Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
J Immunol. 2014 May 1;192(9):4074-82. doi: 10.4049/jimmunol.1301264. Epub 2014 Mar 26.
Structural congenital heart disease (CHD) has not previously been linked to autoimmunity. In our study, we developed an autoimmune model of structural CHD that resembles hypoplastic left heart syndrome (HLHS), a life-threatening CHD primarily affecting the left ventricle. Because cardiac myosin (CM) is a dominant autoantigen in autoimmune heart disease, we hypothesized that immunization with CM might lead to transplacental passage of maternal autoantibodies and a prenatal HLHS phenotype in exposed fetuses. Elevated anti-CM autoantibodies in maternal and fetal sera, as well as IgG reactivity in fetal myocardium, were correlated with structural CHD that included diminished left ventricular cavity dimensions in the affected progeny. Further, fetuses that developed a marked HLHS phenotype had elevated serum titers of anti-β-adrenergic receptor Abs, as well as increased protein kinase A activity, suggesting a potential mechanism for the observed pathological changes. Our maternal-fetal model presents a new concept linking autoimmunity against CM and cardiomyocyte proliferation with cardinal features of HLHS. To our knowledge, this report shows the first evidence in support of a novel immune-mediated mechanism for pathogenesis of structural CHD that may have implications in its future diagnosis and treatment.
结构先天性心脏病（CHD）以前与自身免疫无关。在我们的研究中，我们建立了一种结构 CHD 的自身免疫模型，该模型类似于左心发育不全综合征（HLHS），这是一种主要影响左心室的危及生命的 CHD。由于心肌肌球蛋白（CM）是自身免疫性心脏病中的主要自身抗原，我们假设用 CM 免疫可能导致母体自身抗体经胎盘传递，并使暴露胎儿出现产前 HLHS 表型。母体和胎儿血清中抗 CM 自身抗体的升高，以及胎儿心肌中的 IgG 反应性，与包括受影响后代左心室腔尺寸减小在内的结构性 CHD 相关。此外，出现明显 HLHS 表型的胎儿血清中抗β-肾上腺素能受体 Abs 的滴度升高，以及蛋白激酶 A 活性增加，提示存在观察到的病理变化的潜在机制。我们的母婴模型提出了一个新的概念，将 CM 和心肌细胞增殖的自身免疫与 HLHS 的主要特征联系起来。据我们所知，本报告首次提供了支持结构 CHD 发病机制的新型免疫介导机制的证据，这可能对其未来的诊断和治疗具有重要意义。
