Identification of extracellular vesicle proteins in circulating exosomes from human lung transplant recipients

Abstract

Abstract Molecular mechanisms involved in rejection following human lung transplantation (LTx) are not well understood. We identified proteomic signatures of clinical outcomes in circulating extracellular vesicles (EVs) isolated from human lung transplant recipients (LTxRs) who was diagnosed with chronic rejection (Bronchiolitis Obliterans Syndrome (BOS)), acute rejection (AR), respiratory viral infection requiring intervention (RVI) or stable following transplantation. Differential analysis revealed one protein unique to AR (Skin-specific protein 32), four unique to RVI (Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2, Transmembrane 9 superfamily member 2, Ras-related C3 botulinum toxin substrate 2, and EH domain-containing protein) and two unique to stable (Coagulation factor X, and N-acetylmuramoyl-L-alanine amidase). Comparison of each rejection group to stable identified 128, 180, and 216 significantly differentially expressed proteins (p-value<0.05, fold-change>2) in BOS, AR, and RVI respectively. Although no unique signatures were found in BOS, an increased enrichment of immune processes such as antigen processing and presentation of exogenous peptide antigen via MHC class I and Fc receptor signaling pathway were observed. Functional enrichment analysis (Gene Ontology) associated differentially expressed EV proteins in AR and RVI conditions with wound repair processes. These diverse signatures detected in each condition highlight complex immune mechanisms underlying the pathophysiology of rejection following LTx. Future studies are needed to validate these signatures in larger LTxR cohorts in order to promote early clinical diagnosis and predict outcome.