Impaired clearance of apoptotic cardiocytes is linked to anti-SSA/Ro and -SSB/La antibodies in the pathogenesis of congenital heart block
Impaired clearance of apoptotic cardiocytes is linked to anti-SSA/Ro and -SSB/La antibodies in the pathogenesis of congenital heart block
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DOI：
10.1172/jci27803
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发表时间：
2006-09-01
影响因子：
15.9
通讯作者：
Buyon, Jill P.
中科院分区：
文献类型：
--
作者：
Clancy, Robert M.;Neufing, Petra J.;Buyon, Jill P.
讨论了心肌细胞在生理性清除凋亡细胞中的作用以及抗 SSA/Ro 和 -SSB/La 抗体表面结合的后续影响。最初的实验评估了外在和内在途径对细胞凋亡的诱导。核损伤以及 SSA/Ro 和 SSB/La 抗原易位至胎儿心肌细胞质膜是 Fas 和 TNF 受体连接的常见下游事件，需要 caspase 激活。通过相差评估和共聚焦显微镜证实，健康心肌细胞与通过外在途径凋亡的心肌细胞共培养揭示了一种据我们所知以前从未描述过的清除机制。培养的胎儿心肌细胞表达磷脂酰丝氨酸受体（PSR），患有先天性心脏传导阻滞（CHB）的胎儿和年龄匹配的对照胎儿的心脏组织也是如此。吞噬细胞的摄取被抗 PSR 抗体阻断，并且在将凋亡的心肌细胞与鸡和鼠抗 SSA/Ro 和 -SSB/La 抗体以及来自 CHB 儿童的抗 SSA/Ro 和 -SSB/La 阳性母亲的 IgG 预孵育后，吞噬细胞的摄取受到显着抑制，但与抗 HLA I 类抗体则不受抑制。在小鼠模型中，抗 Ro60 结合并抑制野生型而非 Ro60 敲除小鼠对凋亡心肌细胞的摄取。我们的结果表明，驻留心肌细胞参与凋亡心肌细胞的生理清除，但这种清除受到母体自身抗体调理作用的抑制，导致凋亡细胞积聚，促进炎症和随后的疤痕形成。
The role of cardiocytes in physiologic removal of apoptotic cells and the subsequent effect of surface binding by anti-SSA/Ro and -SSB/La antibodies was addressed. Initial experiments evaluated induction of apoptosis by extrinsic and intrinsic pathways. Nuclear injury and the translocation of SSA/Ro and SSB/La antigens to the fetal cardiocyte plasma membrane were common downstream events of Fas and TNF receptor ligation, requiring caspase activation. As assessed by phase-contrast and confirmed by confocal microscopy, coculturing of healthy cardiocytes with cardiocytes rendered apoptotic via extrinsic pathways revealed a clearance mechanism that to our knowledge has not previously been described. Cultured fetal cardiocytes expressed phosphatidylserine receptors (PSRs), as did cardiac tissue from a fetus with congenital heart block (CHB) and an age-matched control. Phagocytic uptake was blocked by anti-PSR antibodies and was significantly inhibited following preincubation of apoptotic cardiocytes with chicken and murine anti-SSA/Ro and -SSB/La antibodies, with IgG from an anti-SSA/Ro- and -SSB/La-positive mother of a CHB child, but not with anti-HLA class I antibody. In a murine model, anti-Ro60 bound, and inhibited uptake of apoptotic cardiocytes from wild-type but not Ro60-knockout mice. Our results suggest that resident cardiocytes participate in physiologic clearance of apoptotic cardiocytes but that clearance is inhibited by opsonization via maternal autoantibodies, resulting in accumulation of apoptotic cells, promoting inflammation and subsequent scarring.