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

Authors

Bharathi Krishnan, University of Nebraska-LincolnFollow
Chandirasegara Massilamany, University of Nebraska-LincolnFollow
Rakesh H. Basavalingappa, University of Nebraska-LincolnFollow
Arunakumar Gangaplara, National Institutes of Health, Bethesda, MDFollow
Rajkumar Rajasekaran, University of Nebraska-LincolnFollow
Muhammad Z. Afzal, Medical College of Wisconsin, Milwaukee
Vahid Khalilzad-Sharghi, University of Nebraska-LincolnFollow
You Zhou, University of Nebraska - LincolnFollow
Jean-Jack Riethoven, University of Nebraska - LincolnFollow
Shyam S. Nandi, University of Nebraska Medical CenterFollow
Paras K. Mishra, University of Nebraska Medical CenterFollow
Raymond A. Sobel, Stanford University School of MedicineFollow
Jennifer L. Strande, Medical College of Wisconsin, Milwaukee
David Steffen, University of Nebraska - LincolnFollow
Jay Reddy, University of Nebraska - LincolnFollow

ORCID IDs

0000-0001-6307-9391 (A.G.);

0000-0002-9783-1868 (Y.Z.);

0000-0002-2709-7880 (J.-J.R.);

0000-0001-6422-2540 (S.S.N);

0000-0002-7810-9239 (P.K.M.);

0000-0002-0477-9002 (R.A.S.);

0000-0003-4082-9254 (J.R.).

Date of this Version

2018

Citation

The Journal of Immunology, 2018, 200: 523–537.

Comments

U.S. government work

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/IA^k rather than IE^k. By creating IA^k/and IE^k/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.