Baseline Elevations of Leukotriene Metabolites and Altered Plasmalogens Are Prognostic Biomarkers of Plaque Progression in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is associated with an increased incidence of acute and chronic cardiovascular disease as compared to the general population. This study uses a comprehensive metabolomic screen of baseline sera from lupus patients to identify metabolites that predict future carotid plaque progression, following 8-9 years of follow-up. Nine patients had SLE without plaque progression, 8 had SLE and went on to develop atherosclerotic plaques (SLEPP), and 8 patients were controls who did not have SLE. The arachidonic acid pathway metabolites, leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acid (5-HETE), and the oxidized lipids 9/13-hydroxyoctodecadienoic acid (HODE) were found to be significantly altered (p < 0.05 and fold-change >2) in SLEPP patients compared to SLE patients without plaque progression. SLEPP patients also exhibited significantly altered levels of branched chain amino acid (BCAA) metabolites and plasmalogens compared to the non-SLE controls. Taken together with the rich literature on these metabolites, these findings suggest that the identified metabolites may not only be prognostic of cardiovascular disease development in SLE patients, but they may also be active drivers of atheroma formation. Early identification of these high risk SLE patients may help institute preventive measures early in the disease course.

Aptamer-Based Screen of Neuropsychiatric Lupus Cerebrospinal Fluid Reveals Potential Biomarkers That Overlap With the Choroid Plexus Transcriptome.

OBJECTIVE: As no gold-standard diagnostic test exists for neuropsychiatric systemic lupus erythematosus (NPSLE), we undertook this study to execute a broad screen of NPSLE cerebrospinal fluid (CSF) using an aptamer-based platform. METHODS: CSF was obtained from NPSLE patients and subjected to proteomic assay using the aptamer-based screen. Potential biomarkers were identified and validated in independent NPSLE cohorts in comparison to other neurologic diseases. RESULTS: Forty proteins out of the 1,129 screened were found to be elevated in NPSLE CSF. Based on enzyme-linked immunosorbent assay validation, CSF levels of angiostatin, α2-macroglobulin, DAN, fibronectin, hepatocellular carcinoma clone 1, IgM, lipocalin 2, macrophage colony-stimulating factor (M-CSF), and serine protease inhibitor G1 were significantly elevated in a predominantly White NPSLE cohort (n = 24), compared to patients with other neurologic diseases (n = 54), with CSF IgM (area under the curve [AUC] 0.95) and M-CSF (AUC 0.91) being the most discriminatory proteins. In a second Hong Kong-based NPSLE cohort, CSF IgM (AUC 0.78) and lipocalin 2 (AUC 0.85) were the most discriminatory proteins. Several CSF proteins exhibited high diagnostic specificity for NPSLE in both cohorts. Elevated CSF complement C3 was associated with an acute confusional state. Eleven molecules elevated in NPSLE CSF exhibited concordant elevation in the choroid plexus, suggesting shared origins. CONCLUSION: Lipocalin 2, M-CSF, IgM, and complement C3 emerge as promising CSF biomarkers of NPSLE with diagnostic potential.

Neuroprotection by Heat Shock Factor-1 (HSF1) and Trimerization-Deficient Mutant Identifies Novel Alterations in Gene Expression.

Heat shock factor-1 (HSF1) protects neurons from death caused by the accumulation of misfolded proteins by stimulating the transcription of genes encoding heat shock proteins (HSPs). This stimulatory action depends on the association of trimeric HSF1 to sequences within HSP gene promoters. However, we recently described that HSF-AB, a mutant form of HSF1 that is incapable of either homo-trimerization, association with HSP gene promoters, or stimulation of HSP expression, protects neurons just as efficiently as wild-type HSF1 suggesting an alternative neuroprotective mechanism that is activated by HSF1. To gain insight into the mechanism by which HSF1 and HSF1-AB protect neurons, we used RNA-Seq technology to identify transcriptional alterations induced by these proteins in either healthy cerebellar granule neurons (CGNs) or neurons primed to die. When HSF1 was ectopically-expressed in healthy neurons, 1,211 differentially expressed genes (DEGs) were identified with 1,075 being upregulated. When HSF1 was expressed in neurons primed to die, 393 genes were upregulated and 32 genes were downregulated. In sharp contrast, HSF1-AB altered expression of 13 genes in healthy neurons and only 6 genes in neurons under apoptotic conditions, suggesting that the neuroprotective effect of HSF1-AB may be mediated by a non-transcriptional mechanism. We validated the altered expression of 15 genes by QPCR. Although other studies have conducted RNA-Seq analyses to identify HSF1 targets, our study performed using primary neurons has identified a number of novel targets that may play a special role in brain maintenance and function.