Immunopathology of COPD

Chronic obstructive pulmonary disease (COPD) is a major public health problem and its prevalence as well as morbidity and mortality are still rising. Until recently, it is the fourth leading cause of death in the developed world and was expected to move up to become the third leading cause of death worldwide by 2020. The stimulus of long-term exposure to toxic gases and most often cigarette smoke causes parenchymal lung tissue damage, remodeling of small airways, airway obstruction, and a subsequent decline in lung function. Innate inflammatory immune cells, i.e. neutrophils and macrophages, and CD8+ T cells have been described to be considerably involved in lung tissue damage in COPD. However, increasing evidence suggests that the inflammatory response of other specific immune cells, in particular CD4+ T and B cells present in the lungs of COPD patients, contributes to the pathogenesis of COPD. There has been increasing evidence indicating that COPD patients exhibit many of the characteristics of activated T cells, and particularly CD4+ T helper cells, as a feature of chronic pulmonary inflammation, where they persist even after smoking cessation. Although the positively correlation of T cell infiltration with decline lung function and disease progression have been demonstrated, the precise role of particular T helper subsets in disease progression remains poorly defined. More studies are needed to understand the exact role and involvement of these immune cells in the chronic inflammatory response in COPD. 

The overall concept of our research groups are; a) to identify the involvement of T-cells (CD4+: Th1, Th2, Th17 and Treg cells; CD8+: Tc1, Tc2, Tc17-cells) subsets to parenchymal lung tissue damage and small airway remodeling in response to cigarette smoke induced COPD and b) to characterize the role and function of the specific subset of CD4+T helper cell (e.g. Th17) using RAG and IL17 deficient mice in parenchymal lung tissue damage and small airway remodelling in response to cigarette smoke, c) to decipher the role of protein arginine methyltransferases (PRMTs) in the pathogenesis COPD. 

Protein arginine methylation is a posttranslational modification that is carried out by enzymes known as protein arginine methyltransferases (PRMTs) and this enzyme methylate arginine residues, most often at conserved RGG or RGR rich regions. PRMT activity has been found in both nuclear and cytoplasmic compartments, and its targets include transcription factors, histones, RNA binding and metabolic proteins and DNA damage repair proteins. Furthermore, arginine methylation has been implicated in affecting protein localization, stability, and protein-protein interactions. In addition, PRMT activity appears to be dysregulated in numerous human diseases, including heart disease and cancer, suggesting these enzymes as novel therapeutic targets. We have identified the expression and localization of PRMT isoforms in the adult mouse and human lung.