Risk factors for autoimmune-mediated congenital heart block

Placental transfer of maternal Ro/SSA and La/SSB autoantibodies during pregnancy is associated with conduction disturbances and inflammation in the developing fetal heart, termed autoimmune-mediated congenital heart block (CHB). Maternal Ro/SSA and La/SSB autoantibodies are the main risk factors associated with the fetal cardiac manifestations to date, however, the low recurrence rate despite persisting autoantibodies in subsequent pregnancies indicates that additional factors determine fetal susceptibility. The complex interactions between fetal genetic variants and factors that influence the intrauterine environment are thought to trigger or prevent the onset of CHB in Ro/SSA and/or La/SSB exposed pregnancies. The identification of such variants and factors was the main aim of this thesis. Genome-wide SNP association studies in families with at least one child affected by CHB and an anti-Ro52/SSA positive mother identified distinct cellular pathways associated with CHB. Exploration of potential candidate genes in the CHB-associated regions identified auxilin as a novel fetal susceptibility gene affecting cardiac excitation-contraction coupling. Discovery of additional CHB-associated variants affecting genes involved in vesicular or transmembrane transport and cardiac function further supported the idea that genetic variants in pathways connected to cardiac conduction and contractility may influence fetal susceptibility to disease. Furthermore, CHB-associated variants affecting genes with function assigned to immune responses emerged from our association studies and are likely to contribute to the inflammatory and tissue destructive processes connected with CHB. Ro/SSA autoantibodies are associated with interferon activation, and we found that cardiomyocyte expression of CHB-associated genes is affected by interferon-alpha stimulation. PBMCs from neonates with CHB and exposed to Ro/SSA autoantibodies in utero also displayed differential expression of several CHB-associated genes. Interestingly, expression of auxilin was altered in cardiomyocytes and PBMCs, validating the relevance of this particular gene and its pathway in CHB pathogenesis. We further identified and confirmed distinct class I and II HLA allele associations with CHB implementing potential impact for disease. Among the factors that may influence the intrauterine environment, we found that seasonal timing of pregnancy, infections, outdoor activity and psychological stress associated with the risk for CHB in Ro/SSA positive pregnancies. Finally, we also investigated potential cross-targets for the maternal anti-Ro52/p200 antibodies, and fetal intrauterine exposure to these maternal autoantibody specificities may further influence clinical outcomes of CHB. In summary, our data expands the current understanding of CHB pathogenesis, and suggests that the overall fetal susceptibility to CHB and degree of disease severity depends on a combination of genetic risk variants, their overall functional consequences, and their interactions with intrauterine factors in addition to the effect of fetal exposure to maternal Ro/SSA autoantibodies