Paul Riley - Cardiac Sciences - 'Investigating the mechanisms of autoimmunity during heart failure'

Heart Failure (HF) is a rapidly growing public health issue with an estimated prevalence of >37.7 million individuals globally and is a major unmet clinical need. HF is underpinned by cardiomyocyte hypertrophy, interstitial fibrosis, pathological remodelling and ultimately death. Current interventions do not prevent disease progression and cannot restore heart function. A critical contributor to chronic decline of cardiac function in HF is the immune system, notably the adaptive immune response. Following tissue damage there is release of cardiac antigens, such as α-myosin heavy chain (α-MHC), which are captured by dendritic cells (DCs) and presented to T-cells in the draining lymph nodes, inducing an auto-reactive T-cell response. This is due, in part, to T-cells escaping central tolerance towards cardiac self-antigens during development in the thymus. Activation of T-cells, primed against cardiac antigens, is seen as a possible mechanism for prolonged cardiac injury well after the initial insult. In support of this, anti-heart autoantibodies against cardiac epitopes are a well-known clinical epiphenomenon during HF and the presence of autoreactive T-cells post-MI has previously been demonstrated. This project will focus on understanding the mechanisms behind T-cells escaping central tolerance towards cardiac self-antigens during development in the thymus, and whether restoring this tolerance improves disease progression in HF.