Transforming growth factor beta1 in the pathogenesis of autoimmune congenital complete heart block: lesson from twins and triplets discordant for the disease.
OBJECTIVE
Clinical evidence and experimental evidence suggest that anti-Ro/La autoantibodies are necessary but not sufficient for the development of congenital complete heart block (CCHB). Maternal, fetal, and environmental factors may also contribute to heart damage in CCHB. The aim of our study was to investigate polymorphisms of transforming growth factor beta1 (TGFbeta1) and tumor necrosis factor alpha (TNFalpha) genes in twins and triplets discordant for CCHB whose mothers are anti-Ro/La positive.


METHODS
We studied 2 families in which 1 of the mothers gave birth to triplets and the other gave birth to twins. Only 1 child in each family was affected by CCHB, although 1 of the triplets had incomplete heart block. We analyzed TNFalpha and TGFbeta1 polymorphisms in the 2 babies with CCHB and their siblings. TNFalpha polymorphisms at the promoter region and TGFbeta1 polymorphisms at codons 10 and 25 were determined using polymerase chain reaction-restriction fragment length polymorphism analysis. In addition, the production of TGFbeta1 and TNFalpha by resting or mitogen-stimulated peripheral blood mononuclear cells in cell culture supernatants was evaluated by enzyme-linked immunosorbent assay.


RESULTS
The profibrotic TGFbeta1 genotype was detected in the twin with CCHB but not in the healthy twin, while all of the triplets displayed the same TGFbeta1 genotype at codon 10. Peripheral blood mononuclear cells from the children with CCHB displayed higher spontaneous and mitogen-stimulated TGFbeta1 secretion than was observed in their siblings. No differences regarding TNFalpha polymorphisms and secretion of TNFalpha were observed.


CONCLUSIONS
The results of this study suggest that, besides anti-Ro/La autoantibodies, a fetal profibrotic response might contribute to the development of CCHB, but additional pathogenic mechanism(s) are also likely to play a role.
Cimaz
Rolando
R
Clinica Pediatrica, Fondazione Policlinico-Mangiagalli, Via Commenda 9, 20122 Milan, Italy. Rolando.Cimaz@unimi.it
Borghi
Maria Orietta
MO
Gerosa
Maria
M
Biggioggero
Martina
M
Raschi
Elena
E
Meroni
Pier Luigi
PL
D001327:Autoimmune Diseases / Q000151:congenital* / Q000209:etiology* / Q000235:genetics; D002675:Child, Preschool; D006327:Heart Block / Q000151:congenital* / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007223:Infant; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014310:Triplets
C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1