Transforming growth factor β1 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 beta 1 (TGF beta 1) and tumor necrosis factor alpha (TNF alpha) genes in twins and triplets discordant for CCHB whose mothers are anti-Ro/La positive. Methods. We studied 2 families in which I of the mothers gave birth to triplets and the other gave birth to twins. Only I child in each family was affected by CCHB, although 1 of the triplets had incomplete heart block. We analyzed TNFa and TGF beta 1 polymorphisms in the 2 babies with CCHB and their siblings. TNFa polymorphisms at the promoter region and TGF beta 1 polymorphisms at codons 10 and 25 were determined using polymerase chain reaction-restriction fragment length polymorphism analysis. In addition, the production of TGF beta 1 and TNF alpha by resting or mitogen-stimulated peripheral blood mononuclear cells in cell culture supernatants was evaluated by enzyme-linked immunosorbent assay. Results. The proribrotic TGF beta 1 genotype was detected in the twin with CCHB but not in the healthy twin, while all of the triplets displayed the same TGF beta 1 genotype at codon 10. Peripheral blood mononuclear cells from the children with CCHB displayed higher spontaneous and mitogen-stimulated TGF beta 1 secretion than was observed in their siblings. No differences regarding TNFa polymorphisms and secretion of TNF alpha 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.