# Pathogenesis of autoimmune valvular carditis

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $376,619

## Abstract

Abstract
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 ...

## Key facts

- **NIH application ID:** 10169490
- **Project number:** 5R01HL121093-08
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Bryce Binstadt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $376,619
- **Award type:** 5
- **Project period:** 2014-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169490

## Citation

> US National Institutes of Health, RePORTER application 10169490, Pathogenesis of autoimmune valvular carditis (5R01HL121093-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10169490. Licensed CC0.

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