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¹ Rheumatology Unit, Department of Medicine
² Department of Women and Child Health, Karolinska Institutet, 171 76 Stockholm, Sweden
³ Department of Clinical Neuroscience, Karolinska Institutet, 171 76 Stockholm, Sweden
⁴ Department of Physiology, Karolinska Institutet, 171 76 Stockholm, Sweden
⁵ Department of Molecular Biotechnology, Linköping University, 581 83 Linköping, Sweden
⁶ Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

CORRESPONDENCE Marie Wahren-Herlenius: Marie.Wahren{at}cmm.ki.se

Congenital heart block develops in fetuses after placental transfer of Ro/SSA autoantibodies from rheumatic mothers. The condition is often fatal and the majority of live-born children require a pacemaker at an early age. The specific antibody that induces the heart block and the mechanism by which it mediates the pathogenic effect have not been elucidated. In this study, we define the cellular mechanism leading to the disease and show that maternal autoantibodies directed to a specific epitope within the leucine zipper amino acid sequence 200–239 (p200) of the Ro52 protein correlate with prolongation of fetal atrioventricular (AV) time and heart block. This finding was further confirmed experimentally in that pups born to rats immunized with p200 peptide developed AV block. p200-specific autoantibodies cloned from patients bound cultured cardiomyocytes and severely affected Ca²⁺ oscillations, leading to accumulating levels and overload of intracellular Ca²⁺ levels with subsequent loss of contractility and ultimately apoptosis. These findings suggest that passive transfer of maternal p200 autoantibodies causes congenital heart block by dysregulating Ca²⁺ homeostasis and inducing death in affected cells.

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