Faculty Collaboration Database

SR-Ca2+ ATPase as an autoimmunogen in experimental myocarditis. Eur Heart J 1995 Dec;16 Suppl O:92-6

Date

12/01/1995

Pubmed ID

8682113

DOI

10.1093/eurheartj/16.suppl_o.92

Scopus ID

2-s2.0-0029415372 (requires institutional sign-in at Scopus site)   21 Citations

Abstract

The concept of autoimmunity in the pathogenesis of myocarditis or dilated cardiomyopathy is gaining impetus. Since systolic functional impairment and subsequent recovery are frequently observed in myocarditis, we reasoned that the development of autoimmunity to cardiac sarcoplasmic reticulum calcium ATPase (SR-Ca2+ ATPase), which could interfere with intracellular calcium regulation and therefore affect myocardial contractility, should lead to immune-mediated myocarditis in experimental animals. Murine monoclonal antibody 4C11-20.21 (IgM class) generated against canine cardiac SR-Ca2+ ATPase inhibits the cardiac but not the skeletal ATPase activity. Immunization of CAF1/J mice with 4C11-20.21-affinity-column-purified cardiac SR-ATPase produced a time-dependent induction of myocardial injury consistent with the diagnosis of myocarditis. Furthermore, the antibody 4C11-20.21 alone can induce myo-necrosis in severe combined immunodeficiency (SCID) mice indicating a mechanism of cardiomyopathy independent of the cytotoxic T-cell mediated autoimmunopathy. Administration of 4C11-20.21 into immunocompetent CAF1/J mice resulted in minimal myocardial abnormality (40% with perivascular and/or interstitial mononuclear lymphoplasmacytoid aggregates, 10% with borderline myocarditis and 10% with lesions consistent with focal myocarditis). All control animals had normal hearts. Immunoperoxidase electron microscopic examination of the involved cardiac tissues showed antibody localization in the subsarcolemmal myotubular system and focal staining of the immediately adjacent sarcolemma in mice injected with 4C11-20.21 but not with 2C12.1B5. The time-dependent association between cardiac SR-Ca2+ ATPase administration and development of myocardial lesions, as well as potentiated induction of myonecrosis with anti-cardiac SR-Ca2+ ATPase antibody in SCID relative to immunocompetent mice, suggest a potential autoimmunopathogenic role of cardiac SR-Ca2+ ATPase in experimental myocarditis.

Author List

Khaw BA, Narula J, Sharaf AR, Nicol PD, Southern JF, Carles M

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

Animals
Antibodies, Monoclonal
Autoantigens
Autoimmune Diseases
Calcium-Transporting ATPases
Cardiomyopathy, Dilated
Dogs
Female
Male
Mice
Mice, Inbred Strains
Mice, SCID
Myocardial Contraction
Myocarditis
Myocardium
Sarcoplasmic Reticulum