New Aspects of Alveolar Adaptive Immune Responses in COPD

Abstract: Chronic obstructive pulmonary disease (COPD) is characterised by a chronic inflammation in conducting airways and the alveolar parenchyma. The inflammation, which is a consequence of inhalation of noxious gases like tobacco smoke, has traditionally been thought to be driven by innate immune responses. However, more recent studies have revealed an increase in lymphocyte-rich lymphoid aggregates (LAs) and antigen presenting dendritic cells (DCs) in peripheral airways of patients with COPD. These findings suggest that peripheral adaptive immune responses and antigen-driven immune events may contribute to the immunopathology of COPD. However, the involvement of the alveolar compartment has remained unexplored. The aim of this thesis work was to provide new insights into the structural as well as the immunological basis for alveolar antigen uptake and peripheral adaptive immune responses in COPD. To investigate this, detailed immunohistochemical assessments of adaptive immune system components were performed in surgical specimens obtained from patients with different severities of COPD (GOLD stage I-IV), smokers and never-smoking control subjects. Immunohistochemistry and 3D reconstructions of serial sections were used to demonstrate a rich occurrence of alveolar-restricted LAs and reveal that also the vast majority of the bronchiolar- and vascular-associated LAs have alveolar interfaces. Importantly, in COPD patients but not in controls a selective accumulation of langerin+ DCs was observed along the alveolar-lymphoid interfaces. Moreover, these alveolar interface DCs had increased luminal protrusions and more physical contact with lymphoid T cells than the corresponding mucosal DCs. A further investigation of multiple DC subsets in different peripheral lung compartments found that in COPD the most marked increase in DC subsets, including BDCA-2+, CD1a+langerin- and CD11c+CD68-CD163- DCs, was observed in the alveolar tissue. Notably, the DCs in LA interfaces and alveolar tissue differed from airway DCs by a distinct marker expression profile. The 3D analysis revealed an intricate connection between LAs and lymphatic vessels. Further, a marked increase in the number of alveolar lymphatic vessels was detected in patients with advanced COPD. Importantly, in COPD lymphatic vessels had an activated phenotype as revealed by increased lymphatic expression of CCL21 and D6, both of which are involved in DC transport to lymphoid tissues. In conclusion, the studies in this thesis have discovered that the alveolar parenchyma in COPD lungs contain a novel type of DC-rich alveolar-lymphoid epithelium, elevated levels of multiple DC subsets as well as activated lymphatic vessels. Taken together these findings forward the alveolar parenchyma as an important arena for antigen uptake in COPD. This insight calls for future investigations to find out to what extent the resulting adaptive immune responses contribute to the COPD pathogenesis and how they can be pharmacologically targeted.