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Epitope Mapping of SERCA2a Identifies an Antigenic Determinant That Induces Mainly Atrial Myocarditis in A/J Mice
- Source :
- The Journal of Immunology. 200:523-537
- Publication Year :
- 2018
- Publisher :
- The American Association of Immunologists, 2018.
-
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.
- Subjects :
- 0301 basic medicine
SERCA
Myocarditis
Heart Ventricles
T cell
Immunology
Fluorescent Antibody Technique
Gene Expression
Mice, Inbred Strains
Inflammation
Article
Epitope
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Epitopes
Mice
03 medical and health sciences
Bacterial Proteins
T-Lymphocyte Subsets
medicine
Animals
Immunology and Allergy
Myocytes, Cardiac
Heart Atria
Alleles
MHC class II
biology
Immunodominant Epitopes
Endoplasmic reticulum
Histocompatibility Antigens Class II
medicine.disease
Immunohistochemistry
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Epitope mapping
cardiovascular system
biology.protein
Cytokines
Epitopes, B-Lymphocyte
medicine.symptom
Peptides
Epitope Mapping
circulatory and respiratory physiology
Subjects
Details
- ISSN :
- 15506606 and 00221767
- Volume :
- 200
- Database :
- OpenAIRE
- Journal :
- The Journal of Immunology
- Accession number :
- edsair.doi.dedup.....a8a4e077351dc19f9eb9ab0bb0a5c9c5