Maternal MHC Regulates Generation of Pathogenic Antibodies and Fetal MHC-Encoded Genes Determine Susceptibility in Congenital Heart Block

Abstract

Congenital heart block develops in fetuses of anti-Ro52 Ab-positive women. 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. In this study, we demonstrate that besides the maternal MHC controlling Ab specificity, fetal MHC-encoded genes influence fetal susceptibility to congenital heart block. 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, but not in LEW rats (RT1l). Different anti-Ro52 Ab 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 Abs 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. 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.

Pregnancy implications for systemic lupus erythematosus and the antiphospholipid syndrome

“…The features of maternal autoantibodies seem to be relevant [36]: i) specificity: antibodies to amino acid 200-239 (p200) of Ro52 were detected at higher titre in mothers of children with CHB [37]; ii) titre: levels of maternal anti-Ro/SSA antibodies were higher in those cases who had a child with cardiac complications. Genetics may be also important, since foetal susceptibility to cardiac NL has been shown to be associated with MHC-encoded genes [38]and with genes related to inflammatory and apoptotic responses that may promote cardiac damage triggered by maternal autoantibodies [39]. The prevalent role of foetal genetic background rather than maternal one is suggested by a unique case of CHB developed in a child who was a product of ovodonation [40].…”

A comprehensive review of the clinical approach to pregnancy and systemic lupus erythematosus

“…Additional factors such as autoantibodies profile and titre [81,82], as well as genetic background may be able to modulate the action of autoantibodies themselves [83]. Although the pathogenesis is not fully elucidated, it is suspected that heart block results from binding of anti-Ro/SSA and/or anti-La/SSB antibodies to foetal cardiac tissue.…”

Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern

“…This indicates that additional factors are critical for establishing heart block. Fetal genetic susceptibility has been suggested as a potential risk factor,11 12 and polymorphisms in the gene encoding tumor growth factor β have been implicated in the development of heart block 13 14. Variations in the intrauterine environment between pregnancies have also been suggested to contribute to the penetrance of the disease.…”