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

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

Research output: Contribution to journalArticle

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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/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.

Original languageEnglish (US)
Article number1567
JournalFrontiers in immunology
Volume8
Issue numberNOV
DOIs
StatePublished - Nov 20 2017

Fingerprint

T-Lymphocyte Epitopes
Myocarditis
Adrenergic Receptors
T-Lymphocytes
Epitopes
Antigens
Dilated Cardiomyopathy
Autoantibodies
B-Lymphocyte Epitopes
Interleukin-17
Major Histocompatibility Complex
Autoimmunity
Immunoglobulin A
Immunoglobulin E
Antibody Formation
Immunoglobulin M
Immunoglobulin G
Alleles

Keywords

  • Autoimmunity
  • Mouse model
  • Myocarditis
  • T cells
  • β-adrenergic receptor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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. / 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.

In: Frontiers in immunology, Vol. 8, No. NOV, 1567, 20.11.2017.

Research output: Contribution to journalArticle

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. / 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. In: Frontiers in immunology. 2017 ; Vol. 8, No. NOV.
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AU - Basavalingappa, Rakesh H.

AU - Massilamany, Chandirasegaran

AU - Krishnan, Bharathi

AU - Gangaplara, Arunakumar

AU - Rajasekaran, Rajkumar A.

AU - Afzal, Muhammad Z.

AU - Riethoven, Jean Jack

AU - Strande, Jennifer L.

AU - Steffen, David

AU - Reddy, Jay

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N2 - 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.

AB - 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.

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