S05: Immune mechanisms in viral bronchiolitis-a model for virus induced asthma exacerbations?

Abstract

Bronchiolitis in infancy is a severe inflammatory disease of the distal airways, caused by respiratory viruses, most often respiratory syncytial virus (RSV). Respiratory viruses are also the most important triggers for asthma exacerbations. The immune pathology of either condition is not fully understood. The immune response to RSV can be subdivided into: (1) the epithelial phase in the first hours after infection during which epithelial cells and some macrophages release pro-inflammatory cytokines and chemokines, (2) the innate immune response which is characterised by an early influx of natural killer cells and concomitant recruitment of granulocytes, macrophages and dendritic cells (DC), (3) the adaptive immune response by antigen-specific effector T-cells and activated B-cell following activation by DC. T-cells are involved in cytotoxicity, clearing the virus, and in both pro-inflammatory and regulatory pathways. Activated B-cells produce antigen specific antibodies which contribute to viral clearance, in particular in secondary infections. Given the apparent role of T-cells in viral bronchiolitis and viral asthma exacerbations, we studied the impact of RSV infection in vivo on phenotype and function of pulmonary DC, the professional antigen presenting cells that are thought to activate T-cells during infection. Further we investigated the role of airway epithelial cells (AEC) in regulating DC and T-cell activation. Using a mouse model, we observed increases in numbers of lung DC after the initial phase of RSV-infection. These seem to be triggered by an early release of GM-CSF from lung epithelial cells leading to an expansion of local DC-precursors in the lung which mature and become efficient T-cell activators. Early in infection DC preferentially induce Th1- and pro-inflammatory Th17-cells. The latter may contribute to excessive pulmonary inflammation in bronchiolitis and also during subsequent allergen sensitisation possibly facilitating the development of asthma symptoms which have been observed following RSV-bronchiolitis. The subset of plasmacytoid DC which are potent producers of interferon-alpha has a direct antiviral role during RSV-infection limiting maximum replication of RSV and contributing to its clearance. In addition they may have direct regulatory effects, reducing RSV-induced inflammation and lung function changes. Healthy AEC seem to prevent activation of mucosal T cells and DC. However this inhibition is lost after RSV infection of AEC. We conclude that in the early phase of RSV-infection innate, epithelial cell dependent mechanisms dominate the antiviral response, releasing DC and T cells from inhibition, inducing expansion of lung DC and allowing activation of these immune cells. Subsequent innate and adaptive immune responses, including activation of DC and subsequently T-cell subsets contribute to the development and maintenance of pulmonary inflammation and associated lung function changes. Further, these virus-induced immune responses may also contribute to aberrant immune pulmonary responses after the resolution of RSV-bronchiolitis.