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

J Am Heart Assoc. 2015 May 20;4(5):e001836. doi: 10.1161/JAHA.115.001836.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Antibodies, Antinuclear / blood
  • Antibodies, Antinuclear / genetics
  • Antibodies, Antinuclear / immunology*
  • Apoptosis
  • Autoantibodies / blood
  • Autoantibodies / immunology
  • Autoimmune Diseases / blood
  • Autoimmune Diseases / complications*
  • Autoimmune Diseases / immunology
  • Biomarkers / blood
  • Calcium Channels, T-Type / blood
  • Calcium Channels, T-Type / genetics
  • Calcium Channels, T-Type / immunology*
  • Epitopes / blood
  • Epitopes / immunology
  • Female
  • Heart Block / blood
  • Heart Block / congenital*
  • Heart Block / immunology
  • Humans
  • Infant, Newborn
  • Pregnancy
  • Risk Factors
  • Young Adult

Substances

  • Antibodies, Antinuclear
  • Autoantibodies
  • Biomarkers
  • Calcium Channels, T-Type
  • Epitopes
  • SS-A antibodies

Supplementary concepts

  • Congenital heart block