Abstract
Allergy prevalence has increased in industrialized countries. One contributing factor could be pollution, which can cause nitration of allergens exogenously (in the air) or endogenously (in inflamed lung tissue). We investigated the impact of nitration on both the structural and immunological behavior of the major birch pollen allergen Bet v 1.0101 to determine whether nitration might be a factor in the increased incidence of allergy. Bet v 1.0101 was nitrated with tetranitromethane. Immune effects were assessed by measuring the proliferation of specific T-cell lines (TCLs) upon stimulation with different concentrations of nitrated and unmodified allergen, and by measurement of cytokine release of monocyte-derived dendritic cells (moDCs) and primary DCs (primDCs) stimulated with nitrated versus unmodified allergen. HPLC-MS, crystallography, gel electrophoresis, amino acid analysis, size exclusion chromatography and molecular dynamics simulation were performed to characterize structural changes after nitration of the allergen. The proliferation of specific TCLs was higher upon stimulation with the nitrated allergen in comparison to the unmodified allergen. An important structural consequence of nitration was oligomerization. Moreover, analysis of the crystal structure of nitrated Bet v 1.0101 showed that amino acid residue Y83, located in the hydrophobic cavity, was nitrated to 100%. Both moDCs and primDCs showed decreased production of TH1-priming cytokines, thus favoring a TH2 response. These results implicate that nitration of Bet v 1.0101 might be a contributing factor to the observed increase in birch pollen allergy, and emphasize the importance of protein modifications in understanding the molecular basis of allergenicity.
Highlights
Over the past several decades, the incidence of allergy has increased in industrialized countries, affecting about 25% of the population [1]
We compared the proliferation of birch pollen (BP)-specific T-cell lines (TCLs) after stimulation with Bet v 1.0101, mock-Bet v 1.0101 and nitro-Bet v 1.0101, including lower protein concentrations than those used in the previous study (0.625–5 mg/ml)
Nitro-Bet v 1.0101 caused a higher proliferation of BP-specific TCLs in comparison to Bet v 1.0101 or mock-Bet v 1.0101, which stayed high even at decreasing concentrations of allergen (Figure 1). To determine whether this effect is due to the presence of nitrotyrosine in the T-cell epitope presented, the cells were stimulated with three different peptides, representing the immunodominant epitopes of Bet v 1 [17], containing either a tyrosine or nitrotyrosine
Summary
Over the past several decades, the incidence of allergy has increased in industrialized countries, affecting about 25% of the population [1]. Different factors have been blamed for this increase, including pollution [2,3]. Air pollution is associated with enhanced levels of ozone, nitrogen dioxide, sulfur dioxide, and particulate matter. The complex relationship between the effects of air pollution and the occurrence of allergic diseases was reviewed in [4]. One of the consequences of air pollution is nitration of proteins, which can be mediated by NO2 and O3 at atmospheric concentrations [5]. Tyrosine residues of proteins present in aerosol particles, such as pollen fragments, may be nitrated in polluted urban air before entering the airways. As shown by Franze et al, nitrated proteins can be found in urban road dust, window dust and air particulate matter, with degrees of nitration ranging from 0.01% to 0.1% [6]
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