Serum and immunoglobulin G from the mother of a child with congenital heart block induce conduction abnormalities and inhibit L-type calcium channels in a rat heart model
Serum and immunoglobulin G from the mother of a child with congenital heart block induce conduction abnormalities and inhibit L-type calcium channels in a rat heart model
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DOI：
10.1203/00006450-199807000-00002
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发表时间：
1998-07-01
影响因子：
3.6
通讯作者：
Buyon, JP
中科院分区：
文献类型：
--
作者：
Boutjdir, M;Chen, L;Buyon, JP
尽管先天性心脏传导阻滞（CHB）与SSA/Ro和SSB/La蛋白的免疫应答之间存在很强的临床关联，但这些抗体在发病机制中的致病作用刚刚出现。在一份初步报告中，我们已经证明从患有慢性乙型肝炎的母亲的血清中分离出的IgG片段在人类胎儿心脏中具有心律失常性。为了更准确地定义抗ssa /Ro-SSB/La抗体的致心律失常作用，我们使用现成的大鼠心脏模型记录：I) Langendorff跳动心脏的心电图；2)房室（AV）结准备的动作电位；3)全细胞和单通道水平的l型Ca电流，I,；4)其他电流，如瞬时外向K+电流，i -到内向整流K+电流，I-K1，和Na+电流，I-Na，心脏灌注纯化的IgG (800 μ g/mL)，从患有CHB的母亲血清中分离出来，导致心动过缓并伴有2:1的AV阻断。在解剖的大鼠心房和房室结区记录同步动作电位。将这些制剂与同一母体的IgG片段融合，导致2:1的AV阻断，随后AV节动作电位完全抑制。由于AV节点电发生在很大程度上依赖于I，因此随后确定了这些抗体对I的影响。用来自同一母体的全血清或纯化的IgG （80 μ g/mL）灌注肌细胞，可以持续抑制全细胞的平均Ba2+电流（I- ba）和开放状态概率（p(o)），而不影响通道电导。IgG对I，， I…或I，，无显著影响。未检测到抗ssa /Ro或SSB/La抗体的健康母亲的全血清和IgG分数不抑制I，，或I，，。这些结果表明，含有抗ssa /Ro和-SSB/La抗体的IgG在跳动的心脏和多细胞制剂中诱导完全AV阻断，从而暗示这些自身抗体与Ca通道和/或相关调节蛋白优先相互作用。这与观察到的钙通道抑制一致，钙通道抑制可能是导致慢性乙型肝炎发病的关键因素。
Although a strong clinical association exists between congenital heart block (CHB) and an immune response to SSA/Ro and SSB/La proteins, a causative role of these antibodies in the pathogenesis is just emerging. In a preliminary report, we have demonstrated that IgG fractions isolated from the sera of mothers whose children have CHB are arrhythmogenic in the human fetal heart. To more precisely define the arrhythmogenic effect of anti-SSA/Ro-SSB/La antibodies, we used the readily available rat heart model to record: I) ECGs from Langendorff beating hearts; 2) action potentials from atrioventricular (AV) nodal preparations; 3) L-type Ca currents, I,, at the whole-cell and single channel levels; and 4) other currents such as the transient outward K+ current, I-to the inward rectifier K+ current, I-K1, and the Na+ current, I-Na, Perfusion of hearts with purified IgG (800 mu g/mL), isolated from the serum of a mother with SSA/Ro and SSB/La antibodies whose child had CHB, resulted in bradycardia associated with 2:1 AV block. Simultaneous action potentials were recorded from dissected atrial and AV nodal areas of the rat heart. Superfusion of these preparations with the same mother's IgG fraction resulted in 2:1 AV block followed by complete inhibition of AV nodal action potential. Because AV nodal electrogenesis is largely dependent on I,,, the effect of these antibodies on I,, was subsequently determined. Superfusion of myocytes with whole serum or purified IgG (80 mu g/mL) from the same mother consistently inhibited whole cell I,,, ensemble average Ba2+ currents (I-Ba) and open state probability, p(o), without affecting the channel conductance. IgG had no significant effect on I,, I,,, or I,,. Whole sera and IgG fractions from a healthy mother with no detectable anti-SSA/Ro or SSB/La antibodies did not inhibit I,, or I,,. These results demonstrate that IgG containing anti-SSA/Ro and -SSB/La antibodies induces complete AV block in beating hearts and in multicellular preparations, thus implicating a preferential interaction of these autoantibodies with Ca channels and/or associated regulatory proteins. This is consistent with the observed inhibition of Ca channels that may be a critical factor contributing to the pathogenesis of CHB.