Faculty Collaboration Database

Epitope Mapping of SERCA2a Identifies an Antigenic Determinant That Induces Mainly Atrial Myocarditis in A/J Mice. J Immunol 2018 Jan 15;200(2):523-537

Date

12/13/2017

Pubmed ID

29229678

Pubmed Central ID

PMC5760440

DOI

10.4049/jimmunol.1701090

Scopus ID

2-s2.0-85044757348 (requires institutional sign-in at Scopus site)   15 Citations

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.

Author List

Krishnan B, Massilamany C, Basavalingappa RH, Gangaplara A, Rajasekaran RA, Afzal MZ, Khalilzad-Sharghi V, Zhou Y, Riethoven JJ, Nandi SS, Mishra PK, Sobel RA, Strande JL, Steffen D, Reddy J

MESH terms used to index this publication - Major topics in bold

Alleles
Animals
Bacterial Proteins
Cytokines
Disease Models, Animal
Epitope Mapping
Epitopes
Epitopes, B-Lymphocyte
Fluorescent Antibody Technique
Gene Expression
Heart Atria
Heart Ventricles
Histocompatibility Antigens Class II
Immunodominant Epitopes
Immunohistochemistry
Mice
Mice, Inbred Strains
Myocarditis
Myocytes, Cardiac
Peptides
Sarcoplasmic Reticulum Calcium-Transporting ATPases
T-Lymphocyte Subsets