Role of cysteinyl leukotrienes in antigen-induced immune response in the airway: from bronchus to the nose

There are similarities between allergic rhinitis (AR) and atopic bronchial asthma in their pathophysiology, although some differences also exist. For example, some AR patients without asthma demonstrate airway hyperresponsiveness (AHR) of the lower respiratory tract. Similar findings have been noted in patients with atopic dermatitis. This indicates that a systemic sensitization to antigen itself plays a pivotal role in the induction of AHR in sensitized individuals independently of eosinophilic inflammation in the lower airway. To clarify the mechanism, we studied a mouse model and found that transfer of antigen-induced memory/effector cells can induce AHR in normal mice without airway inflammation. Dendritic cells (DCs) play a critical role in antigen-induced immune response. We investigated the role of cysteinyl leukotrienes (cysLTs) in DC functions. BALB/c mice were sensitized with ovalbumin (OVA) and aluminium hydroxide (alum) twice, and subjected to OVA inhalation to induce airway inflammation. Systemic OVA sensitization alone up-regulated cysLTs in the lung and stimulated T-helper type 2 (Th2) cytokines production, whereas leukotriene receptor antagonist (LTRA) suppressed these productions. OVA sensitization enhanced DC functions such as antigen-presenting capacity and cytokine production, and LTRA also attenuated them. Finally, we treated mice with LTRA during systemic sensitization and examined the effect on subsequent airway inflammation induced by OVA inhalation. LTRA suppressed all indicators of inflammation such as airway eosinophilia, Th2-type cytokine production, and AHR along with decreased DC functions of the lung. These results indicate that modulating the antigen-induced up-regulation of DC functions in the early phase could attenuate further development of eosinophilic inflammation in the lower airway. Taking the similarities of lower and nasal airway into account, cysLTs may also play a critical role in the pathogenesis of AR; therefore, LTRA could be effective against AR from the initial presentation to the inflammation phase.