This proposal is to continue studies of a subset of anti-DNA antibodies, termed DNRAbs, that cross-react with the N-methyl-D-aspartate receptor and contribute to neuropsychiatric SLE (NPSLE). The first 5 years of the Program provided the first mechanistic model for antibody mediated injury in NPSLE, demonstrating in mice that DNRAbs could cause both cognitive and behavioral impairments. DNRAbs are present in cerebrospinal fluid (CSF) and brain tissue of patients with NPSLE and titers in CSF correlate with symptom severity. We have also developed a small molecule competitive inhibitor of antibody binding. We propose over the next 5 years to develop a model for reversible functional brain impairment as well as fixed functional impairment. In Project 1, we will determine the contribution of antibody concentration and NMDAR subunit composition to reversible and irreversible injury. We will test whether neuron loss is a prerequisite for fixed impairment or whether DNRAbs- mediated effects can lead to persistent neuronal dysfunction in its absence. We will explore the activation of microglial cells that have ingested dead neurons and their role in maintaining neuronal dysfunction. In Project 2, we will explore the potential for neuroimaging to distinguish DNRAb-mediated damage from other insults in NPSLE. We will explore progression of brain dysfunction through imaging and neuropsychiatric testing. We will develop an imaging metric to use as an outcome measure in trials of NPSLE and DNRAb blockade. In Project 3, we will begin to explore effects of DNRAbs on pituitary cells not protected by a blood brain barrier and the capacity of DNRAbs to augment prolactin production. Because prolactin levels are high in 20 to 25% of SLE patients and because prolactin leads to a more autoreactive B cell repertoire, we will test whether decoy antigens can lead to reduced serum prolactin and might perhaps lead to diminished autoreactivity. These studies derive from extensive published and preliminary data and will continue to develop paradigms for NPSLE. The coordinated study of mice and patients enriches our understanding of pathogenesis, validates our mouse model, and provides an opportunity for future testing of therapeutic agents.