Purpose The destabilisation and rupture of atherosclerotic plaques in major arteries underpins the pathophysiological basis of myocardial infarctions and ischaemic strokes. Together, these manifestations of cardiovascular disease represent the leading global cause of death. Adaptive immune cells, consisting of T and B cells, are powerful mediators of inflammation that have been identified within the chronically inflamed lesions characteristic of atherosclerosis. It has been suggested that their presence underlies plaque destabilisation, though the extent to which they do so and why they respond in the context of this sterile but inflammatory environment remains unclear. However, there is growing evidence that T and B cells elicit autoimmune responses in many chronic inflammatory disorders that arise in the absence of overt pathology, such as in autoimmunity, giving increasing weight to the hypothesis that such responses also play a key role in atherosclerosis. This study aimed to understand the role that adaptive immunity plays in atherogenesis and the immunology underlying plaque destabilisation and rupture. Methodology Comprehensive examination of adaptive immune responses was conducted in a case series of human and murine atherosclerotic plaques. Building on previous work, this study directly compared the immunology of stable and unstable atherosclerotic plaque phenotypes in both mice and humans. Human specimens were collected from patients undergoing carotid and femoral endarterectomy at The Alfred Hospital in Melbourne, Australia. Results Publication of results are pending and remain protected intellectual property. For this reason, the authors request that this information be withheld from publicly available conference publication material. Conclusion Our data strongly support that adaptive immune responses are critical drivers of atherosclerotic plaque destabilisation and rupture, adding significant strength to the autoimmune hypothesis in atherosclerosis.