Allergic Airways Disease Develops after an Increase in Allergen Capture and Processing in the Airway Mucosa

Abstract

Airway mucosal dendritic cells (AMDC) and other airway APCs continuously sample inhaled Ags and regulate the nature of any resulting T cell-mediated immune response. Although immunity develops to harmful pathogens, tolerance arises to nonpathogenic Ags in healthy individuals. This homeostasis is thought to be disrupted in allergic respiratory disorders such as allergic asthma, such that a potentially damaging Th2-biased, CD4+ T cell-mediated inflammatory response develops against intrinsically nonpathogenic allergens. Using a mouse model of experimental allergic airways disease (EAAD), we have investigated the functional changes occurring in AMDC and other airway APC populations during disease onset. Onset of EAAD was characterized by early and transient activation of airway CD4+ T cells coinciding with up-regulation of CD40 expression exclusively on CD11b− AMDC. Concurrent enhanced allergen uptake and processing occurred within all airway APC populations, including B cells, macrophages, and both CD11b+ and CD11b− AMDC subsets. Immune serum transfer into naive animals recapitulated the enhanced allergen uptake observed in airway APC populations and mediated activation of naive allergen-specific, airway CD4+ T cells following inhaled allergen challenge. These data suggest that the onset of EAAD is initiated by enhanced allergen capture and processing by a number of airway APC populations and that allergen-specific Igs play a role in the conversion of normally quiescent AMDC subsets into those capable of inducing airway CD4+ T cell activation.

Origin and functional specializations of DC subsets in the lung

“…No studies so far have studied whether lung DC subsets would differentially express any of these enzymes or endocytic targeting receptors. It was shown that mucosal cDC were more endocytic and better at presenting antigenic peptides to naive CD4 1 lymphocytes than lung parenchymal cDC [10,34]. Despite this peptide presentation, only DC matured in vitro or in vivo presented whole protein to T lymphocytes, indicating a mechanism of regulation at the level of antigen processing.…”

The role of dendritic cells and regulatory T cells in the regulation of allergic asthma

“…A number of studies have shown that RTDC within or beneath the airway epithelial cell layer can extend their dendrites through the epithelial junctions, presumably to directly sample the luminal microenvironment (Vermaelen et al, 2001;Jahnsen et al, 2006;Blank et al, 2007;Wikstrom & Stumbles, 2007). We have shown that airway RTDC become activated and up-regulate their capacity to capture and process inhaled allergen prior to the onset of Th2-mediated airways inflammation in mice, suggesting that RTDC play an important early role in the activation and recruitment of Th2 cells to the airways (von Garnier et al, 2007). In addition to the airway epithelium, RTDC subsets are also present in the submucosa and lung parenchyma although subset distribution and turnover rates differ at these sites (Holt et al, 1994;von Garnier et al, 2005).…”

“…In support of the role of DC in the allergic asthmatic response, adoptive transfer of OVA-pulsed DC to naïve mice followed by a respiratory allergen challenge elicited sensitisation and elevated numbers of activated airway OVA-specific CD4 + cells (Lambrecht et al, 2000a,b) . We have demonstrated an increase in the interactions between RTDC and T cells in the airways in rats, and in the activation and allergen-capture status of RTDC in mice, prior to the onset of EAAD and have demonstrated a role for circulating allergen-specific antibody in mediating T cell activation during this response (Huh et al, 2003;von Garnier et al, 2007). Collectively these data suggest that modulation of RTDC function is a key event in the development of EAAD.…”

“…After exposure to allergen they express high levels of MHC class II and CD11c (Wikstrom & Stumbles, 2007) and are functionally immature as shown by low expression of costimulatory molecules CD40, CD80 and CD86 (Stumbles et al, 1998;Huh et al, 2003;de Heer et al, 2005;van Rijt et al, 2005). They are able to capture antigen rapidly in the main conducting airways (Lambrecht, 2001;Vermaelen et al, 2001;von Garnier et al, 2007). This DC subset has a high migratory capacity for trafficking antigen to the draining lymph nodes (Lambrecht, 2001;Vermaelen et al, 2001;von Garnier et al, 2007).…”

“…They are able to capture antigen rapidly in the main conducting airways (Lambrecht, 2001;Vermaelen et al, 2001;von Garnier et al, 2007). This DC subset has a high migratory capacity for trafficking antigen to the draining lymph nodes (Lambrecht, 2001;Vermaelen et al, 2001;von Garnier et al, 2007). CD11c+MHCIIhi DC in the respiratory mucosa are known to exhibit a high rate of turnover (approximate half-life of 12 h) as antigen-bearing DC continuously migrate to the DLN and are replaced by de novo DC from the bone marrow (Holt et al, 1994;Lambrecht et al, 1998;von Garnier et al, 2005).…”