Epitope Mapping of SERCA2a Identifies an Antigenic Determinant That Induces Mainly Atrial Myocarditis in A/J Mice

Bharathi Krishnan, Chandirasegaran Massilamany, Rakesh H. Basavalingappa, Arunakumar Gangaplara, Rajkumar A. Rajasekaran, Muhammad Z. Afzal, Vahid Khalilzad-Sharghi, You Zhou, Jean-Jack M Riethoven, Shyam S. Nandi, Paras Kumar Mishra, Raymond A. Sobel, Jennifer L. Strande, David J Steffen, N R Jayagopala Reddy

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Sarcoplasmic/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA)2a, a critical regulator of calcium homeostasis, is known to be decreased in heart failure. Patients with myocarditis or dilated cardiomyopathy develop autoantibodies to SERCA2a suggesting that they may have pathogenetic significance. In this report, we describe epitope mapping analysis of SERCA2a in A/J mice that leads us to make five observations: 1) SERCA2a contains multiple T cell epitopes that induce varying degrees of myocarditis. One epitope, SERCA2a 971-990, induces widespread atrial inflammation without affecting noncardiac tissues; the cardiac abnormalities could be noninvasively captured by echocardiography, electrocardiography, and magnetic resonance microscopy imaging. 2) SERCA2a 971-990-induced disease was associated with the induction of CD4 T cell responses and the epitope preferentially binds MHC class II/IAk rather than IEk. By creating IAk/and IEk/SERCA2a 971-990 dextramers, the T cell responses were determined by flow cytometry to be Ag specific. 3) SERCA2a 971-990-sensitized T cells produce both Th1 and Th17 cytokines. 4) Animals immunized with SERCA2a 971-990 showed Ag-specific Abs with enhanced production of IgG2a and IgG2b isotypes, suggesting that SERCA2a 971-990 can potentially act as a common epitope for both T cells and B cells. 5) Finally, SERCA2a 971-990-sensitized T cells were able to transfer disease to naive recipients. Together, these data indicate that SERCA2a is a critical autoantigen in the mediation of atrial inflammation in mice and that our model may be helpful to study the inflammatory events that underlie the development of conditions such as atrial fibrillation in humans.

Original languageEnglish (US)
Pages (from-to)523-537
Number of pages15
JournalJournal of Immunology
Volume200
Issue number2
DOIs
StatePublished - Jan 15 2018

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Epitope Mapping
T-Lymphocyte Epitopes
Myocarditis
Epitopes
T-Lymphocytes
Inflammation
Autoantigens
Dilated Cardiomyopathy
Sarcoplasmic Reticulum
Endoplasmic Reticulum
Autoantibodies
Atrial Fibrillation
Adenosine Triphosphatases
Echocardiography
Microscopy
Flow Cytometry
Electrocardiography
Homeostasis
B-Lymphocytes
Heart Failure

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Krishnan, B., Massilamany, C., Basavalingappa, R. H., Gangaplara, A., Rajasekaran, R. A., Afzal, M. Z., ... Reddy, N. R. J. (2018). Epitope Mapping of SERCA2a Identifies an Antigenic Determinant That Induces Mainly Atrial Myocarditis in A/J Mice. Journal of Immunology, 200(2), 523-537. https://doi.org/10.4049/jimmunol.1701090

Epitope Mapping of SERCA2a Identifies an Antigenic Determinant That Induces Mainly Atrial Myocarditis in A/J Mice. / Krishnan, Bharathi; Massilamany, Chandirasegaran; Basavalingappa, Rakesh H.; Gangaplara, Arunakumar; Rajasekaran, Rajkumar A.; Afzal, Muhammad Z.; Khalilzad-Sharghi, Vahid; Zhou, You; Riethoven, Jean-Jack M; Nandi, Shyam S.; Mishra, Paras Kumar; Sobel, Raymond A.; Strande, Jennifer L.; Steffen, David J; Reddy, N R Jayagopala.

In: Journal of Immunology, Vol. 200, No. 2, 15.01.2018, p. 523-537.

Research output: Contribution to journalArticle

Krishnan, B, Massilamany, C, Basavalingappa, RH, Gangaplara, A, Rajasekaran, RA, Afzal, MZ, Khalilzad-Sharghi, V, Zhou, Y, Riethoven, J-JM, Nandi, SS, Mishra, PK, Sobel, RA, Strande, JL, Steffen, DJ & Reddy, NRJ 2018, 'Epitope Mapping of SERCA2a Identifies an Antigenic Determinant That Induces Mainly Atrial Myocarditis in A/J Mice', Journal of Immunology, vol. 200, no. 2, pp. 523-537. https://doi.org/10.4049/jimmunol.1701090
Krishnan B, Massilamany C, Basavalingappa RH, Gangaplara A, Rajasekaran RA, Afzal MZ et al. Epitope Mapping of SERCA2a Identifies an Antigenic Determinant That Induces Mainly Atrial Myocarditis in A/J Mice. Journal of Immunology. 2018 Jan 15;200(2):523-537. https://doi.org/10.4049/jimmunol.1701090
Krishnan, Bharathi ; Massilamany, Chandirasegaran ; Basavalingappa, Rakesh H. ; Gangaplara, Arunakumar ; Rajasekaran, Rajkumar A. ; Afzal, Muhammad Z. ; Khalilzad-Sharghi, Vahid ; Zhou, You ; Riethoven, Jean-Jack M ; Nandi, Shyam S. ; Mishra, Paras Kumar ; Sobel, Raymond A. ; Strande, Jennifer L. ; Steffen, David J ; Reddy, N R Jayagopala. / Epitope Mapping of SERCA2a Identifies an Antigenic Determinant That Induces Mainly Atrial Myocarditis in A/J Mice. In: Journal of Immunology. 2018 ; Vol. 200, No. 2. pp. 523-537.
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abstract = "Sarcoplasmic/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA)2a, a critical regulator of calcium homeostasis, is known to be decreased in heart failure. Patients with myocarditis or dilated cardiomyopathy develop autoantibodies to SERCA2a suggesting that they may have pathogenetic significance. In this report, we describe epitope mapping analysis of SERCA2a in A/J mice that leads us to make five observations: 1) SERCA2a contains multiple T cell epitopes that induce varying degrees of myocarditis. One epitope, SERCA2a 971-990, induces widespread atrial inflammation without affecting noncardiac tissues; the cardiac abnormalities could be noninvasively captured by echocardiography, electrocardiography, and magnetic resonance microscopy imaging. 2) SERCA2a 971-990-induced disease was associated with the induction of CD4 T cell responses and the epitope preferentially binds MHC class II/IAk rather than IEk. By creating IAk/and IEk/SERCA2a 971-990 dextramers, the T cell responses were determined by flow cytometry to be Ag specific. 3) SERCA2a 971-990-sensitized T cells produce both Th1 and Th17 cytokines. 4) Animals immunized with SERCA2a 971-990 showed Ag-specific Abs with enhanced production of IgG2a and IgG2b isotypes, suggesting that SERCA2a 971-990 can potentially act as a common epitope for both T cells and B cells. 5) Finally, SERCA2a 971-990-sensitized T cells were able to transfer disease to naive recipients. Together, these data indicate that SERCA2a is a critical autoantigen in the mediation of atrial inflammation in mice and that our model may be helpful to study the inflammatory events that underlie the development of conditions such as atrial fibrillation in humans.",
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