Khaw B A, Narula J, Sharaf A R, Nicol P D, Southern J F, Carles M
Center for Drug Targeting and Analysis, Bouve College of Pharmacy and Health Sciences, Northeastern University, Boston, MA 02115, USA.
Eur Heart J. 1995 Dec;16 Suppl O:92-6. doi: 10.1093/eurheartj/16.suppl_o.92.
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.
自身免疫在心肌炎或扩张型心肌病发病机制中的概念正得到越来越多的关注。由于在心肌炎中经常观察到收缩功能障碍及随后的恢复，我们推测，针对心肌肌浆网钙ATP酶（SR-Ca2+ ATP酶）产生的自身免疫反应，可能会干扰细胞内钙调节，进而影响心肌收缩力，这应该会在实验动物中引发免疫介导的心肌炎。针对犬心脏SR-Ca2+ ATP酶产生的鼠单克隆抗体4C11-20.21（IgM类）可抑制心脏而非骨骼肌的ATP酶活性。用4C11-20.21亲和柱纯化的心脏SR-ATP酶免疫CAF1/J小鼠，会产生与心肌炎诊断相符的、随时间变化的心肌损伤诱导。此外，单独的抗体4C11-20.21可在严重联合免疫缺陷（SCID）小鼠中诱导肌坏死，表明存在一种独立于细胞毒性T细胞介导的自身免疫病的心肌病机制。将4C11-20.21注射到有免疫能力的CAF1/J小鼠中，导致心肌异常最小（40%有血管周围和/或间质单核淋巴细胞浆细胞样聚集，10%有临界性心肌炎，10%有与局灶性心肌炎相符的病变）。所有对照动物心脏均正常。对受累心脏组织进行免疫过氧化物酶电子显微镜检查显示，在注射4C11-20.21而非2C12.1B5的小鼠中，抗体定位于肌膜下肌管系统，并在紧邻的肌膜处有局灶性染色。心脏SR-Ca2+ ATP酶给药与心肌病变发展之间的时间依赖性关联，以及相对于有免疫能力的小鼠，SCID小鼠中抗心脏SR-Ca2+ ATP酶抗体对肌坏死诱导作用的增强，提示心脏SR-Ca2+ ATP酶在实验性心肌炎中具有潜在的自身免疫致病作用。
