Cardioimmunology
The Cardioimmunology group is associated with the Cardiovascular Research Division at the Institute of Physiology. Our research focuses 1) on the elucidation of autoimmune mechanisms in inflammatory heart disease, and 2) on the role of inflammatory progenitor cells in remodeling following heart injury
Background
Besides genetic susceptibility, viral infections triggering autoimmunity have been implicated in the pathogenesis of dilated cardiomyopathy, the commonest cause of heart failure in young patients. We have shown that dendritic cells loaded with heart specific self-peptides induce T-cell mediated myocarditis in naïve, non-transgenic mice. After resolution of acute myocarditis, mice develop heart failure. Thus, the model of autoimmune myocarditis (EAM) reflects a unifying theory as to how tissue damage and activation of Toll-like receptors (TLRs) during infections can induce heart specific autoimmunity progressing to end stage heart failure (Figure 1). Hearts of affected mice enlarge massively, showing wall thinning, and tissue fibrosis. Thus, the morphology of the affected mouse hearts mirrors the cardiac phenotype of end-stage heart failure in humans. The autoimmune myocarditis model therefore represents a nice tool to study the role of inflammatory mechanisms in the physiopathology of the failing ventricle. In addition, it is a valuable tool to develop novel treatment strategies or to refine current therapeutic approaches targeting inflammatory pathways in heart disease and heart failure.
Induction of autoimmune myocarditis requires priming of autoreactive CD4+ T-cells that migrate to the heart and interact with resident tissue cells expressing self-antigen. The autoreactive CD4 T cell response results in IL-17 dependent recruitment of inflammatory monocyte-like precursor cells to the heart. Monocyte-like precursor cells represent the major infiltrating cells in acute myocarditis and represent a double-edged sword in inflammatory heart disease: on one hand they contribute to tissue injury at the peak of inflammation and promote pathological cardiac remodeling in the long term. On the other hand they represent a cellular key element in an Interferon-gamma dependent negative feedback mechanism confining self-reactive CD4+ T cell responses (Figure 1).