Arrhythmogenicity of IgG and Anti-52-kD SSA/Ro Affinity-Purified Antibodies From Mothers of Children With Congenital Heart Block

Abstract

An important advance in the description and understanding of congenital heart block (CHB) came in the 1970s with the observation that mothers of affected infants frequently had autoimmune diseases and, in particular, that many maternal sera contained antibodies to SSA/Ro and SSB/La ribonucleoproteins. Although the molecular biology of the candidate antigens has been extensively defined, the arrhythmogenic and electrophysiological effects of their cognate antibodies on the human fetal heart are unknown. In the present study, we provide evidence that IgG-enriched fractions and anti-52-kD SSA/Ro antibodies affinity-purified from sera of mothers whose children have CHB induce complete atrioventricular (AV) block in the human fetal heart perfused by the Langendorff technique and inhibit L-type Ca2+ currents at the whole-cell and single-channel level. Immunization of female BALB/c mice with recombinant 52-kD SSA/Ro protein generated high-titer antibodies that crossed the placenta during pregnancy and were associated with varying degrees of AV conduction abnormalities, including complete AV block, in the pups. These findings strongly suggest that anti-52-kD SSA/Ro antibodies are causally related to the development of CHB.

Neonatal lupus syndrome: the heart as a target of the immune system

“…The two sera that induced conduction blockade in these experiments were obtained from mothers with healthy infants. In contrast to our rabbit model, Boutjdir et al (1997) could only see AV conduction block or reduction in calcium currents in the human fetal hearts when using anti-52 kD affinity purified antibodies from mothers who had children with CHB. The reasons for this discrepancy are not immediately obvious, but we speculate that the target protein(s) at the cell membrane may not be 100% homologous in fetal human and adult rabbit hearts.…”

“…The results in isolated ventricular myocytes correlated well with the observations at the whole heart level, since the conduction in the A-V node is basically dependent on calcium electrogenesis. Our results were later confirmed by Boutjdir et al (1997) using whole hearts and cardiac myocytes derived from human fetuses.…”

Arrhythmias Presenting in Neonatal Lupus

“…After preliminary reports, [11,12] Boutjdir in an outstanding paper [7] showed that IgG-enriched fractions and anti-52-kD SSA ⁄ Ro antibodies affinity-purified from the sera of mothers whose children have CHB reversibly induce complete atrioventricular (AV) block in the human foetal heart perfused by the Langendorff technique. At 33 min of perfusion, complete AV block was observed with the presence of only P waves and missing QRS complexes.…”

“…The other mechanism is the cross-reactivity of maternal antibodies with targets other than SSA ⁄ Ro and SSB ⁄ La antigens. Maternal antibodies were reported to cross-react with laminin and with human cardiac myosin heavy chain at a critical stage during foetal cardiac development [5,6], but the L-type calcium channels seem particularly important in this hypothesis [7][8][9][10].…”

“…The other mechanism is the cross-reactivity of maternal antibodies with targets other than SSA ⁄ Ro and SSB ⁄ La antigens. Maternal antibodies were reported to cross-react with laminin and with human cardiac myosin heavy chain at a critical stage during foetal cardiac development [5,6], but the L-type calcium channels seem particularly important in this hypothesis [7][8][9][10].After preliminary reports, [11,12] Boutjdir in an outstanding paper [7] showed that IgG-enriched fractions and anti-52-kD SSA ⁄ Ro antibodies affinity-purified from the sera of mothers whose children have CHB reversibly induce complete atrioventricular (AV) block in the human foetal heart perfused by the Langendorff technique. At 33 min of perfusion, complete AV block was observed with the presence of only P waves and missing QRS complexes.…”