Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the lung. These diseases are characterized by pulmonary inflammation and poor respiratory function. The underlying mechanisms controlling these diseases are still being elucidated. Interestingly, COPD patients and in some cases asthma patients develop inducible Bronchus Associated Lymphoid Tissue (iBALT). Bronchus Associated Lymphoid Tissue (BALT) was considered by early investigators to be a mucosal secondary lymphoid tissue embedded in the walls of the large airways, similar to Peyer's patches in the small intestine. However, we now know that BALT is not constitutively present in all mammalian species, notably mice and humans, and is induced in response to microbial exposure or other types of pulmonary inflammation. Therefore, the inducible lymphoid tissues in the lung may be more properly referred to as tertiary or ectopic lymphoid tissues and we have coined the term inducible BALT (iBALT) to describe them. Once formed, iBALT is maintained in the lung for several months or even longer and acts as a secondary lymphoid tissue that supports primary and secondary B and T cell responses to pulmonary antigens and pathogens. Importantly, pulmonary immune responses that occur in the presence of iBALT often have dramatically different characteristics than those that occur in the absence of iBALT. Thus, prior exposures of the respiratory tract can lead to lung remodeling and the development of iBALT, which regulates subsequent pulmonary immune responses via poorly defined mechanisms. We now have preliminary data showing that iBALT requires IL-17 and IL-22-expressing T cells for its formation, suggesting that iBALT forms in response to and participates in Th17 immune responses. Given the important role for Th17 cells in pulmonary diseases like asthma and COPD and the dramatic effects that iBALT has on pulmonary immune function to infectious agents, we believe that it is important to define the cellular and molecular mechanisms that control iBALT formation and to determine the mechanisms by which iBALT regulates pulmonary immune responses in the context of inflammatory disease.
The experiments in this proposal will determine the mechanisms underlying the development of specific lymphoid structures that develop in the lung following pulmonary infection or inflammation. They will also determine the function of these structures in the context of pulmonary diseases like asthma and COPD.
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