Clancy Robert M, Kapur Raj P, Molad Yair, Askanase Anca Dinu, Buyon Jill P
Hospital for Joint Diseases, New York University School of Medicine, New York, New York 10003, USA.
Arthritis Rheum. 2004 Jan;50(1):173-82. doi: 10.1002/art.11430.
To assess in vivo the pathologic cascade leading to fibrosis in congenital heart block (CHB). In vitro studies suggest that CHB is initiated via apoptosis, resulting in translocation of SSA/Ro and SSB/La antigens and surface binding by maternal autoantibodies. These opsonized cardiocytes are phagocytosed by macrophages, which secrete factors inducing fibrosis.
Immunohistochemistry analysis was performed on formalin-fixed sections of 4 fetal hearts identified in utero as having CHB or isolated myocarditis; mothers had anti-SSA/Ro and anti-SSB/La antibodies.
Apoptosis was most extensive in fetuses dying early and most pronounced in regions containing conduction tissue. Deposition of IgG was observed in hearts from fetuses with CHB/myocarditis, but not in 3 control hearts, and was colocalized with apoptotic cells. Giant cells and macrophages (frequently seen proximal to IgG and apoptotic cells) were present in septal and thickened fibrous subendocardial regions, most apparent in the youngest fetuses. Septal tissue also revealed extensive areas of fibrosis and microcalcification in which a predominant smooth muscle actin (SMA)-positive infiltrate (myofibroblast scarring phenotype) was observed. In contrast, there were no macrophages or SMA-positive cells (other than those lining blood vessels) in septal tissue from control hearts, although rare macrophages were seen in the working myocardium.
In summary, findings in this unique autopsy material paralleled those in in vitro studies. These data support the notion of exaggerated apoptosis, probably due to ongoing inflammation caused by IgG binding and ingestion by macrophages. Transdifferentiation of cardiac fibroblasts to a scarring phenotype may be a pathologic process initiated by maternal antibodies, and persistence of this phenotype even after birth may relate to the progression of block seen in some infants postpartum.
在体内评估导致先天性心脏传导阻滞（CHB）纤维化的病理级联反应。体外研究表明，CHB通过凋亡启动，导致SSA/Ro和SSB/La抗原易位，并被母体自身抗体进行表面结合。这些被调理素化的心肌细胞被巨噬细胞吞噬，巨噬细胞分泌诱导纤维化的因子。
对4例经产前诊断为CHB或孤立性心肌炎的胎儿心脏的福尔马林固定切片进行免疫组织化学分析；母亲有抗SSA/Ro和抗SSB/La抗体。
凋亡在早期死亡的胎儿中最为广泛，在含有传导组织的区域最为明显。在患有CHB/心肌炎的胎儿心脏中观察到IgG沉积，但在3例对照心脏中未观察到，且IgG与凋亡细胞共定位。巨细胞和巨噬细胞（常在IgG和凋亡细胞附近出现）存在于间隔和增厚的纤维性心内膜下区域，在最年幼的胎儿中最为明显。间隔组织还显示出广泛的纤维化和微钙化区域，其中观察到主要为平滑肌肌动蛋白（SMA）阳性浸润（肌成纤维细胞瘢痕形成表型）。相比之下，对照心脏的间隔组织中没有巨噬细胞或SMA阳性细胞（血管内衬细胞除外），尽管在工作心肌中可见罕见的巨噬细胞。
总之，这种独特尸检材料中的发现与体外研究结果相似。这些数据支持凋亡过度的观点，这可能是由于IgG结合和巨噬细胞摄取引起的持续炎症所致。心脏成纤维细胞向瘢痕形成表型的转分化可能是由母体抗体引发的病理过程，这种表型即使在出生后持续存在可能与一些婴儿产后出现的传导阻滞进展有关。
