Abstract
Ragweed (Ambrosia artemisiifolia) pollen grains, which are generally considered too large to reach the lower respiratory tract, release subpollen particles (SPPs) of respirable size upon hydration. These SPPs contain allergenic proteins and functional NAD(P)H oxidases. In this study, we examined whether exposure to SPPs initiates the activation of human monocyte-derived dendritic cells (moDCs). We found that treatment with freshly isolated ragweed SPPs increased the intracellular levels of reactive oxygen species (ROS) in moDCs. Phagocytosis of SPPs by moDCs, as demonstrated by confocal laser-scanning microscopy, led to an up-regulation of the cell surface expression of CD40, CD80, CD86, and HLA-DQ and an increase in the production of IL-6, TNF-α, IL-8, and IL-10. Furthermore, SPP-treated moDCs had an increased capacity to stimulate the proliferation of naïve T cells. Co-culture of SPP-treated moDCs with allogeneic CD3+ pan-T cells resulted in increased secretion of IFN-γ and IL-17 by T cells of both allergic and non-allergic subjects, but induced the production of IL-4 exclusively from the T cells of allergic individuals. Addition of exogenous NADPH further increased, while heat-inactivation or pre-treatment with diphenyleneiodonium (DPI), an inhibitor of NADPH oxidases, strongly diminished, the ability of SPPs to induce phenotypic and functional changes in moDCs, indicating that these processes were mediated, at least partly, by the intrinsic NAD(P)H oxidase activity of SPPs. Collectively, our data suggest that inhaled ragweed SPPs are fully capable of activating dendritic cells (DCs) in the airways and SPPs' NAD(P)H oxidase activity is involved in initiation of adaptive immune responses against innocuous pollen proteins.
Highlights
Allergic asthma, a chronic inflammatory disorder of the airways, affects over 300 million individuals worldwide and an estimated 35 million in the United States alone [1]
Activated dendritic cells (DCs) can trigger the development of adaptive immune responses; we studied the T cell-priming capacity of internalized cells in a representative measurement from four independent experiments. (B) Visualization of SPPs in human monocyte-derived dendritic cells (moDCs) by confocal laser scanning microscopy
Recent observations indicate that under steady-state conditions, only few mediastinal lymph node DCs originate from the airways and that inflammatory stimuli are generally necessary to provoke substantial accumulation of airway-derived DCs within lymph nodes [32]
Summary
A chronic inflammatory disorder of the airways, affects over 300 million individuals worldwide and an estimated 35 million in the United States alone [1]. One of the most common triggers of allergic asthma is the pollen of short ragweed (Ambrosia artemisiifolia). The prevalence of allergic asthma has increased over the last 40 years [3]; the reasons for this phenomenon cannot yet be explained. Possible explanations include the expansion of ragweed species due to increasing deforestation and economic development [4], and elevated pollen production and growing pollen season length associated with climate change [5,6]. The biochemistry of pollen allergens and the mechanism by which they trigger clinical symptoms in sensitized individuals are relatively well understood; several unresolved questions remain relating to the development of adaptive immune responses against pollen-derived proteins
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