Dying right to live longer: positing apoptosis as a link between maternal autoantibodies and congenital heart block

Abstract

The association of isolated congenital heart block (CHB) with maternal autoantibodies to SSA/Ro and SSB/La ribonucleoproteins is approaching the predictable, even in mothers who are completely asymptomatic. Indeed, this model of passively acquired autoimmunity offers an exceptional opportunity to examine the effector arm of immunity and define the pathogenicity of an autoantibody in mediating tissue injury. The study of CHB exemplifies not only translational research, which inherently draws upon clinical observations and explores them in the laboratory, but “integrational” research which attempts to fit critical clinical and basic observations together, even those seemingly at odds. The spectrum of conduction abnormalities includes second and third-degree block, but injury can extend to the myocardium and endocardium, in rare cases without AV nodal dysfunction. The rarity of disease continues to drive the search for factors (fetal and environmental) that might amplify the effects of the maternal autoantibodies. The identification of exaggerated apoptosis, macrophage/myfibroblast crosstalk, TGFβ expression, and extensive fibrosis in the conducting system and in some cases surrounding myocardium in fetuses dying with CHB, provide in vivo support for several parallel lines of in vitro investigation. Specifically, the consideration of exaggerated apoptosis as the initial link between maternal antibody and tissue injury led to the observation that cardiocytes are capable of phagocytosing autologous apoptotic cardiocytes and anti-Ro/La antibodies inhibit this function. Recognizing that this perturbation of physiologic efferocytosis might divert uptake to professional FcγR-bearing phagocytes fits well with experiments demonstrating macrophage secretion of pro-inflammatory and fibrosing cytokines when coincubated with apoptotic cardiocytes bound by Ro/La antibodies. While CHB is rare, its study should set precedent for defining the role of autoantibodies in driving end organ disease. Lupus (2008) 17, 86—90.

Keywords

CHB anti-SSA/Ro anti-SSB/La neonatal lupus

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