Anti-DFS70/LEDGF Antibodies Are More Prevalent in Healthy Individuals Compared to Patients with Systemic Autoimmune Rheumatic Diseases

Objective.Antinuclear antibodies (ANA) are a serological hallmark of systemic autoimmune rheumatic diseases (SARD) such as systemic lupus erythematosus (SLE). While a number of ANA patterns detected by indirect immunofluorescence (IIF) have diagnostic significance, autoantibodies producing the dense fine speckled (DFS) pattern have been reported to be more prevalent in healthy individuals than in SARD.Methods.Sequential samples submitted for ANA testing were screened for anti-DFS antibodies by IIF (n = 3263). Samples with the DFS pattern were tested for anti-DFS70/lens epithelium–derived growth factor (LEDGF) antibodies by ELISA and by a novel chemiluminescence assay (CIA, Quanta Flash DFS70). Sera from patients with various diseases and healthy individuals were tested for anti-DFS70/LEDGF antibodies by CIA. A cohort of 251 patients with SLE was used to analyze serological and clinical associations of anti-DFS70 antibodies.Results.The frequency of anti-DFS antibodies by IIF was 1.62%. The prevalence of anti-DFS70/LEDGF antibodies as detected by CIA in the different cohorts was 8.9% in healthy individuals, 2.8% in SLE, 2.6% in rheumatoid arthritis, 4.0% in asthma, 5.0% in interstitial cystitis, 1.7% in Graves' disease, and 6.0% in Hashimoto's thyroiditis. Of note, the prevalence of anti-DFS70/LEDGF antibodies was significantly higher in healthy individuals compared to patients with SARD (p = 0.00085). In SLE results, anti-DFS70/LEDGF antibodies were not significantly associated with clinical features or other autoantibodies typically found in SLE. Only 1/7 SLE sera showed anti-DFS70/LEDGF, but no other autoantibody reactivity.Conclusion."Monospecific" anti-DFS70/LEDGF antibodies may represent a biomarker for differentiating SARD from non-SARD individuals, but there is a need for a reliable assay to ensure reactivity to DFS70

The Role of Arc in Regulating Spine Morphology and Neural Network Stability In Vivo

The understanding of human memory is one of the greatest challenges facing neuroscience today. The brain's extraordinary ability to integrate information and appropriately adapt in response to various stimuli is at the core of learning and memory. At a cellular and molecular level, learning and memory relies on a neuron's ability to facilitate activity-dependent changes in synaptic efficacy. In order to better understand the mechanism behind such changes, we investigate the function of Arc, an immediate-early gene essential for both long-term and homeostatic plasticity. We find that through AMPA receptor endocytosis, Arc expression modulates spine morphology to favor more plastic thin spines and filopodia. Thus, Arc expression simultaneously reduces synaptic efficacy through AMPA receptor endocytosis while increasing structural plasticity by favoring thin spines. Supporting this, we find that loss of Arc in vivo leads to a decrease in the proportion of thin spines as well as neural network hyperexcitability. Given Arc's role in spine morphology we also investigate possible actin-regulating Arc-binding partners. We find that Arc directly binds to Wave3, an actin-nucleating factor, in neurons. We further demonstrate that reduction of Wave3 expression leads a marked decrease in primary dendrite length. In mature neurons, reduction of Wave3 results in decreased spine density and increased filopodia. Finally, Arc expression partially rescued these reductions in primary dendrite length and spine density, supporting a functional role for the Arc-Wave3 interaction. Thus, our investigations of Arc and Wave3 have contributed to the understanding of synaptic plasticity, and suggest new links between synaptic efficacy, structural plasticity, homeostasis and memory

Arc in the nucleus regulates PML-dependent GluA1 transcription and homeostatic plasticity

The activity-regulated cytoskeletal protein Arc/Arg3.1 is required for long-term memory formation and synaptic plasticity. Arc expression is robustly induced by activity, and Arc protein localizes both to active synapses and the nucleus. While its synaptic function has been examined, it is not clear why or how Arc is localized to the nucleus. We found that murine Arc nuclear expression is regulated by synaptic activity in vivo and in vitro. We identified distinct regions of Arc that control its localization, including a nuclear localization signal, a nuclear retention domain, and a nuclear export signal. Arc localization to the nucleus promotes an activity-induced increase in promyelocytic leukemia nuclear bodies, which decreases GluA1 transcription and synaptic strength. Finally, we show that Arc nuclear localization regulates homeostatic plasticity. Thus, Arc mediates the homeostatic response to increased activity by translocating to the nucleus, increasing promyelocytic leukemia levels, and decreasing GluA1 transcription, ultimately downscaling synaptic strength