In the rheumatic mothers, production of Ro52 Abs has been repeatedly linked to MHC class II DRB1*03 alleles ( 6, 7). Congenital heart block is a potentially lethal manifestation of the neonatal lupus syndrome, which develops in fetuses of rheumatic women with Ro52 autoantibodies ( 5). Pregnancy in autoimmune conditions is often marred by complications, and the fetus may be directly affected by maternal autoantibodies to develop neonatal lupus, myastenia, hypothyroidism, or learning disabilities ( 1– 4). Our findings show that generation of pathogenic Ro52 Abs is restricted by maternal MHC, whereas the fetal MHC locus regulates susceptibility and determines the fetal disease outcome in anti-Ro52–positive pregnancies. This was further confirmed in that RT1 l pups more frequently developed heart block than RT1 av1 pups after passive transfer of RT1 av1 anti-Ro52 sera. Maternal and fetal influence was determined in an F 2 cross between LEW.AV1 and LEW strains, which revealed higher susceptibility in RT1 l than RT1 av1 pups once pathogenic Ro52 Abs were present. Different anti-Ro52 Ab fine specificities were generated in RT1 av1 versus RT1 l animals. Using MHC congenic rat strains, we show that heart block develops in rat pups of three strains carrying MHC haplotype RT1 av1 (DA, PVG.AV1, and LEW.AV1) after maternal Ro52 immunization, but not in LEW rats (RT1 l). In this study, we demonstrate that besides the maternal MHC controlling Ab specificity, fetal MHC-encoded genes influence fetal susceptibility to congenital heart block. A recurrence rate of 20%, despite the persistence of maternal autoantibodies, indicates that there are additional, yet unidentified, factors critical for development of congenital heart block. Congenital heart block develops in fetuses of anti-Ro52 Ab-positive women.
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