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.
Neuropsychiatric manifestations of lupus occur in approximately 80% of lupus patients and contribute significantly to the burden of disease. These studies reveal mechanisms of NPSLE, test therapeutic strategies and develop metrics for clinical trials. Project 1: Modeling variable outcomes of antibody exposure Project Leader (PL): Bruce Volpe DESCRIPTION (as provided by applicant): This project will further our studies of the contribution of cross-reactive anti-DNA anti-N- methyl-D-aspartate receptor (NMDAR) antibodies, denoted DNRAbs, to neuropsychiatric lupus (NPSLE). NPSLE affects approximately 80% of lupus patients and substantially diminishes quality of life. We previously pioneered models for DNRAb-mediated fixed cognitive or behavioral impairment;we will now develop a model of DNRAb-mediated transient impairment. Based on our observation of variable DNRAb concentration in cerebrospinal fluid of lupus patients, we will explore the concentration of tissue penetrating antibody in reversible and irreversible damage. We will explore the contribution of NMDAR subunit composition to reversible and irreversible damage and will determine whether there can be irreversible injury in the absence of neuronal death. We propose the highly novel hypothesis that microglia are altered in NPSLE as a consequence of ingesting apoptotic neurons and microglial activation functions to sustain neuronal damage. Finally, we will explore therapeutic strategies for preventing irreversible brain injury. These studies will develop new paradigms for antibody-mediated brain disease. We will utilize standard methodologies such as electrophysiology in hippocampal slice preparation, behavioral and cognitive testing and immunocytochemistry. We will pioneer the use of in vivo electrophysiology, microPET studies in a mouse model of NPSLE and RNA-seq of microglial cells.
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|Honig, Gerard; Mader, Simone; Chen, Huiyi et al. (2016) Blood-Brain Barrier Deterioration and Hippocampal Gene Expression in Polymicrobial Sepsis: An Evaluation of Endothelial MyD88 and the Vagus Nerve. PLoS One 11:e0144215|
|Malkiel, Susan; Jeganathan, Venkatesh; Wolfson, Stacey et al. (2016) Checkpoints for Autoreactive B Cells in the Peripheral Blood of Lupus Patients Assessed by Flow Cytometry. Arthritis Rheumatol 68:2210-20|
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