TY - JOUR
T1 - 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
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
N1 - Funding Information:
This work was supported by the National Institutes of Health (HL114669). We thank the sonographer, Leanne Harmman for the echocardiogram images.
Publisher Copyright:
© 2017 Basavalingappa, Massilamany, Krishnan, Gangaplara, Rajasekaran, Afzal, Riethoven, Strande, Steffen and Reddy.
PY - 2017/11/20
Y1 - 2017/11/20
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.
KW - Autoimmunity
KW - Mouse model
KW - Myocarditis
KW - T cells
KW - β-adrenergic receptor
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U2 - 10.3389/fimmu.2017.01567
DO - 10.3389/fimmu.2017.01567
M3 - Article
C2 - 29209317
AN - SCOPUS:85034630224
SN - 1664-3224
VL - 8
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - NOV
M1 - 1567
ER -