title: 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 RT1(av1) (DA, PVG.AV1, and LEW.AV1) after maternal Ro52 immunization, but not in LEW rats (RT1(l)). Different anti-Ro52 Ab fine specificities were generated in RT1(av1) versus RT1(l) animals. 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. 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. 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.
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Linn S
authors.initials: LS
authors.lastname: Strandberg
authors.forename: Aurelie
authors.initials: A
authors.lastname: Ambrosi
authors.forename: Maja
authors.initials: M
authors.lastname: Jagodic
authors.forename: Vijole
authors.initials: V
authors.lastname: Dzikaite
authors.forename: Peter
authors.initials: P
authors.lastname: Janson
authors.forename: Mohsen
authors.initials: M
authors.lastname: Khademi
authors.forename: Stina
authors.initials: S
authors.lastname: Salomonsson
authors.forename: Lars
authors.initials: L
authors.lastname: Ottosson
authors.forename: Robert
authors.initials: R
authors.lastname: Klauninger
authors.forename: Ulrika
authors.initials: U
authors.lastname: Adén
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Sonesson
authors.forename: Maria
authors.initials: M
authors.lastname: Sunnerhagen
authors.forename: Katrien L
authors.initials: KL
authors.lastname: de Graaf
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Adnane
authors.initials: A
authors.lastname: Achour
authors.forename: Ola
authors.initials: O
authors.lastname: Winqvist
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Marie
authors.initials: M
authors.lastname: Wahren-Herlenius
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity / Q000235:genetics; D054537:Atrioventricular Block / Q000151:congenital / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis*; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006649:Histocompatibility Antigens / Q000235:genetics* / Q000276:immunology; D008431:Maternal-Fetal Exchange / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D011247:Pregnancy; D051381:Rats; D011917:Rats, Inbred Lew; D012261:Ribonucleoproteins / Q000008:administration & dosage / Q000276:immunology*; D000099207:SS-A Antigen
chemical_list: D001323:Autoantibodies; D006649:Histocompatibility Antigens; D012261:Ribonucleoproteins; D000099207:SS-A Antigen; C038353:histocompatibility antigens RT, rat