What causes allergy and asthma? Early postnatal influences

A number of studies have implicated viral lower respiratory tract infections early in life as a risk factor for the subsequent development of asthma (1). In particular, it has been suggested that respiratory syncytial virus (RSV) infection may enhance the development of ‘‘allergic’’ inflammatory responses when the host is exposed to allergens after an episode of bronchiolitis. Some predisposing conditions frequently associated with severe RSV disease are also independent risk factors for chronic airway dysfunction: preterm birth per se is known to result in persistent alterations of lung function (2, 3) and chronic lung disease of prematurity (CLD) is associated with the development of obstructive lung disease and airway hyperreactivity (4). Although RSV infection is usually self-limiting and the virus is cleared from the respiratory tract of immunecompetent children within a few weeks, there is growing evidence suggesting that RSV infection has long-term sequelae in the developing respiratory tract (5). In fact, epidemiological evidence from several retrospective studies, as well as more recent well-controlled prospective studies (6, 7) supports the association of RSV lower respiratory tract illness in early life with recurrent episodes of wheezing and the development of asthma during the first decade of life. Indeed, both RSV bronchiolitis and asthma share several clinical features (wheezing, increased work of breathing, tachypnea, and reversible changes in pulmonary function), but they also differ substantially in terms of response to bronchodilator and anti-inflammatory therapies. Despite extensive research effort, the precise mechanisms and pathways by which RSV infection causes airway inflammation and affects long-term control of airway functions subsequent to the initial insult are still unclear. Compromised epithelial integrity, the elaboration of local proinflammatory mediators, and dysfunction of neural pathways may all influence airway responses to environmental stimuli. Some investigators postulate that infection with RSV or other viral pathogens can precipitate an imbalance in local cell-mediated immune responses (8). Others theorize that infant bronchiolitis may result in alterations to neuronal pathways that influence smooth muscle tone and airway patency via the release of neurotransmitters (9). Our group has proposed that combined neuro-immune interactions primed by the virus can both initiate and propagate a cascade of events leading to recurrent cycles of airway inflammation and obstruction (10). In the airways, a dense network of sensory nerve fibers is strategically placed just below the epithelial surface so that any change in the bronchial environment may stimulate the release of the proinflammatory neuropeptide substance P (11). During RSV infection, stimulation of these nerves causes a marked increase in airway vascular permeability when compared with pathogenfree controls, and results in an increase in overall inflammatory status (12). Our work has revealed that these changes are mediated by the high affinity receptor for substance P (NK1 receptor), whose expression is greatly increased by RSV (12, 13). This up-regulation presumably occurs at the gene expression level, as NK1 receptor mRNA levels increase substantially during RSV infection. We have also shown that T-lymphocytes subpopulations, predominantly CD4þ cells, within the bronchial-associated lymphoid tissue (BALT) of RSVinfected lungs express high levels of the NK1 receptor (14). As a consequence, stimulation of the sensory nerves by any airborne irritant has the potential of causing a new inflammatory cycle mediated by NK1 receptor-expressing T-helper lymphocytes and monocytes attracted into the airways and activated by substance P. This mechanism may establish important neuroimmune interactions, which undergo long-term dysregulation following RSV infection and predispose to airway inflammation and hyperreactivity. RSV also affects dramatically the distribution and function of mast cells resident in the airway mucosa (15). Histopathological analysis with an antibody against tryptase identified numerous mast cells in the sections from RSV-infected