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
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...
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doaj-892c4a515e254cef9c166d5606401b772020-11-24T23:22:40ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-11-01810.3389/fimmu.2017.01567312612β1-Adrenergic Receptor Contains Multiple IAk and IEk Binding Epitopes That Induce T Cell Responses with Varying Degrees of Autoimmune Myocarditis in A/J MiceRakesh H. Basavalingappa0Chandirasegaran Massilamany1Bharathi Krishnan2Arunakumar Gangaplara3Rajkumar A. Rajasekaran4Muhammad Z. Afzal5Jean-Jack Riethoven6Jennifer L. Strande7David Steffen8Jay Reddy9School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, United StatesSchool of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, United StatesSchool of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, United StatesSchool of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, United StatesSchool of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, United StatesDepartment of Medicine, Division of Cardiology, Medical College of Wisconsin, Milwaukee, WI, United StatesCenter for Biotechnology, University of Nebraska-Lincoln, Lincoln, NE, United StatesDepartment of Medicine, Division of Cardiology, Medical College of Wisconsin, Milwaukee, WI, United StatesSchool of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, United StatesSchool of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, United StatesMyocarditis/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/IAk or IEk alleles, and by creating IAk and IEk 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.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01567/fullautoimmunityβ1-adrenergic receptormyocarditismouse modelT cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rakesh H. Basavalingappa Chandirasegaran Massilamany Bharathi Krishnan Arunakumar Gangaplara Rajkumar A. Rajasekaran Muhammad Z. Afzal Jean-Jack Riethoven Jennifer L. Strande David Steffen Jay Reddy |
spellingShingle |
Rakesh H. Basavalingappa Chandirasegaran Massilamany Bharathi Krishnan Arunakumar Gangaplara Rajkumar A. Rajasekaran Muhammad Z. Afzal Jean-Jack Riethoven Jennifer L. Strande David Steffen Jay Reddy 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 Frontiers in Immunology autoimmunity β1-adrenergic receptor myocarditis mouse model T cells |
author_facet |
Rakesh H. Basavalingappa Chandirasegaran Massilamany Bharathi Krishnan Arunakumar Gangaplara Rajkumar A. Rajasekaran Muhammad Z. Afzal Jean-Jack Riethoven Jennifer L. Strande David Steffen Jay Reddy |
author_sort |
Rakesh H. Basavalingappa |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2017-11-01 |
description |
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/IAk or IEk alleles, and by creating IAk and IEk 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. |
topic |
autoimmunity β1-adrenergic receptor myocarditis mouse model T cells |
url |
http://journal.frontiersin.org/article/10.3389/fimmu.2017.01567/full |
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