Project 3: Abstract We have shown that antibodies cross-reactive with DNA and the N-methyl D-aspartate receptor (NMDAR), termed DNRAbs and present in approximately 30% of patients with Systemic Lupus Erythematosus, can exit the maternal circulation, enter the fetal circulation and the fetal brain leading to the death of female fetuses and impaired cognition in male offspring. We now propose to understand the mechanism of DNRAb-mediated brain injury in female and male fetuses and whether FcR-mediated mechanisms are involved. We will also determine the contribution of each of the NMDAR subunits, GluN2A and GluN2B, both of which are targets of DNRAb, to the antibody-mediated damage. Finally, we have demonstrated that some mutations in the Fc portion of IgG render an antibody unable to cross the placenta and enter the fetal circulation. We will attach NMDAR subunits or DWEYS peptide to these Fc constructs to create a decoy antigen that will not cross the placenta in order to develop a strategy to protect the fetus from maternal DNRAb. This last goal could lead to a generalizable strategy to protect a fetus from maternal antibody with pathogenic potential.

Project 3 Narrative: We have shown that lupus antibodies, DNRAbs, with specificity for DNA and the N-methyl-D- aspartate receptor can cause death of female fetuses and cognitive impairment in male offspring. We will determine the mechanism of antibodies-mediated fetal brain injury and develop a strategy to protect the fetuses from these antibodies when they are present in maternal circulation.