Jill P. Buyon, MD

Isolated congenital heart block (CHB), detected in utero in a previously normal heart, is strongly associated with autoantibodies that recognize the intracellular soluble ribonucleoproteins 48kD SSB/La, 52kD SSA/Ro, and 60kD SSA/Ro. Neonatal disease is presumed to be due to the transplacental passage of these IgG autoantibodies into the fetal circulation from the mother who may have systemic lupus erythematosus, Sjogren syndrome, or be entirely asymptomatic. However, the role of these antibodies in the direct pathogenesis of cardiac injury is unknown. After characterizing numerous affected neonates and their mothers with respect to health status and antibody profile, we have focused on explaining two major clinical observations: 1) permanent disease does not occur in other fetal organs and the maternal heart is unaffected despite exposure to the identical circulating antibodies; and 2) not all mothers with these antibodies have offspring with disease implying involvement of as yet unknown factors. In addition to these considerations is the overriding question of how intracellular antigens become accessible targets of maternal autoantibodies. We demonstrated that a major antigenic target characterizing the autoimmune response in mothers whose children have manifestations of neonatal lupus is the 52kD Ro protein (52a), which contains an N-terminal zinc finger domain and central leucine zipper. We recently identified an alternative 52mRNA derived from splicing exon 4 inclusive of the leucine zipper, which encodes a smaller protein, 52b, with a predicted molecular weight of 45kD which is immunoprecipitated by over 80% of sera from CHB mothers. Expression of 52b is greatest between 14 and 16 wks of gestation, a time of cardiac ontogeny when maternal antibodies gain access to the fetal circulation just prior to the clinical detection of CHB. Additionally, protein interactions with 52a and 52b are being sought using human adult and fetal (14-24 wk) heart libraries in a two-hybrid system. Human fetal cardiocytes are being cultured to address issues of antigen localization and accessibility to antibody under different conditions. To further the study of neonatal lupus and congenital heart block, we established a national Research Registry for Neonatal Lupus which currently includes 352 affected families.