Sjogren autoantibodies modify neonatal cardiac function via M1 muscarinic acetylcholine receptor activation

Isolated congenital heart block may be associated with primary Sjogren syndrome. In this work we describe circulating antibodies in the sera of primary Sjogren syndrome patients that are able to interact with neonatal myocardium by activating muscarinic acetylcholine receptors of M-1 subtype. We report on the presence of autoantibodies against the second extracellular loop of human M-1 muscarinic acetylcholine receptors in primary Sjogren syndrome mothers whose children have congenital heart block using a synthetic peptide in indirect immunofluorescence technique. Autoantibodies from primary Sjogren syndrome patients gave positive image on neonatal atria but not on adult atria slices. The synthetic M-1 peptide selectively abrogated indirect immunofluorescence recognition. The primary Sjogren syndrome-immunoglobulin G also displayed an 'agonist like' activity modifying the intracellular events associated with muscarinic acetylcholine receptor activation. The mechanism appears to occur secondarily to stimulation of phosphoinositides turnover via phospholipase C activation. This, in turn, triggers cascade reactions involving calcium/calmodulin and leads to activation of nitric oxide synthase and soluble guanylate cyclase. All of these effects were selectively blunted by pirenzepine and neutralized by M-1 synthetic peptide. These biological effects were not obtained using adult instead of neonatal rat atria and neither occurred with the sera of normal healthy women of childbearing age. It could be concluded that antibodies against neonatal M-1 muscarinic acetylcholine receptor may be another serum factor to be considered in the pathophysiology of the development of congenital heart block associated with primary Sjogren syndrome mothers. (C) 1999 Elsevier Science Ireland Ltd. An rights reserved.