Autoantibodies against neonatal heart M-1 muscarinic acetylcholine receptor in children with congenital heart block

Isolated congenital heart block may be associated with autoimmune disorder such as Sjogren Syndrome and systemic lupus erythematosus. In this work we demonstrate circulating autoantibodies against neonatal heart M-1 muscarini c acetylcholine receptor (mAChR) in the sera of children with congenital he art block. This antibody were able to react with the second extracellular l oop of the human M-1 mAChR as demonstrated using a synthetic peptide in enz yme immune assay and binding assay. Affinity purified anti-peptide IgG as w ell as total IgG from children with congenital heart block, interfered with the specific radioligand occupancy from neonatal heart M-1 mAChR, interact ing irreversibly. The antipeptide antibodies also displayed an 'agonist-lik e' activity, i.e. decreased contractility, activated nitric oxide synthase activity and increased production of cyclic GMP. All of these effects were selectively blunted by pirenzepine and neutralized by the synthetic M-1 pep tide. Both binding and biological effects were obtained using neonatal rat heart instead adult heart and were independent of Ro/SS-A and La/SS-B antib odies and were also absent in the sera of normal children. A clinical relev ance of these findings is demonstrated by a strong association between the existence of circulating M-1 mAChR antipeptide antibodies and the presence of isolated congenital heart block, making these antibodies a proper marker of this disease. (C) 2001 Academic Press.