β1-Adrenergic Receptor Contains Multiple IA^k and IE^k Binding Epitopes That Induce T Cell Responses with Varying Degrees of Autoimmune Myocarditis in A/J Mice

Authors

Rakesh H. Basavalingappa, University of Nebraska-LincolnFollow
Chandirasegaran Massilamany, University of Nebraska-LincolnFollow
Bharathi Krishnan, University of Nebraska-LincolnFollow
Arunakumar Gangaplara, University of Nebraska-Lincoln
Rajkumar A. Rajasekaran, University of Nebraska-LincolnFollow
Muhammad Z. Afzal, Medical College of Wisconsin
Jean-Jack Riethoven, University of Nebraska - LincolnFollow
Jennifer L. Strande, Medical College of Wisconsin
David J. Steffen, University of Nebraska-LincolnFollow
Jay Reddy, University of Nebraska-LincolnFollow

Document Type

Article

Date of this Version

2017

Citation

Basavalingappa RH, Massilamany C, Krishnan B, Gangaplara A, Rajasekaran RA, Afzal MZ, Riethoven J-J, Strande JL, Steffen D and Reddy J (2017) β1-Adrenergic Receptor Contains Multiple IA^k and IE^k Binding Epitopes That Induce T Cell Responses with Varying Degrees of Autoimmune Myocarditis in A/J Mice. Front. Immunol. 8:1567. doi: 10.3389/fimmu.2017.01567

Comments

Copyright © 2017 Basavalingappa, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

Abstract

Myocarditis/dilated cardiomyopathy (DCM) patients can develop autoantibodies to various cardiac antigens and one major antigen is β1-adrenergic receptor (β₁AR). Previous reports indicate that animals immunized with a β₁AR 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 β₁AR 171–190, β₁AR 181–200, and β₁AR 211–230 as the major T cell epitopes that bind major histocompatibility complex class II/IA^k or IE^k alleles, and by creating IA^k and IE^k 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, β₁AR 181–200 to induce severe myocarditis in naive mice. Finally, we demonstrate that all three β₁AR epitopes to be unique for T cells as none of them induced antibody responses. Conversely, animals immunized with a non-T cell activator, β₁AR 201–220, an equivalent of β₁AR 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 β₁AR may be helpful to determine β₁AR-reactive autoimmune responses in various experimental settings in A/J mice.