Identification of an Epitope from Adenine Nucleotide Translocator 1 That Induces Inflammation in Heart in A/J Mice.

Heart failure, a leading cause of death in humans, can emanate from myocarditis. Although most individuals with myocarditis recover spontaneously, some develop chronic dilated cardiomyopathy. Myocarditis may result from both infectious and noninfectious causes, including autoimmune responses to cardiac antigens. In support of this notion, intracellular cardiac antigens, like cardiac myosin heavy chain-α, cardiac troponin-I, and adenine nucleotide translocator 1 (ANT), have been identified as autoantigens in cardiac autoimmunity. Herein, we demonstrate that ANT can induce autoimmune myocarditis in A/J mice by generating autoreactive T cells. We show that ANT encompasses multiple immunodominant epitopes (namely, ANT 21-40, ANT 31-50, ANT 171-190, and ANT 181-200). Although all four peptides induce comparable T-cell responses, only ANT 21-40 was found to be a major myocarditogenic epitope in immunized animals. The myocarditis-inducing ability of ANT 21-40 was associated with the generation of T cells producing predominantly IL-17A, and the antigen-sensitized T cells could transfer the disease to naïve recipients. These data indicate that cardiac mitochondrial proteins can be target autoantigens in myocarditis, supporting the notion that the antigens released as a result of primary damage may contribute to the persistence of chronic inflammation through autoimmunity.