Impaired clearance of apoptotic cardiocytes is linked to anti-SSA/Ro and -SSB/La antibodies in the pathogenesis of congenital heart block.
The role of cardiocytes in physiologic removal of apoptotic cells and the subsequent effect of surface binding by anti-SSA/Ro and -SSB/La antibodies was addressed. Initial experiments evaluated induction of apoptosis by extrinsic and intrinsic pathways. Nuclear injury and the translocation of SSA/Ro and SSB/La antigens to the fetal cardiocyte plasma membrane were common downstream events of Fas and TNF receptor ligation, requiring caspase activation. As assessed by phase-contrast and confirmed by confocal microscopy, coculturing of healthy cardiocytes with cardiocytes rendered apoptotic via extrinsic pathways revealed a clearance mechanism that to our knowledge has not previously been described. Cultured fetal cardiocytes expressed phosphatidylserine receptors (PSRs), as did cardiac tissue from a fetus with congenital heart block (CHB) and an age-matched control. Phagocytic uptake was blocked by anti-PSR antibodies and was significantly inhibited following preincubation of apoptotic cardiocytes with chicken and murine anti-SSA/Ro and -SSB/La antibodies, with IgG from an anti-SSA/Ro- and -SSB/La-positive mother of a CHB child, but not with anti-HLA class I antibody. In a murine model, anti-Ro60 bound and inhibited uptake of apoptotic cardiocytes from wild-type but not Ro60-knockout mice. Our results suggest that resident cardiocytes participate in physiologic clearance of apoptotic cardiocytes but that clearance is inhibited by opsonization via maternal autoantibodies, resulting in accumulation of apoptotic cells, promoting inflammation and subsequent scarring.
Clancy
Robert M
RM
Department of Medicine, Division of Rheumatology, New York University School of Medicine, New York, New York 10016, USA. bodbclancy@aol.com
Neufing
Petra J
PJ
Zheng
Ping
P
O'Mahony
Marguerita
M
Nimmerjahn
Falk
F
Gordon
Tom P
TP
Buyon
Jill P
JP
D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis / Q000502:physiology*; D001324:Autoantigens / Q000276:immunology*; D002462:Cell Membrane / Q000502:physiology; D002467:Cell Nucleus / Q000502:physiology; D002648:Child; D005260:Female; D047109:Fetal Development; D006321:Heart / Q000196:embryology* / Q000502:physiology; D006327:Heart Block / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D006330:Heart Defects, Congenital / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000302:isolation & purification; D051379:Mice; D009206:Myocardium / Q000473:pathology*; D012016:Reference Values; D012261:Ribonucleoproteins / Q000276:immunology*; D019014:fas Receptor / Q000502:physiology; D000097585:SS-B Antigen; D000099207:SS-A Antigen
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D007074:Immunoglobulin G; D012261:Ribonucleoproteins; D019014:fas Receptor; D000097585:SS-B Antigen; D000099207:SS-A Antigen