Patients with chronic inflammatory/rheumatic diseases suffer increased cardiovascular morbidity and mortality. Improving outcomes requires understanding how chronic inflammation causes cardiovascular pathology. The focus of this proposal is on valvular carditis. The most common cause of valvular carditis is rheumatic heart disease (RHD), which affects >30 million people worldwide and causes >300,000 deaths annually. Valvular carditis also occurs in patients with lupus and the related antiphospholipid antibody syndrome. Our group has pioneered a mouse model of co-existing valvular carditis and inflammatory arthritis, with pathologic features recapitulating those in human patients. Our group was the first to show a critical role for myeloid cells in promoting valvular carditis. Specifically, we showed that autoantibodies engage particular Fc receptors on macrophages, leading to pro-inflammatory cytokine production and macrophage polarization, leading to chronic valve inflammation and fibrosis. We have identified the cytokine interleukin-13 (IL-13) as a key driver of this process. The current proposal builds on these findings and extends them. Here we will identify the cell type producing IL-13; preliminary data suggest type 2 innate lymphoid cells (ILC2s). We will also identify the pathways that lead to increased IL-13 production, focused on cytokines made by endothelial cells. Type 2 immune responses are known to promote tissue fibrosis, which occurs in the cardiac valves of patients with RHD and in our mouse model, characterized by the presence of myofibroblasts in the valves. The cell from which these myofibroblasts originate is not known. We propose sophisticated cell lineage tracing experiments to identify myofibroblast progenitors among valve interstitial cells (VICs) in valvular carditis. Understanding the origin of the myofibroblasts is critical to targeting them therapeutically. Finally, we are focused on the puzzling question of why valvular carditis preferentially affects the left-sided heart valves (mitral and aortic) and not the right-sided ones ? this is true in both human patients and the mouse model. Many possibilities exist. Our preliminary data show that the expression of key genes and proteins involved in type 2 immunity or in sensing biophysical variables (e.g. oxygen tension and shear stress) differs between the left- and right-sided valves in normal mice. We therefore propose to perform comprehensive analysis of cardiac valve gene expression to identify molecular pathways that underlie this left-sided predilection. Guided by these data, we will interrogate the most promising of these pathways. In sum, we will define how discrete populations of immune cells interact with endothelial cells and VICs to cause chronic valve inflammation and fibrosis. Further, we will reveal why the milieu of the left side of the heart promotes inflammation and fibrosis. Although we are focused here on valvular carditis, we expect that our findings will be generalizable to other types of cardiovascular inflammation, including atherosclerosis.
Cardiac valve inflammation and fibrosis occur in patients with autoimmune diseases and with rheumatic fever; the global burden of rheumatic heart disease is 33.4 million cases. The studies proposed here seek to identify how particular cells of the immune system interface with cells in the cardiac valves to cause inflammation and fibrosis. The long-term goal is to identify specific pathways that can be targeted to reduce the morbidity and mortality associated with immune-mediated cardiac valve disease.
| Meier, Lee A; Binstadt, Bryce A (2018) The Contribution of Autoantibodies to Inflammatory Cardiovascular Pathology. Front Immunol 9:911 |
| Meier, Lee A; Auger, Jennifer L; Engelson, Brianna J et al. (2018) CD301b/MGL2+ Mononuclear Phagocytes Orchestrate Autoimmune Cardiac Valve Inflammation and Fibrosis. Circulation 137:2478-2493 |
| Auger, Jennifer L; Cowan, Hannah M; Engelson, Brianna J et al. (2016) Brief Report: Arthritis in KRN T Cell Receptor-Transgenic Mice Does Not Require Interleukin-17 or Th17 Cells. Arthritis Rheumatol 68:1849-55 |
| Breed, Elise R; Binstadt, Bryce A (2015) Autoimmune valvular carditis. Curr Allergy Asthma Rep 15:491 |
