Another possible scenario, besides interaction with Ro52, is that the maternal anti-Ro52 autoantibodies cross-react with another protein expressed in foetal cardiac tissue. There are several proteins that have been suggested as cross-reactive targets of Ro52 IDH inhibitor antibodies including the 5-HT4 serotoninergic receptor [35], the α1C and the α1D

subunits of the L-type calcium channel [36], as well as the T-type calcium channel [37]. Eftekhari and colleagues [35] demonstrated that antibodies reactive with the second extracellular loop of the 5-HT4 serotoninergic receptor, cloned from human adult atrium, can bind to Ro52 and that sera from mothers with affected children recognize the 5-HT4 receptor. However, others have not been able to confirm the 5-HT receptor as a target of the immune response in mothers with affected children [38]. Several publications have shown

arrythmogenic effects of anti-Ro52 antibodies and evidence is emerging to support a direct effect of the antibodies on cardiocyte function, possibly because of cross-reactivity. This hypothesis has been supported by the demonstration that human affinity purified Ibrutinib anti-Ro52-positive sera induce AV block in whole young rabbit hearts [39], and human foetal hearts [40] and inhibit inward calcium fluxes across Glycogen branching enzyme cell membranes [39, 40]. More specifically, maternal antibodies have been proposed to interact with the pore-forming α1C subunit of calcium channels, possibly leading to internalization with subsequent cell death and exposure of intracellular Ro and La proteins, ultimately resulting in an inflammatory reaction [41]. Ro/La-positive IgG

has been demonstrated to inhibit currents through both subunits of the L-type calcium channel as well as the T-type calcium channel [36, 41, 42]. The Ca channel α1D subunit has been shown to be expressed in human foetal hearts [36]. In a recent study, it has been demonstrated that a fraction of sera from mothers of children with congenital heart block react to the extracellular loop of the calcium channel α1D subunit and that these maternal antibodies can inhibit α1D calcium currents in vitro [43]. The potential role of the specific anti-Ro52 antibodies targeting p200 in the mechanism underlying congenital heart block remains to be embellished; however, experimental findings suggest that anti-p200 antibodies may interact with cardiomyocytes and disturb calcium homeostasis [18] supporting a mechanism involving a direct interaction with the calcium ion channel complex. In addition to antibodies directed to the Ro and La proteins, several other targets have been suggested to be associated with development of congenital heart block.