Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block.
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.
Salomonsson
Stina
S
Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Sonesson
Sven-Erik
SE
Ottosson
Lars
L
Muhallab
Saad
S
Olsson
Tomas
T
Sunnerhagen
Maria
M
Kuchroo
Vijay K
VK
Thorén
Peter
P
Herlenius
Eric
E
Wahren-Herlenius
Marie
M
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000378:metabolism; D005260:Female; D005315:Fetal Diseases / Q000209:etiology / Q000378:metabolism*; D006327:Heart Block / Q000151:congenital* / Q000209:etiology / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007150:Immunohistochemistry; D008431:Maternal-Fetal Exchange / Q000502:physiology; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D013548:Sweden; D000099207:SS-A Antigen
D001323:Autoantibodies; D002118:Calcium; D000939:Epitopes; D011994:Recombinant Proteins; D012261:Ribonucleoproteins; D000099207:SS-A Antigen