Project Description Narrative:
Chronic respiratory diseases are commonly identified as causes of disability and death. They are a heterogeneous group of diseases characterized by excessive inflammatory cell recruitment and destruction. The most prevalent chronic respiratory diseases are asthma, chronic obstructive pulmonary disease (COPD) and bronchiectasis. These are incurable and can promote premature death; however, treatments options can improve and control symptoms. Chronic respiratory diseases are thought to be caused by a combination of complex and incompletely understood environmental exposures and genetic interactions that vary by disease.
The commonly shared etiology of chronic respiratory diseases frequently involves a form of immune dysregulation whether immune deficiency, autoimmunity, or malignancy. In 2021, 16.4% of Wisconsin residents were living with a diagnosis of asthma and/or COPD. Chronic respiratory diseases were the fourth leading cause of death in the state of Wisconsin in 2021. Patients with severe chronic respiratory diseases have a decreased quality of life, and the needed medical care creates a great economic burden. Globally, chronic respiratory diseases account for 6.3% of disability and are attributed to an increase in the average number of years lived with disability. The burden of lifelong disease, decreased quality of life, and economic cost highlights the need for attention to this group of chronic diseases. Chronic respiratory diseases affect both men and women, although the prevalence of asthma, COPD, and bronchiectasis is higher in women. Chronic respiratory diseases are associated with the development of bronchus associated lymphoid tissue. Following chronic pulmonary inflammation, leukocytes that infiltrate the lung often assemble into structures known as BALTs. Like conventional lymphoid organs, BALTs have segregated B and T cell areas, specialized stromal cells, high endothelial venules (HEVs), and lymphatic vessels. BALTs facilitate antigen-specific immune responses, including those that are unrelated to the BALT-initiating antigen and often alter the clinical course of disease. BALTs are frequently observed in a range of disease states characterized by chronic inflammation (asthma, COPD, and ARDS), autoimmunity (Rheumatoid arthritis (RA) and Sjögren syndrome (SS)), and infection. In contrast to their protective role in lung infections, BALTs are associated with exacerbation of inflammation and a more severe disease course in chronic respiratory diseases.
A critical barrier is a poor understanding of the key factors initiating and maintaining BALT, as these factors could determine how BALT impacts local and systemic immunity. Further insight may clarify the distinct roles of BALT during infection and inflammation. Preliminary data underpinning this project suggest inherited prothrombotic mutations may put individuals at risk for chronic respiratory diseases by initiating chronic pulmonary inflammation and BALT. This project seeks to build an understanding of how thrombophilia promotes vascular and immunological changes that lead to the development of BALT. These findings could aid in the identification of therapeutic interventions potentially beneficial to multiple chronic inflammatory and autoimmune diseases.