Abstract
BackgroundCongenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB.Methodology/Principal FindingsWe demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18–22.6 weeks gestation). Using human fetal hearts (20–22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305–319 of the extracellular loop linking transmembrane segments S5–S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells.Conclusions/SignificanceTaken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets.
Highlights
Congenital heart block (CHB) is a passively acquired autoimmune disease that occurs in pregnancies of rheumatic mothers, and in healthy mothers, and has been associated with maternal anti-Ro/SSA and anti-La/SSB antibodies
We found that a1G is expressed in human fetal hearts and that CHB-affected maternal sera contains antibodies reacting to the a1G protein
Ion channel blockers demonstrate preferential inhibition of newborn heart AV conduction likely conferred by a1G Since CHB affects the fetal heart, but not the maternal heart, we wanted to identify ion channels that may be preferentially affected by autoantibodies in fetal hearts
Summary
Congenital heart block (CHB) is a passively acquired autoimmune disease that occurs in pregnancies of rheumatic mothers, and in healthy mothers, and has been associated with maternal anti-Ro/SSA and anti-La/SSB antibodies. In a population of women with anti-Ro/SSA and anti-La/SSB autoantibodies, the incidence of CHB is approximately 1–2% [17], yet the recurrence rate in these mothers is approximately 18% [1,18,19], despite persisting antibodies [20], indicating that additional factor(s) contribute to the fetal susceptibility of CHB. Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit a1G may be a fetal target of maternal sera autoantibodies in CHB
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