MOLECULAR BASIS OF ALLERGENICITY AND CROSS-REACTIVITY IN PLANT FOOD

Group leader: Araceli Díaz Perales - Assistant Professor

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Personnel:

Main research lines of Plant Allergens group:
  • Molecular basis of allergenicity of plant food allergy.
  • Interactions of allergens with mucosa and immune cells.
  • Production of new diagnostic methods by generating allergen microarrays.
  • Design of new strategies for treatment of allergies through production of hypoallergenic forms.

 

The Plant Allergens group is involved in the Spanish Allergy Health Network (RETIC-Programme Carlos III Institute) and has been studying the molecular basis of plant allergy for over 20 years, characterizing allergens, and improving their diagnosis and treatment.

 

Our research activity has been following in recent years two different but complementary strategies. We use techniques and methods from Biochemistry, Molecular Biology, and Immunology to identify and characterize the molecular mechanisms underlying the allergic response.

 

We also resort to computational methods to study the physicochemical and structural properties of allergens. Docking analyses, electrostatic potentials, Molecular Mechanics calculations and Molecular Dynamics simulations have been employed to investigate modes of protein-ligand binding and oligomerization states of allergens.

 

 

This dual approach has been applied to deepen our knowledge on the molecular basis of allergenicity using two model, prototypical allergens such as Pru p 3 (the major allergen from peach) and Alt a 1 (the principal allergen of Alternaria fungi associated to chronic asthma).

 

 

 

 

In the search for common denominators for allergenicity, the presence of ligands carried by allergen proteins has been found to play a key role in the sensitization phase of allergic disease.

A tale of two allergens

Pru p 3

What is the role of an allergen in plant?

Pru p 3 is located on the stigma of pollinated flower and its localization and timing expression suggest a role in flowering linked to pollination.

 

Pru p 3 is also expressed in a very limited time period in peel fruit. The protein is primarily localized in trichome secretory cells during fruit development. So, Pru p 3 may be involved in processes to inhibit second pollination in flower and herbivore feeding until seed is completely developed.

What is carried by an allergen?

The native ligand of Pru p 3 is a derivative of the alkaloid camptothecin bound to a long hydrophobic tail of phytosphingosine.

This ligand inhibits topoisomerase I activity, as camptothecin does, and also participates actively in maturation of antigen-presenting cells by a TLR4-mediated mechanism.

The ligand also seems the responsible for the immune capacity of the peach allergen Pru p 3.

 

 

Alt a 1

Where is a fungal allergen in infected fruit?

 

Alt a 1 is firstly localized inside ungerminated fungal spores by immunofluorescence with specific monoclonal antibody. The most intense signal is observed in the spore wall. Inoculating kiwifruits with isolated spores from Alternaria, no hyphae development occurs until 14 dpi.

However, even though hyphae are not observed, the presence of the allergen is confirmed in the kiwi pulp after 7 dpi.

What happens when Alt a 1 induces an allergic response in humans?

 

Combining in vitro experimental and in silico computational results it is possible to track the molecular events that occur when Alternaria spores arrive at bronchial epithelium in humans. Different oligomerization states, the presence of a flavonol ligand, effects of variations of pH, recognition by cell receptors and interaction with defense proteins such as human LCN2 are pieces that come from those results. These pieces fit together to provide a picture on the molecular mechanism of the inflammatory response induced by Alt a 1 that leads to activation of immune cells and imbalance towards a Th2 response.

 

Patents
  • Authors: Araceli Díaz Perales, Cristina Gómez Casado, Luis Fernández Pacios (UPM) Josef Singer1, Erika Jensen-Jarolim1, Franziska Roth-Walter 2 (1 Medical University of Vienna, 2 Veterinary Medicine University of Vienna)
  • Title: Methods and means for diagnosing and treating allergy
  • Type: European Patent
  • Reference: EP14150965.3
  • Priority date: 13-01-14
  • Authors:Araceli Díaz Perales, Luis Fernández Pacios (UPM) Cristobalina Mayorga Mayorga 1, Mª José Torres Jaen 1, Miguel Blanca Gómez 1, Francisco Javier Rojo Marcos 2, Ainhoa Mascaraque González 2, Francisco Javier Ramos Soriano 2, David Andreu Martínez 3, Javier Valle García 3 (1 Servicio Andaluz de Salud, 2 CSIC, 3 Universitat Pompeu Fabra)
  • Title: Composición para el tratamiento de la alergia
  • Type: Patente Española
  • Reference: P201531341
  • Priority date: 21-09-15

 

 

 

Representative Publications

Mas, S; Oeo-Santos, C; Cuesta-Herranz, J; Diaz-Perales, A; Colas, C; Fernandez, J; Barber, D; Rodriguez, R; de Los Rios, V; Barderas, R; Villalba, M. 2017. "A relevant IgE-reactive 28kDa protein identified from Salsola kali pollen extract by proteomics is a natural degradation product of an integral 47kDa polygalaturonase". Biochimica et Biophysica Acta. DOI: 10.1016/j.bbapap.2017.05.007".

Benedé, S; Garrido-Arandia, M; Martín-Pedraza, L; Bueno, C; Díaz-Perales, A; Villalba, M. 2017. "Multifactorial modulation of food-induced anaphylaxis". Frontiers in Immunology. DOI: 10.3389/fimmu.2017.00552".

Cubells-Baeza, N; Gómez-Casado, C; Tordesillas, L; Ramírez-Castillejo, C; Garrido-Arandia, M; González-Melendi, P; Herrero, M; Pacios, LF; Díaz-Perales, A. 2017. "Identification of the ligand of Pru p 3, a peach LTP". Plant Molecular Biology. DOI: 10.1007/s11103-017-0590-z".

