The impact of tyrosine nitration on the allergenicity of airborne allergens

Previous research has shown that nitration of allergens can occur following exposure to ozone, nitric oxide and water in polluted environments. Moreover, allergens might be nitrated in inflamed lung tissues. The nitration of proteins mainly affects the tyrosine residues, resulting in the formation of nitrotyrosine. The specificity of this modification can be related to a multitude of factors, such as the position of the tyrosine residue, the secondary structure of the protein and the nitration agent. However, the exact mechanism behind nitration events under natural conditions is still unknown. For research purposes, tetranitromethan is used to nitrate proteins in vitro and determine the biological effects of these modified proteins in comparison to the naive proteins.

Over the past years, we have studied the effects of Bet v 1a (the major birch pollen allergen) nitration on the immunogenicity of this protein. Recently, it was shown that the presentation of nitrated Bet v 1a derived peptides by dendritic cells is increased and that the diversity in nitro-Bet v 1a epitopes is enhanced (when compared to normal Bet v 1a) and that this increased presentation results in an increased T cell activation. Moreover, nitration affects dendritic cell activation. These results implicate that nitration leads to protein alterations, resulting in an increased uptake or better intracellular digestion. So far, characterisation of the nitrated Bet v 1a has shown that the modification resulted in protein multimerisation.

Our main goal in this study will be to determine the effects of allergen nitration on the protein itself and on immune reactions induced by these modified proteins; this study can be divided in three parts. First of all, we want to study whether allergy patients have in general enhanced levels of IgE specific antibodies to the disease specific nitrated allergens compared to unmodified allergens. Secondly, the effects of nitration on the conformation and aggregation of different allergens will be investigated. In the final part, the effect of the nitration grade on the immunological and chemical factors described above will be addressed and these levels will be compared with those found for natural allergens and allergens that have been nitrated under physiological circumstances. The latter study will focus on birch pollen allergens.

The results of the proposed study will not only enhance our knowledge with respect to the effects of protein nitration on allergic responses, but will also provide information on protein nitration in general. Moreover, the study will initiate the unravelling of the most likely pathways for protein nitration and the effects of such a nitration on protein structure, folding and interactions. The inclusion of several different allergens will increase the knowledge regarding the specificity of nitration and impact of these specific chemical modifications.

 

This project is funded by the Austrian "Fond zur Förderung der Wissenschaftlichen Forschung", Grant P22236-B13.

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