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Background Neuropsychiatric systemic lupus erythaematosus (NP-SLE) is one of the major manifestations of lupus. However, the mechanisms involved in NP-SLE are still largely unknown. The abnormal activation of the type I IFN signalling pathway is involved in SLE pathogenesis and is linked to NP-SLE, but the effect of IFN-α on NP-SLE encephalopathy has not been systematically studied. Methods An intravenous injection of Adv-IFN-α (10 mice, 10 × 10 9 vp) was administered to the IFN-α-treated group, and Adv-ctrl (10 mice, 10 × 10 9 vp) (ViGene Biosciences, China) was administered to the control group. Gene expression was determined by real-time quantitative polymerase chain reaction (RT-qPCR). Enzyme-linked immunosorbent assay (ELISA) was used to detect antibodies in the serum, and urinary protein levels were measured with a BCA Protein Assay kit. Haematoxylin-eosin (H&E) and periodic acid-Schiff (PAS)-light green staining were used for kidney histology. The elevated plus-maze test, novelty-suppressed feeding assay, open-field test, tail suspension test, social dominance tube test, three-chamber social interaction test, step-down passive avoidance test and novelty Y-maze task were used to assess behaviour. Results In this study, we performed a series of behavioural tests to assess the neuropsychiatric phenotypes of IFN-α-treated NZB/NZW F1 mice and found that these mice developed a series of mental disorders such as anxiety-like phenotypes, depression-like phenotypes, deficits in sociability and cognitive impairments, which mimic the neuropsychiatric manifestations of NP-SLE, with a consistent onset and progression. Conclusions Our research verified that IFN-α plays a critical role in NP-SLE and provides a comprehensive NP-SLE mouse model for dissecting the mechanisms of NP-SLE and developing novel therapies for intervention.

Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) affect over one-half of SLE patients, yet underlying mechanisms remain largely unknown. We demonstrate that SLE-prone mice (CReCOM) develop NP-SLE, including behavioral deficits prior to systemic autoimmunity, reduced brain volumes, decreased vascular integrity, and brain-infiltrating leukocytes. NP-SLE microglia exhibit numerical expansion, increased synaptic uptake, and a more metabolically active phenotype. Microglia from multiple SLE-prone models express a \"NP-SLE signature\" unrelated to type I interferon. Rather, the signature is associated with lipid metabolism, scavenger receptor activity and downregulation of inflammatory and chemotaxis processes, suggesting a more regulatory, anti-inflammatory profile. NP-SLE microglia also express genes associated with disease-associated microglia (DAM), a subset of microglia thought to be instrumental in neurodegenerative diseases. Further, expression of \"NP-SLE\" and \"DAM\" signatures correlate with the severity of behavioral deficits in young SLE-prone mice prior to overt systemic disease. Our data are the first to demonstrate the predictive value of our newly identified microglia-specific \"NP-SLE\" and \"DAM\" signatures as a surrogate for NP-SLE clinical outcomes and suggests that microglia-intrinsic defects precede contributions from systemic SLE for neuropsychiatric manifestations.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multi-systemic involvement. Nervous system involvement in SLE leads to a series of uncommon and heterogeneous neuropsychiatric (NP) manifestations. Current knowledge on the underlying pathogenic processes and their subsequent pathophysiological changes leading to NP-SLE manifestations is incomplete. Several putative laboratory biomarkers have been proposed as contributors to the genesis of SLE-related nervous system damage. Alongside the laboratory biomarkers, several neuroimaging tools have shown to reflect the nature of tissue microstructural damage associated with SLE, and thus were suggested to contribute to the understanding of the pathophysiological changes and subsequently help in clinical decision making. However, the number of useful biomarkers in NP-SLE in clinical practice is disconcertingly modest. In some cases it is not clear whether the biomarker is truly involved in pathogenesis, or the result of non-specific pathophysiological changes in the nervous system (e.g., neuroinflammation) or whether it is the consequence of a concomitant underlying abnormality related to SLE activity. In order to improve the diagnosis of NP-SLE and provide a better targeted care to these patients, there is still a need to develop and validate a range of biomarkers that reliably capture the different aspects of disease heterogeneity. This article critically reviews the current state of knowledge on laboratory and neuroimaging biomarkers in NP-SLE, discusses the factors that need to be addressed to make these biomarkers suitable for clinical application, and suggests potential future research paths to address important unmet needs in the NP-SLE field.

Background One of the more profound features of systemic lupus erythematosus (SLE) is that females have a 9:1 prevalence of this disease over males. Up to 80% of SLE patients have cognitive defects or affective disorders. The mechanism of CNS injury responsible for cognitive impairment is unknown. We previously showed that ERα deficiency significantly reduced renal disease and increased survival in lupus-prone mice. We hypothesized that ERα deficiency would be similarly protective in the brain, and that ERα may play a role in modulating blood-brain barrier (BBB) integrity and/or neuroinflammation in lupus-prone mice. Methods MRL/lpr ERα+/+ and ERαKO mice (n = 46) were ovariectomized, received 17β-estradiol pellets, and underwent radial arm water maze (WRAM) and novel object recognition (NOR) testing starting at eight weeks of age. Mice were sacrificed and brains were hemisected and processed for either immunohistochemistry, or hippocampus and parietal cortex dissection for Western blotting. Results MRL/lpr ERαKO mice (n = 21) performed significantly better in WRAM testing than wild-type MRL/lpr mice (n = 25). There was a significant reduction in reference memory errors ( P <0.007), working memory errors ( P <0.05), and start arm errors ( P <0.02) in ERαKO mice. There were significant differences in NOR testing, particularly total exploration time, with ERα deficiency normalizing behavior. No significant differences were seen in markers of tight junction, astrogliosis, or microgliosis in the hippocampus or cortex by Western blot, however, there was a significant reduction in numbers of Iba1+ activated microglia in the hippocampus of ERαKO mice, as evidenced by immunohistochemietry (IHC). Conclusion ERα deficiency provides significant protection against cognitive deficits in MRL/lpr mice as early as eight weeks of age. Additionally, the significant reduction in Iba1+ activated microglia in the MRL/lpr ERαKO mice was consistent with reduced inflammation, and may represent a biological mechanism for the cognitive improvement observed.

