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

Rakesh H. Basavalingappa, Chandirasegaran Massilamany, Bharathi Krishnan, Arunakumar Gangaplara, Guobin Kang, Vahid Khalilzad-Sharghi, Zhongji Han, Shadi Othman, Qingsheng Li, Jean Jack Riethoven, Raymond A. Sobel, David Steffen, Jay Reddy

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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 (ANT1), have been identified as autoantigens in cardiac autoimmunity. Herein, we demonstrate that ANT1 can induce autoimmune myocarditis in A/J mice by generating autoreactive T cells. We show that ANT1 encompasses multiple immunodominant epitopes (namely, ANT1 21-40, ANT1 31-50, ANT1 171-190, and ANT1 181-200). Although all four peptides induce comparable T-cell responses, only ANT1 21-40 was found to be a major myocarditogenic epitope in immunized animals. The myocarditis-inducing ability of ANT1 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.

Original languageEnglish (US)
Pages (from-to)3160-3175
Number of pages16
JournalAmerican Journal of Pathology
Volume186
Issue number12
DOIs
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Basavalingappa, R. H., Massilamany, C., Krishnan, B., Gangaplara, A., Kang, G., Khalilzad-Sharghi, V., Han, Z., Othman, S., Li, Q., Riethoven, J. J., Sobel, R. A., Steffen, D., & Reddy, J. (2016). Identification of an Epitope from Adenine Nucleotide Translocator 1 That Induces Inflammation in Heart in A/J Mice. American Journal of Pathology, 186(12), 3160-3175. https://doi.org/10.1016/j.ajpath.2016.08.005