Induction of neonatal lupus in pups of mice immunized with synthetic peptides derived from amino acid sequences of the serotoninergic 5-HT4 receptor

We have previously suggested that the recognition of a cross-reactive epito pe on the 5-HT4 receptor and the 52-kDa SSA/Ro protein by serotonin-antagon izing autoantibodies could explain the electrophysiological symptoms of con genital heart block in neonatal lupus. To confirm this hypothesis, we immun ized female mice with four synthetic peptides corresponding to the recogniz ed epitopes. All mice developed anti-peptide antibodies, which cross-reacte d with the Ro52 and 5-HT4 receptor peptides and recognized both cognate pro teins. Peptide-immune mice were mated. The pups from mice immunized with th e Ro52 peptides had no symptoms of neonatal lupus apart from bradycardia. H owever, pups from mice immunized with the 5-HT4 receptor peptides and brady cardia, atrioventricular block of type I or II, longer QT intervals, skin r ashes and neuromotoric problems. The 5-HT4 receptor was detectable in the d ifferent fetal tissues affected (heart, skin and brain) by immunohistochemi stry. Hearts from diseased pups were less developed and showed disorganized myocardial hyperplasia, compared to the normal littermates. These results demonstrate that the serotoninergic 5-HT4 receptor is the antigenic target of physiopathological autoantibodies in neonatal lupus.