Objective: To determine whether single photon emission tomography (SPECT) and magnetic resonance spectroscopy (1H-MRS) can predict the appearance of new lesions in systemic lupus erythematosus (SLE), detectable by magnetic resonance imaging (MRI). Methods:99Tcm-HMPAO-SPECT, brain MRI, and 1H-MRS were done in eight women with SLE (mean age 31.8 years; disease duration 5.5 years). NAA/Cho, NAA/Cre, and Cho/Cre ratios were assessed in hypoperfused and normoperfused areas detected by SPECT that were normal on MRI examination. Reference values were obtained in 20 normal healthy controls. In five patients, MRI was repeated four to six years after the first evaluation. Results: Mean NAA/Cho and Cho/Cre ratios in hypoperfused and normoperfused frontal areas were, respectively, lower and higher than control. There were no differences in NAA/Cre ratios. Mean Cho/Cre ratios were increased in hypoperfused v normoperfused brain areas (mean (SD): 1.43 (0.27) v 1.00 (0.07); p<0.023). NAA/Cre ratios were not altered (2.18 (0.30) v 1.99 (0.28); p = 0.381). Three of five patients who had a second MRI had new lesions in areas previously abnormal on MRS and SPECT but normal on first MRI. One patient with positive MRI, SPECT, and MRS showed an increase in the number of MRI lesions; one patient with negative MRI, SPECT, and MRS did not show any new lesions. Conclusions: Abnormalities reflecting altered perfusion or neuronal-chemical changes can be demonstrated by functional imaging techniques even in the absence of morphological lesions detectable by MRI. The abnormal areas identified by SPECT and MRS may predict future parenchymal damage.

MRI and 2D-CSI spectroscopy were performed in eight patients with systemic lupus erythematosus who presented with acute onset of neuropsychiatric lupus (NP-SLE), and in seven normal controls to evaluate for differences in metabolic peaks and metabolic ratios between the two groups. Also, the interval change of the metabolic peaks and their ratios during treatment in the NP-SLE patient group was evaluated. Metabolic peaks for N-acetyl-aspartate (NAA), choline (Cho), creatine (Cr), and lactate/lipids (LL) and their ratios (NAA/Cr, NAA/Cho, Cho/Cr, LL/Cr) were determined at initial presentation and 3 and 6 months later. In the eight lupus patients compared to the seven normal controls, NAA/Cho ratios were lower at presentation (1.05 vs 1.25; p = 0.004) and decreased even further at the three month follow-up (0.92 vs 1.05; p = 0.008). In contrast, both Cho/Cr (1.42 vs 1.26; p = 0.026) and LL/Cr ratios (0.26 vs 0.19; p = 0.002) were higher in the lupus patients at presentation compared to the controls and did not significantly change at three and six months follow-up. The NAA/Cr ratios were lower in the lupus patients compared to the controls at presentation but the difference was not statistically significant. However, the mean NAA/Cr significantly decreased from the initial examination to the three month follow-up (1.42 vs 1.32; p = 0.049) but did not significantly change from the three to the six month follow-up examinations. The NAA/Cr, Cho/Cr, and NAA/Cho ratios varied significantly (p < 0.05, p < 0.05, p < 0.05, respectively) between the 17 different locations measured in the brain in all eight patients and seven controls. Both the NAA/Cr ratios and the Cho/Cr ratios were also significantly lower in the gray matter than in the white matter (p < 0.0001) in both patients and controls, whereas the LL/Cr and NAA/Cho ratios were not significantly different. In conclusion, 2D-CSI MR spectroscopy may be useful in the early detection of metabolic CNS changes in NP-SLE patients with acute onset of new neurological symptoms as well as in the follow-up after treatment to assess presence and changes in metabolic brain injury. However, although there are detectable differences between normal individuals and lupus patients it is currently unclear whether these relate to the acute episode. Future studies are needed comparing NP-SLE patients with active CNS involvement with those inactive disease.

Cerebellar vasculopathy is an uncommon but clinically important neuropsychiatric syndrome of systemic lupus erythematosus (NP-SLE) for its ominous outcome and need for prompt interventions. We described a young Chinese lady with systemic lupus erythematosus and normal tension glaucoma, who had sudden headache, nausea and vomiting coupled with rapid neurological deterioration leading to comatose status. Diagnosis of lupus cerebellar vasculopathy was made and intense immunosuppressive therapy consisting of prednisolone and cyclophosphamide was commenced. Clinical condition was salvaged with marked improvement of both sensorium and general well-being.