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 anli-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 β1 (TGFβ1) and tumor necrosis factor α (TNFα) 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 TNFα and TGFβ1 polymorphisms in the 2 babies with CCHB and their siblings. TNFα polymorphisms at the promoter region and TGFβ1 polymorphisms at codons 10 and 25 were determined using polymerase chain reaction-restriction fragment length polymorphism analysis. In addition, the production of TGFβ1 and TNFα by resting or mitogen-stimulated peripheral blood mononuclear cells in cell culture supernatants was evaluated by enzyme-linked immunosorbent assay. Results. The profibrotic TGFβ1 genotype was detected in the twin with CCHB but not in the healthy twin, while all of the triplets displayed the same TGFβ1 genotype at codon 10. Peripheral blood mononuclear cells from the children with CCHB displayed higher spontaneous and mitogen-stimulated T6Fβ1 secretion than was observed in their siblings. No differences regarding TNFα polymorphisms and secretion of TNFα were observed. Conclusion. 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.