Autoantibodies in congenital heart block
Abstract: Neonatal lupus erythematosus (NLE) affects neonates of Ro/SSA and La/SSB positive women. NLE is associated with several clinical manifestations including skin rash, cytopenia and congenital heart block (CHB). CHB is the most severe manifestation which can develop into a lethal atrioventricular (AV) block. There is a strong association between maternal Ro/SSA and La/SSB antibodies and development of CHB, but a recurrence rate of 20% in following pregnancies despite persisting maternal autoantibodies indicates that also other factors contribute to development of CHB. The aim of this thesis was to investigate transfer of autoantigen-specific immunoglobulins of different isotypes from the mother to the child, and the significance of the postnatal maternal Ro52-, p200-, Ro60- and La antibody levels in infants during their first year. Further, we aimed to identify factors other than autoantibodies influencing the fetal outcome in Ro52 positive pregnancy using experimental models. These studies were focused on investigating fetal susceptibility. Sera from Ro/SSA and La/SSB positive women and their children were analyzed by ELISA using purified, recombinant antigens and synthetic peptides. Ro52, Ro60 and La IgG antibodies all transferred from the mothers to their fetus in utero and were present in the infant at birth, but had decreased significantly in the infants at 4-5 weeks of age. Little or no Ro/La specific IgM or IgA was present in the infants, and NLE developed independently of breastfeeding. We conclude that Ro/La autoantibodies are predominantly transferred to the child via the placenta, and that there appears to be no reason for a Ro/SSA positive mother to refrain from breast feeding. Using MHC congenic rat strains we show that heart block develops in rat pups of three strains carrying MHC haplotype RT1av1 (DA, PVG.AV1 and LEW.AV1) after maternal Ro52 immunization, while pups from LEW rats (RT1l) rarely developed block. Different anti-Ro52 antibody fine-specificities were generated in RT1av1 versus RT1l animals. Maternal and fetal influence was determined in an F2 cross between LEW.AV1 and LEW strains, which revealed higher susceptibility in RT1l than RT1av1 pups once pathogenic Ro52-antibodies were present. This was further confirmed in that RT1l pups more frequently developed heart block than RT1av1 pups after passive transfer of RT1av1 anti-Ro52 sera, and by microarray analysis of fetal hearts that revealed increased expression of distinct MHC-encoded genes in RT1l compared to RT1av1 pups. Our findings suggest that generation of the pathogenic Ro52 antibodies is restricted by maternal MHC, and that a different set of genes encoded by the fetal MHC locus regulate susceptibility and determine the fetal disease outcome in anti-Ro52 positive pregnancies.
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