LOW-MOLECULAR-WEIGHT TUMOR-NECROSIS-FACTOR RECEPTOR P55 CONTROLS INDUCTION OF AUTOIMMUNE HEART-DISEASE

Background Tumor necrosis factor-alpha (TNF-alpha) is involved in the pathogenesis of myocarditis and can bind to either tumor necrosis fact or receptor (TNF-R) p55 or TNF-Rp75. However, it is not known which TN F-R mediates the specific functions of TNF in disease. To determine th e role of the TNF/TNF-R system in chronic heart disease, we used a mur ine model of cardiac myosin-induced myocarditis that closely resembles the chronic stages of virus-induced myocarditis in humans. Methods an d Results Mice lacking TNF-Rp55 expression after targeted disruption o f the TNF-Rp55 gene were backcrossed into a genetic background suscept ible to the induction of myocarditis with cardiac myosin. Here, we dem onstrate that TNF-Rp55 gene-deficient mice did not develop any inflamm atory 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-Rp5 5(-/-) mice produced cardiac myosin-specific IgG autoantibodies, indic ating that activation of autoaggressive T and B lymphocytes had occurr ed. However, heart interstitial cells failed to express major histocom patibility complex (MHC) class II molecules in TNF-Rp55(-/-) animals, and adoptive transfer of autoreactive T cells resulted in heart diseas e only in TNF-Rp55(+/+) but not in TNF-Rp55(-/-) littermates. Conclusi ons 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 susceptib ility. The data presented here show that the TNF-Rp55 is a key regulat or for the induction of autoimmune heart disease by its controlling ta rget organ susceptibility.