Gomez, F; Bogas, G; Gonzalez, M; Campo, P; Salas, M; Diaz-Perales, A; Rodriguez, MJ; Prieto, A; Barber, D; Blanca, M; Torres, MJ; Mayorga, C. 2017. "The clinical and immunological effects of Pru p 3 SLIT on peach and peanut allergy in patients with systemic reactions". Clinical & Experimental Allergy. DOI: 10.1111/cea.12901".

Lavilla, M; Orcajo, J; Díaz-Perales, A; Gamboa, P. 2016. "Examining the effect of High Pressure Processing on the allergenic potential of the major allergen in peach (Pru p 3)". Innovative Food Science & Emerging Technologies. DOI: 10.1016/j.ifset.2016.06.021".

Gómez-Casado, C; Díaz-Perales, A. 2016. "Allergen-associated immunomodulators: modifying allergy outcome". Archivum Immunologiae et Therapiae Experimentalis. DOI: 10.1007/s00005-016-0401-2".

Cubells-Baeza, N; Verhoeckx, KCM; Larre, C; Denery-Papini, S; Gavrovic-Jankulovic, M; Diaz Perales, A. 2016. "Applicability of epithelial models in protein permeability/transport studies and food allergy". Drug Discovery Today: Disease Models. DOI: 10.1016/j.ddmod.2016.08.002".

Garrido-Arandia, M; Silva-Navas, J; Ramírez-Castillejo, C; Cubells-Baeza, N; Gómez-Casado, C; Barber, D; Pozo, JC; Melendi, PG; Pacios, LF; Díaz-Perales, A. 2016. "Characterisation of a flavonoid ligand of the fungal protein Alt a 1". Scientific Reports. DOI: 10.1038/srep33468".

Poulicard, N; Pacios, LF; Gallois, J-L; Piñero, D; García-Arenal, F. 2016. "Human management of a wild plant modulates the evolutionary dynamics of a gene determining recessive resistance to virus infection". PLoS Genetics. DOI: 10.1371/journal.pgen.1006214".

Pastor-Vargas, C; Maroto, AS; Díaz-Perales, A; Villalba, M; Esteban, V; Ruiz-Ramos, M; Rodriguez de Alba, M; Vivanco, F; Cuesta-Herranz, J. 2016. "Detection of major food allergens in amniotic fluid: initial allergenic encounter during pregnancy". Pediatric Allergy and Immunology. DOI: 10.1111/pai.12608".

Garrido-Arandia, M; Bretones, J; Gómez-Casado, C; Cubells, N; Díaz-Perales, A; Pacios, LF. 2016. "Computational study of pH-dependent oligomerization and ligand binding in Alt a 1, a highly allergenic protein with a unique fold". Journal of Computer-Aided Molecular Design. DOI: 10.1007/s10822-016-9911-6".

Pascal, M; Muñoz-Cano, R; Milà, J; Sanz, ML; Diaz-Perales, A; Sánchez-López, J; García-Moral, A; Juan, M; Valero, A; Yagüe, J; Picado, C; Bartra, J. 2016. "Nonsteroidal anti-inflammatory drugs enhance IgE-mediated activation of human basophils in patients with food anaphylaxis dependent and independent of nonsteroidal anti-inflammatory drugs". Clinical & Experimental Allergy. DOI: 10.1111/cea.12735".

Goikoetxea, M; D’Amelio, C; Martínez-Aranguren, R; Gamboa, P; Garcia, B; Gómez, F; Fernández, J; Bartra, J; Parra, A; Alvarado, M; Alonso, M; González, E; Terrados, S; Moya, C; Blanca, N; Feo-Brito, F; Villalba, M; Díaz-Perales, A; Sanz, M. 2016. "Is Microarray Analysis Really Useful and Sufficient to Diagnose Nut Allergy in the Mediterranean Area?". Journal of Investigational Allergology and Clinical Immunology. DOI: 10.18176/jiaci.0005".

Martín-Muñoz, MF; Rivero, D; Díaz Perales, A; Polanco, I; Quince, S. 2016. "Wheat allergy in celiac children". Pediatric Allergy and Immunology. DOI: 10.1111/pai.12487".

Jensen-Jarolim, E; Pacios, LF; Bianchini, R; Hofstetter, G; Roth-Walter, F. 2015. "Structural similarities of human & mammalian lipocalins, and their function in innate immunity and allergy". Allergy. DOI: 10.1111/all.12797".

Mas, S; Boissy, P; Monsalve, RI; Cuesta-Herranz, J; Díaz-Perales, A; Fernández, J; Colás, C; Rodríguez, R; Barderas, R; Villalba, M. 2015. "A recombinant Sal k 1 isoform as an alternative to the polymorphic allergen from Salsola kali pollen for allergy diagnosis". International Archives of Allergy and Immunology. DOI: 10.1159/000434680".

Fraile, A; Hily, J-M; Pagán, I; Pacios, LF; García-Arenal, F. 2014. "Host resistance selects for traits unrelated to resistance-breaking that affect fitness in a plant virus". Molecular Biology and Evolution. DOI: 10.1093/molbev/msu045".

Gómez-Casado, C; Roth-Walter, F; Jensen-Jarolim, E; Díaz-Perales, A; Pacios, LF. 2013. "Modeling iron-catecholates binding to NGAL protein". Journal of Molecular Graphics & Modelling. DOI: http://dx.doi.org/10.1016/j.jmgm.2013.08.013".

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