Sjogren autoantibodies modify neonatal cardiac function via M-1 muscarinicacetylcholine receptor activation

Isolated congenital heart block may be associated with primary Sjogren synd rome. In this work we describe circulating antibodies in the sera of primar y Sjogren syndrome patients that are able to interact with neonatal myocard ium by activating muscarinic acetylcholine receptors of M-1 subtype. We rep ort on the presence of autoantibodies against the second extracellular loop of human M-1 muscarinic acetylcholine receptors in primary Sjogren syndrom e mothers whose children have congenital heart block using a synthetic pept ide in indirect immunofluorescence technique. Autoantibodies from primary S jogren syndrome patients gave positive image on neonatal atria but not on a dult atria slices. The synthetic M-1 peptide selectively abrogated indirect immunofluorescence recognition. The primary Sjogren syndrome-immunoglobuli n G also displayed an 'agonist like' activity modifying the intracellular e vents associated with muscarinic acetylcholine receptor activation. The mec hanism appears to occur secondarily to stimulation of phosphoinositides tur nover via phospholipase C activation. This, in turn, triggers cascade react ions involving calcium/calmodulin and leads to activation of nitric oxide s ynthase and soluble guanylate cyclase. All of these effects were selectivel y blunted by pirenzepine and neutralized by M-1 synthetic peptide. These bi ological effects were not obtained using adult instead of neonatal rat atri a and neither occurred with the sera of normal healthy women of childbearin g age. It could be concluded that antibodies against neonatal M-1 muscarini c acetylcholine receptor may be another serum factor to be considered in th e pathophysiology of the development of congenital heart block associated w ith primary Sjogren syndrome mothers. (C) 1999 Elsevier Science Ireland Ltd . An rights reserved.