AUTHOR=Basavalingappa Rakesh H. , Massilamany Chandirasegaran , Krishnan Bharathi , Gangaplara Arunakumar , Rajasekaran Rajkumar A. , Afzal Muhammad Z. , Riethoven Jean-Jack , Strande Jennifer L. , Steffen David , Reddy Jay 

TITLE=β1-Adrenergic Receptor Contains Multiple IAk and IEk Binding Epitopes That Induce T Cell Responses with Varying Degrees of Autoimmune Myocarditis in A/J Mice

JOURNAL=Frontiers in Immunology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01567

DOI=10.3389/fimmu.2017.01567

ISSN=1664-3224

ABSTRACT=<p>Myocarditis/dilated cardiomyopathy (DCM) patients can develop autoantibodies to various cardiac antigens and one major antigen is β1-adrenergic receptor (β<sub>1</sub>AR). Previous reports indicate that animals immunized with a β<sub>1</sub>AR fragment encompassing, 197–222 amino acids for a prolonged period can develop DCM by producing autoantibodies, but existence of T cell epitopes, if any, were unknown. Using A/J mice that are highly susceptible to lymphocytic myocarditis, we have identified β<sub>1</sub>AR 171–190, β<sub>1</sub>AR 181–200, and β<sub>1</sub>AR 211–230 as the major T cell epitopes that bind major histocompatibility complex class II/IA<sup>k</sup> or IE<sup>k</sup> alleles, and by creating IA<sup>k</sup> and IE<sup>k</sup> dextramers, we demonstrate that the CD4 T cell responses to be antigen-specific. Of note, all the three epitopes were found also to stimulate CD8 T cells suggesting that they can act as common epitopes for both CD4 and CD8 T cells. While, all epitopes induced only mild myocarditis, the disease-incidence was enhanced in animals immunized with all the three peptides together as a cocktail. Although, antigen-sensitized T cells produced mainly interleukin-17A, their transfer into naive animals yielded no disease. But, steering for T helper 1 response led the T cells reacting to one epitope, β<sub>1</sub>AR 181–200 to induce severe myocarditis in naive mice. Finally, we demonstrate that all three β<sub>1</sub>AR epitopes to be unique for T cells as none of them induced antibody responses. Conversely, animals immunized with a non-T cell activator, β<sub>1</sub>AR 201–220, an equivalent of β<sub>1</sub>AR 197–222, had antibodies comprising of all IgG isotypes and IgM except, IgA and IgE. Thus, identification of T cell and B cell epitopes of β<sub>1</sub>AR may be helpful to determine β<sub>1</sub>AR-reactive autoimmune responses in various experimental settings in A/J mice.</p>