Allergic asthma is characterized by airway hyperresponsiveness, inflammation, and a cellular infiltrate dominated by eosinophils. Numerous epidemiological studies have related the exacerbation of allergic asthma with an increase in ambient inhalable particulate matter from air pollutants. This is because inhalable particles efficiently deliver airborne allergens deep into the airways, where they can aggravate allergic asthma symptoms. However, the cellular mechanisms by which inhalable particulate allergens (pAgs) potentiate asthmatic symptoms remain unknown, in part because most in vivo and in vitro studies exploring the pathogenesis of allergic asthma use soluble allergens (sAgs). Using a mouse model of allergic asthma, we found that, compared with their sAg counterparts, pAgs triggered markedly heightened airway hyperresponsiveness and pulmonary eosinophilia in allergen-sensitized mice. Mast cells (MCs) were implicated in this divergent response, as the differences in airway inflammatory responses provoked by the physical nature of the allergens were attenuated in MC-deficient mice. The pAgs were found to mediate MC-dependent responses by enhancing retention of pAg/IgE/FcεRI complexes within lipid raft-enriched, CD63 + endocytic compartments, which prolonged IgE/ FcεRI-initiated signaling and resulted in heightened cytokine responses. These results reveal how the physical attributes of allergens can co-opt MC endocytic circuitry and signaling responses to aggravate pathological responses of allergic asthma in mice.

The mRNA expression of three histamine receptors (H1, H2 and H3) and H1 and H3 receptor binding were mapped and quantified in normal human thalamus by in situ hybridization and receptor binding autoradiography, respectively. Immunohistochemistry was applied to study the distribution of histaminergic fibres and terminals in the normal human thalamus. mRNAs for all three histamine receptors were detected mainly in the dorsal thalamus, but the expression intensities were different. Briefly, H1 and H3 receptor mRNAs were relatively enriched in the anterior, medial, and part of the lateral nuclei regions; whereas the expression level was much lower in the ventral and posterior parts of the thalamus, and the reticular nucleus. H2 receptor mRNA displayed in general very low expression intensity with slightly higher expression level in the anterior and lateropolar regions. H1 receptor binding was mainly detected in the mediodorsal, ventroposterolateral nuclei, and the pulvinar. H3 receptor binding was detected mainly in the dorsal thalamus, predominantly the periventricular, mediodorsal, and posterior regions. Very high or high histaminergic fibre densities were observed in the midline nuclear region and other nuclei next to the third ventricle, ventroposterior lateral nucleus and medial geniculate nucleus. In most of the core structures of the thalamus, the fibre density was very low or absent. The results suggest that histamine in human brain regulates tactile and proprioceptory thalamocortical functions through multiple receptors. Also, other, e.g. visual areas and those not making cortical connections expressed histamine receptors and contained histaminergic nerve fibres.

Although much is known regarding the exocytic responses of mast cells following allergen/IgE-mediated activation, little is currently known of the fate of the activating allergens, many of which are particles. We have found that IgE-bound particulate allergens were phagocytosed by activated mast cells in a lipid raft-dependent manner. The nascent allergen-containing phagosomes were found to transform into granule compartments by acquiring VAMP7 and serotonin and exhibited the capacity to empty their contents upon mast cell activation. When allergen-harboring mast cells were stimulated, the intracellular allergens were expelled intact and shown to activate adjacent mast cells. This capacity of mast cells to phagocytose and retain whole and antigenically intact allergens could potentially contribute to the course of inflammatory diseases such as asthma.

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Numerous epidemiological studies have related the exacerbation of allergic asthma with exposure to increased ambient particles from air pollutants. However, the mechanism by which particulate allergens (pAg) exacerbate allergic asthma remains undefined. To evaluate this, we modeled environmental pAg induced allergic asthma by exposing mice to polystyrene beads coated with natural allergen extracts. Compared to equal amounts of soluble allergen extracts (sAg), pAg triggered markedly enhanced airway hyper-responsiveness and pulmonary eosinophila in allergen sensitized mice. The cellular basis for this effect was determined to be mast cells (MCs), as both airway allergic responses were attenuated in MC deficient mice compared to MC sufficient mice. The divergent responses of MCs to pAg versus sAg were due to differences in the termination rate of IgE/FcϵRI initiated signaling. Following ligation of sAg, IgE/FcϵRI rapidly shuttled into a degradative endosome/lysosome pathway. However, following ligation by pAg, IgE/FcϵRI migrated into lipid raft enriched compartments and subsequently failed to follow a degradative pathway, which resulted in a prolonged signaling and heightened synthesis of proinflammatory mediators. These observations highlight the overlooked contributions of the particulate nature of allergens and mast cell endocytic circuitry to the aggravation of allergic asthma.