Congenital heart block (CHB) is associated with transplacental passage of maternal autoantibodies to the ribonucleoproteins (RNP), 48kD SSB/La, and 52kD and 60kD SSA/Ro. The affected mothers might have SLE, or Sjogren's syndrome or might be asymptomatic. Why the developing fetal heart is specially vulnerable to such autoantibodies and why CHB occurs in the children of only a fraction of mothers with the autoantibodies, are not known. Moreover, the putative autoantigens are intracellular RNP particles, therefore it is not clear how they cause damage to the fetal cardiocytes.
In Aim 1, the applicants propose to identify proteins that interact with the Ro and La RNP complexes and are selectively expressed in the human fetal heart. Novel autoantigens unique to fetal heart that are recognized by antisera from mothers of children with CHB might be discovered and a better understanding of the biological function of the Ro and La autoantigens may result from these studies.
In Aim 2, the applicants will determine if the candidate autoantigens associated with autoimmune-CHB come to the surface membrane of cardiocytes during apoptosis thus being accessible to the maternally transmitted autoantibodies.
In Aim 3, the applicants will develop a mouse model of CHB to understand the pathogenesis of the human disease in depth.
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