Anti-SSA/Ro52 autoantibodies blocking the cardiac 5-HT4serotoninergic receptor could explain neonatal lupus congenital heart block

Abstract

The 52‐kDa SSA/Ro (Ro52) ribonucleoprotein is an antigenic target strongly associated with the autoimmune response in mothers whose children develop neonatal lupus and congenital heart block. When sera from patients with systemic lupus erythematosus were used as autoimmune controls in an enzyme immunoassay to screen for antibodies against the human serotoninergic 5‐HT4‐receptor, a high correlation was found between the presence of anti‐Ro52 protein antibodies in such sera and antibodies reacting with a synthetic peptide, corresponding to the second extracellular loop of the human 5‐HT4 receptor (amino acid residues 165–185). Homology scanning between the 5‐HT4 peptide and the sequence of the Ro52 protein indicated two potential common epitopes located between residues 365 and 396 of the Ro52 protein. Cross‐reactivity was found between the peptide derived from the 5‐HT4 receptor, and a peptide corresponding to residues 365–382 of the Ro52 protein. Autoantibodies, affinity‐purified on the 5‐HT4 receptor peptide, specifically recognized both the Ro52 protein and the 5‐HT4 receptor protein in immunoblots. The affinity‐purified antibodies antagonized the serotonin‐induced L‐type Ca channel activation on human atrial cells. This effect could explain the electrophysiological abnormalities in neonatal lupus.

Key Residues of a Major Cytochrome P4502D6 Epitope Are Located on the Surface of the Molecule

“…This, together with the recent demonstration that the CYP2D6 molecule is expressed on the hepatocyte membrane and is targeted by LKM1 (37,38), suggests that this sequence may be directly involved in autoantibody mediated liver cell damage, akin to the scenario in myasthenia gravis (39), autoimmune thyroiditis (40), autoimmune thrombocytopenia purpura (41), hemolytic anemia (42), and neonatal systemic lupus erythematosus (43).…”

Ca2+ currents in cardiac myocytes: Old story, new insights

“…The L-type Ca 2+ channel may not be the only target for maternal anti-SSA/Ro and/or SSB/La antibodies, because a specific cross-reaction between the recombinant 52kDa SSA/Ro protein and the second extracellular loop of serotoninergic 5-HT 4 receptor expressed in human atrial cells has been identified (sequence G21V) (Eftekhari et al, 2000). In contrast to the results describe above, anti-G21V affinity-purified autoantibodies from lupus patients or from rabbits immunized with the G21V peptide do not inhibit basal I CaL in adult human atrial myocytes.…”

“…In contrast to the results describe above, anti-G21V affinity-purified autoantibodies from lupus patients or from rabbits immunized with the G21V peptide do not inhibit basal I CaL in adult human atrial myocytes. However, these antibodies antagonize serotonin-induced activation of I CaL (Eftekhari et al, 2000;Salle et al, 2001); the authors hypothesized that during the early phase of fetal development the serotoninic pathway is more prominent than the β-adrenergic pathway so that 5-HT 4 receptor block leads to a reduction of I Ca which could in turn induce bradycardia and atrioventricular block .…”

Anti-μ-opioid-receptor IgG antibodies are commonly present in serum from healthy blood donors: evidence for a role in apoptotic immune cell death

“…32 Accordingly, it has been considered that disease-associated autoantibodies may emerge from the natural autoantibody repertoire. 33 In this context, characterization of agonistic anti-G protein-coupled receptor autoantibodies in several pathologic conditions, including Graves disease, 34 preeclampsia, 35 neonatal lupus congenital heart block, 36 and schizophrenia, 37 may presume that these kinds of autoantibodies, including anti-hMOR autoantibodies, are a common feature of the natural autoantibody repertoire.…”