Reactivity to the p305 Epitope of the α1G T‐Type Calcium Channel and Autoimmune‐Associated Congenital Heart Block

Abstract

Background Only 2% of mothers positive for anti‐SSA/Ro (Ro) antibodies have children with congenital heart block (CHB). This study aimed to determine whether reactivity with p305, an epitope within the α1G T‐type calcium channel, confers added risk over anti‐Ro antibodies. Methods and Results Using sera from anti‐Ro‐exposed pregnancies resulting in offspring with CHB, no disease but CHB‐sibling, and no disease and no CHB‐sibling, as well as disease (lupus without anti‐Ro) and healthy controls, reactivities were determined for binding to Ro60, p305, and an epitope within Ro60, p133‐Ro60, which shares structural properties with p305, including key amino acids and an α‐helical structure. Candidate peptides were further evaluated in an in vitro model that assessed the binding of maternal antibodies to apoptotic cells. In anti‐Ro‐positive mothers, anti‐p305 autoantibodies (>3 SD above healthy controls) were detected in 3/59 (5%) CHB pregnancies, 4/30 (13%) unaffected pregnancies with a CHB‐sibling, and 0/42 (0%) of unaffected pregnancies with no CHB‐sibling. For umbilical bloods (61 CHB, 41 healthy with CHB sibling), no association of anti‐p305 with outcome was detected; however, overall levels of anti‐p305 were elevated compared to mothers during pregnancy in all groups studied. For anti‐p133‐Ro60, reactivity paralleled that of anti‐p305. In the screen employing apoptotic cells, p133‐Ro60, but not p305, significantly attenuated the binding of immunoglobulin G isolated from a mother whose child had CHB (42.1% reduced to 13.9%, absence/presence of p133‐Ro60, respectively, P<0.05). Conclusions These data suggest that anti‐p305 is not a robust maternal marker for assessing increased risk of CHB during an anti‐SSA/Ro pregnancy.

Keywords

• apoptosis
• heart block
• risk factors