Antibody-triggered mouse models of neuropsychiatric lupus: heterogeneity, mechanisms and therapeutic approaches

Abstract - Project 1: Antibody-triggered mouse models of neuropsychiatric lupus: heterogeneity, mechanisms and therapeutic approaches This project will continue to develop murine models of neuropsychiatric lupus (NPSLE) that phenocopy the human disease and are initiated by penetration of anti-DNA, anti-N methyl D-aspartate antibodies (DNRAbs) into brain parenchyma. We have previously developed and characterized a model with hippocampal injury and memory dysfunction. We propose to characterize a model with injury in the amygdala and anxiety and will try to develop a model with depression and fatigue. In all models, we will characterize glial neuronal interactions. We will determine if agonism of the aryl hydrocarbon receptor is a therapeutic strategy for brain inflammation or if, in fact, it exacerbates the inflammatory process. We will determine whether, and how, type 1 interferon contributes to brain pathology. Finally, we will utilize a microglia-neuron co-culture system to understand the contribution of particular pathways to the in vivo pathology. These studies interdigitate with our studies of patients, Both projects are designed to understand disease heterogeneity and the cellular and molecular basis for major manifestations of disease, cognitive impairment, anxiety, depression and fatigue, and to develop therapeutic strategies that take heterogeneity of pathogenetic mechanism into account.