Low-Molecular-Weight Tumor Necrosis Factor Receptor p55 Controls Induction of Autoimmune Heart Disease
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Background Tumor necrosis factor-α (TNF-α) is involved in the pathogenesis of myocarditis and can bind to either tumor necrosis factor receptor (TNF-R) p55 or TNF-Rp75. However, it is not known which TNF-R mediates the specific functions of TNF in disease. To determine the role of the TNF/TNF-R system in chronic heart disease, we used a murine model of cardiac myosin–induced myocarditis that closely resembles the chronic stages of virus-induced myocarditis in humans.
Methods and Results Mice lacking TNF-Rp55 expression after targeted disruption of the TNF-Rp55 gene were backcrossed into a genetic background susceptible to the induction of myocarditis with cardiac myosin. Here, we demonstrate that TNF-Rp55 gene–deficient mice did not develop any inflammatory infiltration into the heart after autoantigen injection, whereas control littermates showed autoimmune myocarditis at high prevalence and severity. Despite the absence of autoimmune heart disease, TNF-Rp55−/− mice produced cardiac myosin–specific IgG autoantibodies, indicating that activation of autoaggressive T and B lymphocytes had occurred. However, heart interstitial cells failed to express major histocompatibility complex (MHC) class II molecules in TNF-Rp55−/− animals, and adoptive transfer of autoreactive T cells resulted in heart disease only in TNF-Rp55+/+ but not in TNF-Rp55−/− littermates.
Conclusions Cardiac myosin–induced myocarditis is dependent on autoaggressive T cells and on autoantigen presentation in association with MHC class II molecules within the heart. Thus, lack of TNF-Rp55 expression could interfere with either lymphocyte activation or target organ susceptibility. The data presented here show that the TNF-Rp55 is a key regulator for the induction of autoimmune heart disease by its controlling target organ susceptibility.
- Received June 19, 1996.
- Revision received September 11, 1996.
- Accepted September 30, 1996.
- Copyright © 1997 by American Heart Association