disease involves the production of IgE antibodies upon allergen exposure in a process called sensitization. IgE binds to receptors on the surface of mast cells and basophils, and subsequent allergen exposure leads to cross-linking of IgE antibodies and release of cell mediators that cause allergy symptoms. Although this process is quite well-understood, very little is known about the epitopes on the allergen recognized by IgE, despite the importance of the allergen-antibody interaction for the allergic response to occur. This review discusses efforts to analyze allergen-antibody interactions, from the original epitope mapping studies using linear peptides or recombinant allergen fragments, to more sophisticated technologies, such as X-ray crystallography and nuclear magnetic resonance. These state-of-the-art approaches, combined with site-directed mutagenesis, have led to the identification of conformational IgE epitopes. The first structures of an allergen (egg lysozyme) in complex with Fab fragments from IgG antibodies were determined in the 1980s. Since then, IgG has been used as surrogate for IgE, due to the difficulty of obtaining monoclonal IgE antibodies. Technical developments including phage display libraries have contributed to progress in epitope mapping thanks to the isolation of IgE antibody constructs from combinatorial libraries made from peripheral blood mononuclear cells of allergic donors. Most recently, single B cell antibody sequencing and human hybridomas are new breakthrough technologies for finally obtaining human IgE monoclonal antibodies, ideal for epitope mapping. The information on antigenic determinants will facilitate the design of hypoallergens for immunotherapy and the investigation of the fundamental mechanisms of the IgE response.

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Section: Structures Of Allergen-antibody Complexes By X-ray Crystallomentioning

confidence: 99%

Section: Structures Of Allergen-antibody Complexes By X-ray Crystallomentioning

confidence: 99%

Structural Aspects of the Allergen-Antibody Interaction

2020

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“…The ribosome inactivation exerted by ribotoxins leads to cellular death 23 . Hence, in vitro MTT viability assays are widely used for studying the effect of immunotoxins on the metabolic activity rate of different cell lines.…”

Section: Cell Viability Inhibitionmentioning

confidence: 99%

Der p 1-based immunotoxin as potential tool for the treatment of dust mite respiratory allergy

Lázaro-Gorines

López-Rodríguez

Benedé

et al. 2020

Sci Rep

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Immunotoxins appear as promising therapeutic molecules, alternative to allergen-specificimmunotherapy. In this work, we achieved the development of a protein chimera able to promote specific cell death on effector cells involved in the allergic reaction. Der p 1 allergen was chosen as cell-targeting domain and the powerful ribotoxin α-sarcin as the toxic moiety. The resultant construction, named proDerp1αS, was produced and purified from the yeast Pichia pastoris. Der p 1-protease activity and α-sarcin ribonucleolytic action were effectively conserved in proDerp1αS. Immunotoxin impact was assayed by using effector cells sensitized with house dust mite-allergic sera. Cell degranulation and death, triggered by proDerp1αS, was exclusively observed on Der p 1 sera sensitized-humRBL-2H3 cells, but not when treated with non-allergic sera. Most notably, equivalent IgE-binding and degranulation were observed with both proDerp1αS construct and native Der p 1 when using purified basophils from sensitized patients. However, proDerp1αS did not cause any cytotoxic effect on these cells, apparently due to its lack of internalization after their surface IgEbinding, showing the complex in vivo panorama governing allergic reactions. In conclusion, herein we present proDerp1αS as a proof of concept for a potential and alternative new designs of therapeutic tools for allergies. Development of new, and more specific, second-generation of immunotoxins following proDerp1αS, is further discussed. Allergy or type I hypersensitivity reactions are widely described as a loss of tolerance to certain harmless exogenous antigens, such as airborne allergens, foods or insect venoms. Allergies prevalence currently reaches the 30% among the population in the industrialized countries, experiencing an alarming increment over the last few decades 1. Allergies cause a substantial social and economic impact, being the development of new treatments a crucial goal for biomedical research. Common symptoms of allergies, such as asthma and rhinitis, share a strong T-helper type 2 (Th2) immune polarisation, in combination with a significant decreased activity of the IFNγsecreting Th1 cells. Because of this shift, several active mediators are released (e.g. histamine, leukotrienes and prostaglandins, among others) by basophils and mast cells, ultimately resulting in the main immune-pathological features of the allergic response 2,3. Despite the well accepted fact that our understanding of the mechanisms underlying allergies has dramatically improved lately, we are still far from developing an effective therapy because of the multifactorial origin of this pathology. Accordingly, oral tolerance induction has shown to be highly effective in patients at early ages, but it dramatically fails once most immune responses have already been established. Within this same idea, allergen-specific-immunotherapy (AIT) arises as a unique alternative 4,5 , but carries powerful limitations that completely offset its clinical benefits. These limitations include: the variable q...

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“…Testing the activity profile of Der p 1 has revealed a distinct substrate specificity which is determined by alanine at the P2 position [ 24 , 25 ]. Further X-ray structures obtained from antibody-bound Der p 1 revealed epitopes for IgE-binding and IgE-crossreactivity with Der f 1 [ 26 , 27 ]. The strong protease activity of Der p 1 has drawn keen interest in allergy research.…”

Section: Introductionmentioning

confidence: 99%

Allergens with Protease Activity from House Dust Mites

Reithofer

Jahn‐Schmid

2017

IJMS

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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.

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Antigenic Determinants of Der p 1: Specificity and Cross-Reactivity Associated with IgE Antibody Recognition

Cited by 24 publications

References 31 publications

Structural Aspects of the Allergen-Antibody Interaction

Structural Aspects of the Allergen-Antibody Interaction

Der p 1-based immunotoxin as potential tool for the treatment of dust mite respiratory allergy

Allergens with Protease Activity from House Dust Mites

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