Pathogenesis of Myocarditis and Inflammatory Dilated Cardiomyopathy: the Sign of Four
Embargo until
Date
2014-04-10
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Johns Hopkins University
Abstract
Myocarditis and inflammatory dilated cardiomyopathy (DCMi) are major causes of heart failure in individuals below the age of 40. In the work presented in this dissertation, using a model of mouse experimental autoimmune myocarditis (EAM) and DCMi, the roles of four pathogenic factors: CD4+ T lymphocytes, interleukin 23 (IL-23), interleukin 17A (IL-17A), and granulocyte macrophage colony-stimulating factor (GM-CSF), are investigated. With transgenic IL-23a-/- and IL-17ra-/- mice, we demonstrate that IL-23 drives the pathogenicity of CD4+ T cells and maintains their IL-17A production. IL-17A induces chemokine production by cardiac fibroblasts, resulting in an infiltrate rich in neutrophils and Ly6Chi MO/MΦs in the heart, which aggravate disease and lead to worse prognosis. Furthermore, IL-17A directs monocytic infiltrates into an even more inflammatory phenotype by inducing GM-CSF production from cardiac fibroblasts. Taken together, this IL-23 – CD4+ T lymphocytes – IL-17A – GM-CSF axis provides a novel target for the treatment of DCMi and related inflammatory cardiac diseases.
Adviser: Noel R. Rose, M.D., Ph. D.
Readers: Daniela Čiháková, M.D., Ph.D., Fengyi Wan, Ph.D., Alan Scott, Ph.D., Patrizio Caturegli, M.D., Pierre A. Couloumbe, Ph.D., Jay H. Bream, Ph.D.
Description
Keywords
Myocarditis, Inflammatory Dilated Cardiomyopathy