Autoimmune-associated congenital heart block: dissecting the cascade from immunologic insult to relentless fibrosis

Anat Rec A Discov Mol Cell Evol Biol. 2004 Oct;280(2):1027-35. doi: 10.1002/ar.a.20072.


Few diseases exemplify the integration of research from bench to bedside as well as neonatal lupus, often described as a model of passively acquired autoimmunity. The signature histologic lesion of autoimmune congenital heart block (CHB) is fibrosis of the conducting tissue and, in some cases, the surrounding myocardium. Although anti-SSA/Ro-SSB/La antibodies are detected in > 85% of mothers whose fetuses are identified with conduction abnormalities in a structurally normal heart, the risk for a woman with the candidate antibodies to have a child with CHB is 2%. The mechanism by which maternal anti-SSA/Ro-SSB/La antibodies initiate and finally eventuate in atrioventricular nodal scarring is not yet defined, but it is clear that the antibodies alone are insufficient to cause disease and fetal factors are likely contributory. Previous in vitro and in vivo studies suggest that the pathologic cascade is initiated via apoptosis, resulting in translocation of SSA/Ro-SSB/La antigens to the cell surface where they are bound by maternal autoantibodies. Subsequently, the Fc portion of the bound immunoglobulin engages Fcgamma receptors on tissue macrophages, resulting in release of TGF-beta at a threshold favoring a profibrotic milieu and irreversible scarring. This cascade also involves tissue-specific activation of TGF-beta, which promotes the modulation of fibroblasts into myofibroblasts, a scarring phenotype. Recent findings point to genetic polymorphisms that promote high production of TGF-beta as possible fetal risk factors for CHB. Further elucidation of maternal and fetal contributory factors should provide insight into the pathogenesis of CHB and the rarity of irreversible injury.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Autoantigens / immunology
  • Autoantigens / metabolism
  • Autoimmune Diseases / congenital*
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • Fibrosis / etiology*
  • Fibrosis / pathology
  • Heart Block / congenital*
  • Heart Block / immunology
  • Heart Block / pathology
  • Heart Defects, Congenital
  • Humans
  • Isoantibodies / immunology
  • Isoantibodies / metabolism
  • Lupus Erythematosus, Systemic / congenital*
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / pathology
  • Macrophages / pathology
  • Myocytes, Cardiac / immunology
  • Myocytes, Cardiac / pathology


  • Autoantigens
  • Isoantibodies