Exosomes in lung diseases –understanding their role in disease and exploring them as biomarkers

Background: Exosomes are nanovesicles released from virtually all cells in the body. They are 30-100 nm in size and express MHC class I and II, as well as co-stimulatory molecules. Exosomes loaded with antigen can stimulate or inhibit activation of T and B cells depending on their origin.

We have discovered the presence of exosomes in bronchoalveolar lavage fluid (BALF), and that patients with Chronic Obstructive Pulmonary Disease (COPD), asthma and sarcoidosis display an altered protein- and/or RNA profile. We have also shown that patients with sarcoidosis and asthma have proinflammatory exosomes in the lung, and believe that they contribute to disease. We have also discovered the presence of leukotriene-forming enzymes in exosomes.

Objective: We want to understand the role of exosomes in the lung, especially in sarcoidosis and COPD. We want to characterize proteomic and transcriptomic content of exosomes from lungs and plasma from patients with COPD and sarcoidosis, to develop exosomes as disease biomarkers. We also want to understand the mechanisms behind how exosomes induce immune responses, in order to block damaging exosomes or to use disease-preventing exosomes for therapy.

We have seen different patterns of exosomes in smokers who are healthy and those with COPD, so we also want to analyze exosomes longitudinally in a COPD mouse model of smoke exposure to determine causality.

Work Plan: BAL and plasma exosomes from patients with sarcoidosis and COPD, are compared with healthy individuals, in FACS, western blot and mass spectrometry. Also mRNA and miRNA are analyzed. Candidate proteins are taken to the novel proximity barcoding assay to characterize and detect rare individual exosomes.

We also want to study molecular mechanisms for how exosomes from patients stimulate different cells. Patient’s exosomes are added both to primary human cells and to mouse lungs to determine the effects on different immune cells in vitro and in vivo. In a 12-week COPD smoking mouse model we will determine proteome and function of exosomes longitudinally.

Significance: This work could lead to new treatment strategies for sarcoidosis and COPD, but also new diagnostic tests within a couple of years. By finding out how exosomes affect inflammation, we can develop treatments that block or counteract disease promoting exosomes. Exosomes produced in vitro could also be used to control an incorrect immune response in asthma or sarcoidosis within 7-10-years.