Identification of isolated congenital heart block (CHB) in a fetus predicts with near certainty that the mother, who may have a rheumatic disease or be asymptomatic, will have autoantibodies (Ab) to SSA/Ro ribonucleoproteins. CHB, a pathologic readout of passively acquired autoimmunity, provides an exceptional opportunity to examine the effector arm of immunity and define the mechanism whereby an Ab mediates fibrosis, which is particularly aberrant in fetal wounding. The study of CHB exemplifies not only translational research, which draws upon clinical clues and explores them in the laboratory, but integrational research which attempts to fit key clinical and basic observations together. In the previous funding periods we leveraged several rare fetal/neonatal autopsy specimens to interrogate clues to pathogenesis. Exaggerated apoptosis, macrophage/myfibroblast crosstalk, TGF? expression, and extensive fibrosis in the conduction system (and, in some, the surrounding myocardium) of CHB-hearts, provided in vivo support for parallel in vitro investigation. Positing apoptosis as the initial link between Ab and tissue injury led to the first-time observation that healthy cardiocytes are capable of phagocytosing apoptotic cardiocytes, and that anti-Ro/La Abs inhibit this function. That this perturbation of physiologic efferocytosis diverts uptake to professional Fc?R-bearing phagocytes fits well with ongoing experiments demonstrating macrophage secretion of pro-inflammatory and fibrosing cytokines when coincubated with apoptotic cardiocytes bound by anti-Ro/La Ab. The macrophage engagement of Toll-like receptors (TLR) via binding to the RNA moiety of the target autoantigen was suggested by recent experiments. The potential for relative oxygen insult during pregnancy, and the need to explain CHB- discordance in monozygotic twins, directed attention to hypoxia as an amplification factor on the distal fibrosing component. Footprints of hypoxic injury comprised expression of hypoxia-inducible factor (HIF)-?1 in affected hearts and increased erythropoietin levels in several CHB-cord bloods.
In Aim 1, the specificity and mechanism of anti-Ro/La Ab in inhibiting efferocytosis by autologous human fetal cardiocytes will be evaluated. It is hypothesized that binding of anti-Ro/La Ab to apoptotic cardiocytes not only inhibits clearance but, by opsonizing these cells, provides the immune complex for subsequent uptake by professional phagocytes.
In Aim 2, the nexus of Fc? receptor (Fc?R) and TLR signaling following macrophage uptake of opsonized apoptotic cardiocytes will be addressed with regard to release of mediators that promote inflammation and fibrosis. The hypothesis driving this aim is that opsonization of apoptotic cardiocytes induces macrophage uptake by an Fc?R-dependent pathway and activation via TLR ligation, which set in motion the final step to irreversible scar. The experiments of Aim 3 address the mechanism by which the inflammatory cascade initiated by anti-Ro/La Abs induces a persistent fibrosing phenotype in the cardiac fibroblast. The hypothesis is that macrophage products prime the fibroblast toward scar, which is further abetted by an in utero stress such as hypoxia. Fetuses of mothers who are otherwise healthy or who suffer from a rheumatic disease but have autoantibodies to SSA/Ro are at risk for having permanent heart damage, which requires permanent pacing at some point in life or can be fatal. Understanding the mechanism by which these autoantibodies cause cardiac scarring is critical to the development of strategies for treatment or prevention of this condition, known as congenital heart block.
Fetuses of mothers who are otherwise healthy or who suffer from a rheumatic disease but have autoantibodies to SSA/Ro are at risk for having permanent heart damage, which requires permanent pacing at some point in life or can be fatal. Understanding the mechanism by which these autoantibodies cause cardiac scarring is critical to the development of strategies for treatment or prevention of this condition, known as congenital heart block.
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