Immunomodulation by maternal autoantibodies of the fetal serotoninergic 5-HT4 receptor and its consequences in early BALB/c mouse embryonic development

摘要

Background The presence of functional 5-HT₄ 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-HT₄ receptor gave birth to pups with heart block. To explain this phenomenon we investigated the expression of 5-HT₄ receptors during mouse embryogenesis. At the same time we looked whether the consequence of 5-HT₄ receptor immunomodulation observed earlier is in relation to receptor expression. We studied the expression of 5-HT₄ 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 8th, 12th, 18th 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 8th, 12th, 18th GD and 1 DPN. Results 5-HT₄ receptor mRNA increased in brain from 12th 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 12th GD were documented in pups of mice showing anti-5-HT₄ receptor antibodies. Conclusion serotoninergic 5-HT₄ 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-HT₄ receptor autoantibodies in early embryogenesis.