Degenerative abdominal aortic aneurysms (AAA) are characterised by aortic smooth muscle apoptosis, elastin degradation and a chronic inflammatory cell infiltrate. The inciting antigen is yet unknown. AAAs share many features with autoimmune conditions whilst overlapping several risk factors with atherosclerosis. The majority of AAAs of an operable size are lined with intraluminal thrombus (ILT), which is in constant contact with the aortic wall and flowing arterial blood. Flow mediated dilatation (FMD) is a surrogate marker for endothelial dysfunction and a predictor of future cardiovascular events. Patients with AAAs have a deteriorating FMD, which improves after surgery, thus implicating the aneurysm-thrombus complex as a potential driver of the systemic endothelial dysfunction.
The immunological contribution of ILT to the pathology is under investigated. This thesis aims to comprehensively define the immune landscape of the aortic wall and intraluminal thrombus through deep phenotyping, thus providing new insights into the mechanisms of degeneration in advanced stage aneurysms. Furthermore, it aims to explore a mechanistic link between ILT and systemic endothelial dysfunction.
Patients were prospectively recruited on to the Oxford Abdominal Aortic Aneurysm study. Peripheral blood, aortic wall and ILT specimens were collected intraoperatively and optimised for deep phenotyping with Time-of-flight mass cytometry (CyTOF). Cell sorting the aortic complex tissues provided high quality single cell suspensions for discovery analyses using different approaches.
The aortic wall was replete with T and B cells demonstrating new evidence of T and B cell crosstalk. In particular, T follicular helper cells were identified, thus providing evidence for class-switching to memory B cells in the aortic wall. The aortic and ILT lymphocytes contained the cytotoxic granule Granzyme B. This is a novel alternate mechanism of tissue destruction in late stage disease and its finding in the peripheral blood suggests a role as a potential biomarker. The myeloid cells had significant overlap in their markers of expression and the ILT also contained active monocyte derived dendritic cells, which is another novel finding. Both the T cells and myeloid cells had no dominant effector phenotype and rather represented a complex continuum aiming to achieve homeostatic balance. Finally, the ILT secretome was found to be cytotoxic to aortic endothelial cells and induced changes in gene expression consistent with endothelial dysfunction.
This thesis defines in detail the immune landscape of the aortic aneurysm-thrombus complex. It highlights the involvement of both innate and adaptive immune systems, as well as pro- and anti-inflammatory pathways involved in chronic non-resolving inflammation. The finding that ILT induces gene changes of endothelial dysfunction provides a novel mechanistic link for the changes in FMD of patients with AAA. These observations highlight potential targets for translational therapeutics. </p
