In the rodent this DC network develops fastest in the nasal turbinates, which represent the collection point for the bulk of TGF-beta inhibitor inspired particulate antigen, including microbial agents [42]. This suggests
that postnatal maturation of the airway DC network may be driven by stimulation from environmental irritants, including those associated with microbial pathogens, and data from infants who succumb to infections which demonstrate markedly increased AMDC density in the airway mucosa [43] are consistent with this possibility. Moreover, kinetic studies in a rat model of respiratory parainfluenza infection, which demonstrate rapid expansion of the AMDC network during early infection [44], provide further support for this idea, and similar findings are available for inhalation of bacterial stimuli [45]. Intriguingly, in the case of viral infection, the AMDC network does not return to baseline for several weeks post pathogen https://www.selleckchem.com/products/PD-0325901.html clearance [44], suggesting long-term effects of viral infection (related possibly to covert persistence of low levels of virus) on homeostasis of this DC population. These findings have prompted
us to add a specific AMDC component to the ‘two-hit’ model for asthma development [36]. In particular, we point to the possibility that viral infection may enhance the pathogenicity of nascent aeroallergen-specific Th2 immunity in the airway mucosa of recently sensitized children by expanding the population of available APCs which are necessary for local T memory cell activation
[36]. It is generally assumed that the triggering of wheezing attacks in humans sensitized to perennial ‘indoor’ allergens occurs directly via inhalation of supra-threshold levels of the relevant allergens. This can undoubtedly almost occur, and the phenomenon can be reproduced readily in murine models; however, it is by no means the only route via which asthma attacks can be triggered in atopics. This is particularly the case with respect to asthma exacerbations of sufficient severity to require hospitalization, which appear to be triggered instead by lower respiratory tract viral infection (reviewed in [36]). Our recent studies have identified a pathway by which host–anti-viral immunity can recruit allergen-specific Th2 recall responses into the inflammatory response at the airway mucosal infection site. The key element in this process is up-regulation of IgE-FcR expression on the myeloid precursors of AMDC, thus arming these cells optimally for subsequent presentation of activating signals to Th2 memory cells [46]. The resulting Th2 milieu in the airway mucosa is likely to blunt Th1 polarized anti-viral defences, and as such may represent an example of successful viral invasion of sterilizing immunity.