Analysis of Neuron-derived Blood Exosomes in Anti-n-methyl-d-aspartate Receptor Encephalitis and Neuropsychiatric Lupus
Ryan Kammeyer1, Kimberly Chapman1, Jennifer Cooper2, Susan Boackle3, Maxwell McCabe1, Sean Selva1, Alanna Ritchie1, Kavita Nair1, JoAnn Zell1, Ekemini Ogbu4, Andrea Knight5, Joaquin Espinosa1, Jeffrey Bennett1, Robert Fuhlbrigge2, Amanda Piquet1, Christina Coughlan1
1University of Colorado School of Medicine, 2Children's Hospital Colorado, 3Physician-Scientist, Rheumatology, 4Cincinnati Children's Hospital Medical Center, 5Division of Rheumatology, University of Toronto Temerty Faculty of Medicine
Objective:
To identify novel minimally invasive biomarkers of disease for anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) and neuropsychiatric lupus (NPSLE) using neuron-derived blood exosomes.
Background:
NMDARE and NPSLE are driven by neuroinflammation and can cause significant morbidity and mortality. New minimally invasive biomarkers are needed to facilitate earlier diagnosis, identify disease mechanisms and drug targets, and monitor efficacy of interventions. Exosomes secreted by neurons contain proteins and other cargo that reflect the biochemical processes occurring within neurons. Analysis of these exosomes from peripheral blood may provide unique insights into the development and etiology of NMDARE and NPSLE.
Design/Methods:
In a case-control pilot study, we compared neuronal exosomes from the serum and/or plasma of healthy controls, controls with SLE without prior/active NPSLE (non-NPSLE), active NMDARE, and active NPSLE. Active disease was defined as <6 months from last new/worsening neuropsychiatric symptom. The NPSLE syndromes of interest included strokes, demyelination, cranial neuropathy, and aseptic meningitis. Demographics and clinical data were obtained for each participant. Biosamples underwent immunoprecipitation and immunopurification for neuron-derived exosomes using a patent-pending magnetic bead separation technique. Proteomic analysis was performed using liquid chromatography tandem mass spectrometry. Relative protein abundance was compared between disease/control groups with a false discovery rate (FDR) of <1% considered significant. Gene Set Enrichment Analysis was used to identify pathways that were up or downregulated in the disease states with FDR <25% considered significant.
Results:
Six participants were identified for each disease and control group. 24 proteins were significantly different between NMDARE and healthy controls, and 2 were significant between NPSLE and non-NPSLE. 7 pathways were significantly enriched in NMDARE compared to healthy controls, and 1 pathway in NPSLE compared to non-NPSLE. These proteins and pathways are associated with neuronal or local inflammation, cell death, and endothelial dysfunction/coagulation.
Conclusions:
Neuron-derived blood exosomes may provide novel and minimally invasive disease biomarkers for NMDARE and NPSLE.
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