Immunomodulation by maternal autoantibodies of the fetal serotoninergic 5-HT(4 )receptor and its consequences in early BALB/c mouse embryonic development

BACKGROUND: The presence of functional 5-HT(4 )receptors in human and its involvement in neonatal lupus erythematosus (NLE) have prompted us to study the receptor expression and role during embryogenesis. Earlier we managed to demonstrate that female BALB/c mice immunized against the second extracellular loop (SEL) of the 5-HT(4 )receptor gave birth to pups with heart block. To explain this phenomenon we investigated the expression of 5-HT(4 )receptors during mouse embryogenesis. At the same time we looked whether the consequence of 5-HT(4 )receptor immunomodulation observed earlier is in relation to receptor expression. We studied the expression of 5-HT(4 )receptor at the mRNA level and its two isoforms 5-HT(4(a) )and 5-HT(4(d) )at the protein level in embryos from BALB/c mice, at 8(th), 12(th), 18(th )gestation days (GD) and 1 day post natal (DPN). Simultaneously the receptor activity was inhibited by rising antibodies, in female mice against SEL of the receptor. The mice were mated and embryos were collected at 8(th), 12(th), 18(th )GD and 1 DPN. RESULTS: 5-HT(4 )receptor mRNA increased in brain from 12(th )GD to 1 DPN. Its expression gradually decreased in heart and disappeared at birth. This was consistent with expression of the receptor isoforms 5-HT(4(a) and (d)). Abnormalities like decreased number of embryos, growth delay, spina bifida and sinus arrhythmia from 12(th )GD were documented in pups of mice showing anti-5-HT(4 )receptor antibodies. CONCLUSION: serotoninergic 5-HT(4 )receptor plays an important role in mouse foetal development. In BALB/c mice there is a direct relation between the expression of receptor and the deleterious effect of maternal anti-5-HT(4 )receptor autoantibodies in early embryogenesis.