Cardiac inflammation: the relative contribution of autoimmunity and genes
Federica M Marelli-Berg1,
Silvia Fanti1*, Edward Stephenson1,2*, Etel Rocha-Vieira1,3, Alexandros Protonotarios2,4, Stavroula Kanoni1, Perry Elliott2,4, Saidi A Mohiddin1,2*,
1William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
2Barts Heart Centre, Barts Health NHS Trust, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE
3Federal University of Vales do Jequitinhonha e Mucuri, Diamantina, Minas Gerais, Brazil
4Institute of Cardiovascular Science, University College London, 72 Huntley Street, London WC1E 6AG
Autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. The functional features of cardiac autoimmunity in humans remain undefined, due to the challenge of studying immune responses in-situ. We have previously described a subset of cMet-expressing memory T-lymphocytes, which preferentially migrate to cardiac tissue in mice and humans.
In-depth phenotyping of peripheral blood T-cells, including cMet+ T-cells, was undertaken in groups of patients with inflammatory and non-inflammatory cardiomyopathies, patients with non-cardiac autoimmunity and healthy controls. Validation studies were carried out using human cardiac tissue and in an experimental model of cardiac inflammation.
We show that cMet+ T-cells are selectively increased in the circulation and in the heart of patients with inflammatory cardiomyopathies. cMet+ T-cells display distinct phenotype and function compared to cMet-negative T-cells, including preferential proliferation to cardiac myosin and co-production of multiple cytokines (IL-4, IL-17 and IL-22). Further, circulating cMet+ T-cell subpopulations in different heart muscle diseases identify distinct and overlapping mechanisms of heart inflammation including in genetic cardiomyopathies.
In experimental autoimmune myocarditis, rise of autoantigen-specific cMet+ T-cells in peripheral blood marks the loss of immune tolerance to the heart. Importantly, disease development can be halted by pharmacological cMet inhibition, indicating a causative role for cMet+ T-cells.