The plasmacytoid dendritic cell: at the cross-roads in asthma

Abstract

The onset, progression and exacerbations of asthma are frequently associated with viral infections of the lower respiratory tract. An emerging paradigm suggests that this relationship may be underpinned by a defect in the host's antiviral response, typified by the impaired production of type I and type III interferons (IFNs). The failure to control viral burden probably causes damage to the lung architecture and contributes to an aberrant immune response, which together compromise lung function.Although a relatively rare cell type, the plasmacytoid dendritic cell dedicates much of its transcriptome to the synthesis of IFNs and is pre-armed with virus-sensing pattern recognition receptors. Thus, plasmacytoid dendritic cells are specialised to ensure early viral detection and the rapid induction of the antiviral state to block viral replication and spread. In addition, plasmacytoid dendritic cells can limit immunopathology, and promote peripheral tolerance to prevent allergic sensitisation to harmless antigens, possibly through the induction of regulatory T-cells. Thus, this enigmatic cell may lie at an important intersection, orchestrating the immediate phase of antiviral immunity to effect viral clearance while regulating tolerance.Here, we review the evidence to support the hypothesis that a primary defect in plasmacytoid dendritic function may underlie the development of asthma. @ERSpublications A review of the evidence on the role of plasmacytoid dendritic function in the development of asthma

IRF-3, IRF-7, and IPS-1 Promote Host Defense against Acute Human Metapneumovirus Infection in Neonatal Mice

“…Nevertheless, in our neonatal model, a robust IFN-a4 response failed to clear hMPV infection, inferring a more critical role for IFN-b in viral clearance. It would be interesting to investigate the infiltration of pDCs in hMPVinfected, factor-deficient mice, because these data suggest that, unlike other acute viral models in which pDCs are critical for viral clearance, 30,34 pDCs are less involved in the control of hMPV infection. Taken together, our data suggest that IFN-b, produced via a cytosolic RLReIPS-1eIRF3 signaling cascade, together with a downstream positive feedback effect of IRF7 expression, is required for optimal antiviral defense against hMPV.…”

Human Metapneumovirus Impairs Apoptosis of Nasal Epithelial Cells in Asthma via HSP70

“…This mechanism was independent of the IFN response, as NECs from both asthmatics and non-asthmatics produced IFN-β and -λ 1 similarly, and the level of intracellular viral RNA was not correlated to the IFN response. An impaired IFN response by asthmatic individuals has been associated with increased viral susceptibility [8][9][10] and there is significant evidence that this impairment exists in haematopoietic cells, such as plasmacytoid dendritic cells [21] . However, our data adds to the accumulating evidence [11,13,22] that AECs from mild-to-moderate asthmatic individuals are IFN-competent and that IFN-independent mechanisms contribute to elevated susceptibility to infection.…”

Dendritic Cells in Human Lung Disease

“…This regulatory mechanism may be lost in asthma. In humans, pDC are identified by surface markers such as BDCA-2 (CD303, a C-type lectin), BDCA-4 (CD304 or neuropilin-1), immunoglobulin-like transcript 7 (ILT7), and the IL-3 receptor-α chain (CD123) 7 .…”

“…pDC are best characterized by their ability to synthesize prolific amounts of interferon (IFN) in response to virus infections 7 . It is estimated that pDCs dedicate as much as 60% of their transcriptome to type I IFN production 8 and can release 100-fold more IFNα than any other known cell type 9 .…”