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Transdifferentiation of Cardiac Fibroblasts, a Fetal Factor in Anti-SSA/Ro-SSB/La Antibody-Mediated Congenital Heart Block¹

Robert M. Clancy^2,*, Anca D. Askanase^*, Raj P. Kapur, Efstathia Chiopelas^*, Natalie Azar^*, M. Eugenia Miranda-Carus^* and Jill P. Buyon^*

^* Department of Rheumatology, Hospital for Joint Diseases, New York University School of Medicine, New York, NY 10003; and Department of Laboratories, Children’s Hospital and Regional Medical Center, University of Washington, Seattle, WA 98105

The signature lesion of autoantibody-associated congenital heart block (CHB) is fibrosis of the conducting tissue. To date, participation of myofibroblasts in the cascade to injury has been unexplored. The importance of myofibroblast/macrophage cross-talk is demonstrated by the novel finding of these cell types in the heart of a neonate dying of CHB. This clue to pathogenesis prompted consideration of the mechanism by which maternal anti-SSA/Ro-SSB/La Abs initiate an inflammatory response and promote fibrosis. Isolated cardiocytes from 16–24 wk abortuses were rendered apoptotic by exposure to poly (2-) hydroxyethylmethacrylate; flow cytometry confirmed surface expression of Ro/La. Apoptotic cardiocytes were incubated with affinity-purified Abs to 52 and 60 kDa Ro from CHB mothers (opsonized) or IgG fractions from healthy donors (nonopsonized). Macrophages cultured with opsonized apoptotic cardiocytes expressed proinflammatory markers, supported by a three-fold increase in active _V3 integrin. Fetal cardiac fibroblasts exposed to supernatants obtained from macrophages incubated with opsonized apoptotic cardiocytes (but not nonopsonized) dramatically increased expression of the myofibroblast marker -smooth muscle actin (SMAc). The "opsonized" supernatant reversed an inhibitory effect of the "nonopsonized" supernatant on proliferation of fibroblasts (120 vs 69%, p < 0.05). Parallel experiments examined the effects of two cytokines and their neutralizing Abs on fibroblasts. TGF1 increased SMAc staining but decreased proliferation. TNF- did not affect either readout. Addition of anti-TGF1 Abs to the "opsonized" supernatant blocked SMAc expression but increased proliferation, while anti-TNF- blocking Abs had no effects. These data suggest that transdifferentiation of cardiac fibroblasts to a scarring phenotype is a pathologic process initiated by maternal Abs.

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