The cardiac disease of neonatal lupus (cardiac NL), while typically characterized by fibrosis of the atrioventricular node, can extend to the working myocardium and endocardium ( 1).
The identification of isolated congenital heart block in utero during the mid to late second trimester is almost universally associated with maternal Abs to a component of the SSA/Ro-SSB/La ribonucleoprotein complex, even in asymptomatic women. In aggregate these data suggest that intact β 2GPI in the fetal circulation may be a novel cardioprotective factor in anti-Ro60-exposed pregnancies. Plasmin-mediated cleavage of β 2GPI prevented binding to Ro60 and promoted the formation of pathogenic anti-Ro60 IgG-apoptotic cardiomyocyte complexes.
β 2GPI levels were significantly lower in neonates with cardiac NL. ELISA was used to quantify β 2GPI in umbilical cord blood from 97 neonates exposed to anti-Ro60 antibodies, 53 with cardiac NL and 44 with no cardiac disease. In competitive inhibition experiments, β 2GPI prevented opsonisation of apoptotic cardiomyocytes by maternal anti-Ro60 IgG. Initial flow cytometry experiments conducted on apoptotic human fetal cardiomyocytes demonstrated dose-dependent binding of β 2GPI. Accordingly, the current study was initiated to test two complementary hypotheses a) competition between β 2GPI and maternal anti-Ro60 antibodies for binding apoptotic induced surface translocated Ro60 occurs on human fetal cardiomyocytes and b) circulating levels of β 2GPI influence injury in anti-Ro60 exposed fetuses. Previous studies have demonstrated that beta2-glycoprotein I (β 2GPI) interacts with Ro60 on the surface of apoptotic Jurkat cells and prevents binding of anti-Ro60 IgG. One mechanism to molecularly explain the strong association of maternal anti-Ro60 antibodies with cardiac disease in neonatal lupus (NL) is that these antibodies initiate injury by binding to apoptotic cardiomyocytes in the fetal heart.
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