The lung is constantly exposed to a variety of inhaled antigens and pathogens to which the immune system must respond. In particular, respiratory immune responses must be robust enough to eliminate respiratory pathogens, but must also be controlled enough so that the resulting inflammation does not interfere with lung function. A failure to achieve balance between immunity and inflammation leads to failed immunity and to a variety of idiopathic, progressive or chronic lung diseases. Understanding the mechanisms that keep pulmonary immunity and the associated inflammatory response in check, and yet prepared to respond quickly to potentially deadly or disease-causing pathogens is important to developing rational approaches to intervening in many pulmonary diseases. However, pulmonary immunology is an understudied area of lung research and little has been done to characterize the pulmonary immune system per se. Local lymphoid tissues, such as inducible Bronchus Associated Lymphoid Tissue (iBALT), are likely to play a central role in respiratory immune responses. However, the role of iBALT in respiratory immunity is poorly understood. Our preliminary data demonstrate that iBALT primes influenza-specific T and B cells in the absence of conventional lymphoid organs. Surprisingly, respiratory immune responses generated exclusively in iBALT lead to less morbidity and mortality, suggesting that iBALT may confer anti-inflammatory properties on local immune responses. In contrast, other studies correlate the presence of iBALT with the pathology associated with autoimmune disease or chronic respiratory infections. Thus, the role of iBALT in respiratory immunity remains enigmatic. Interestingly, respiratory inflammation in neonates appears to more efficiently elicit iBALT than inflammation in adults, suggesting that there is a developmental window for the formation of iBALT. We will test the hypothesis that the formation of iBALT in neonates will permanently change the architecture and function of the lung and that these changes will be manifest as (i) altered sensitivity to respiratory antigens, (ii)changes in the number, phenotype and migratory habits of dendritic cells in the lung, (iii)changes in T cell responses to respiratory antigens and (iv) changes in the outcome of immune responses to respiratory antigens and pathogens. These experiments will lead to a new understanding of how iBALT functions in respiratory immunity. Relevance to human health. The results from these experiments will lead to a new understanding of how iBALT functions in respiratory immunity to innocuous antigens and to pathogens of the respiratory tract. We expect that the results from these experiments will help to develop therapies that take advantage of the beneficial properties of iBALT (by promoting immunie responses to pathogens) and prevent iBALT from exacerbating respiratory pathology (asthma and chronic inflammatory diseases of the lung).
Showing the most recent 10 out of 51 publications
