Congenital heart block (CHB) is a devastating condition, in which a normally developing fetus suffers irreversible damage to the heart in utero. This damage is caused by transplacental passage of maternal IgG autoantibodies (aAbs) directed against components of the Ro/SSA-La/SSB ribonucleoprotein complex. To date, no preventive therapies have been developed. Theoretically, blocking the pathogenic aAbs pharmacologically during the 8-week period of susceptibility in gestation would be expected to prevent CHB. The knowledge gap that impedes the development of this therapy is that the diversity of pathogenic epitopes targeted by the aAbs is unknown: if there are only one or two pathogenic epitopes, a single biologic (protein therapeutic) may prevent CHB. The goal of this proposal is to characterize the diversity of pathogenic epitopes targeted by anti-Ro aAbs, focusing on patients considered most likely to have the highest risk aAbs; women who have had two or more children with CHB and/or women whose fetus has died in utero from the condition. We will take the novel approach of isolating monoclonal antibodies (mAbs) from the blood of these patients as a way of sampling their polyclonal anti-Ro aAb population. We have already isolated the first human anti-Ro mAbs. These mAbs will be tested on human fetal cardiac myocytes to assess their pathogenic potential. We hypothesize that the pathogenic anti-Ro Abs in these patients target a limited number of pathogenic epitopes, therefore, a therapeutic strategy to block them with one or a few rationally designed peptides may be feasible. Since mAbs are isolated from circulating memory B-cells and plasma cells, our data may elucidate the cellular source of pathogenic aAbs in CHB as well as many other related autoimmune diseases. This research proposal outlines the first steps of a new research direction in the field of aAb-mediated autoimmunity and in CHB. Concurrently, the sponsor, collaborating scientists and research techniques addressed in this existing research program constitute an outstanding environment for pre-doctoral training.
Congenital heart block affects the fetuses of women with clinically silent or obvious antibody-mediated autoimmune disease, wherein pathogenic autoantibodies cross the placenta and irreversibly damage the heart of the fetus. We have devised a research strategy to provide the knowledgebase on the scope of reactivity of the causal autoantibodies necessary to prevent this condition.
|Martinez-Ortiz, Wilnelly; Cardozo, Timothy J (2018) An Improved Method for Modeling Voltage-Gated Ion Channels at Atomic Accuracy Applied to Human Cav Channels. Cell Rep 23:1399-1408|
|Sisirak, Vanja; Sally, Benjamin; D'Agati, Vivette et al. (2016) Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity. Cell 166:88-101|
|Markham, Androo J; Rasmussen, Sara E; Salmon, Jane E et al. (2015) Reactivity to the p305 Epitope of the ?1G T-Type Calcium Channel and Autoimmune-Associated Congenital Heart Block. J Am Heart Assoc 4:|