Maternal MHC regulates generation of pathogenic antibodies and fetal MHC-encoded genes determine susceptibility in congenital heart block.
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.
Strandberg
Linn S
LS
Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Ambrosi
Aurelie
A
Jagodic
Maja
M
Dzikaite
Vijole
V
Janson
Peter
P
Khademi
Mohsen
M
Salomonsson
Stina
S
Ottosson
Lars
L
Klauninger
Robert
R
Adén
Ulrika
U
Sonesson
Sven-Erik
SE
Sunnerhagen
Maria
M
de Graaf
Katrien L
KL
Kuchroo
Vijay K
VK
Achour
Adnane
A
Winqvist
Ola
O
Olsson
Tomas
T
Wahren-Herlenius
Marie
M
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
D001323:Autoantibodies; D006649:Histocompatibility Antigens; D012261:Ribonucleoproteins; D000099207:SS-A Antigen; C038353:histocompatibility antigens RT, rat