Personalized therapy design for systemic lupus erythematosus based on the analysis of protein-protein interaction networks.

We analyzed protein expression data for Lupus patients, which have been obtained from publicly available databases. A combination of systems biology and statistical thermodynamics approaches was used to extract topological properties of the associated protein-protein interaction networks for each of the 291 patients whose samples were used to provide the molecular data. We have concluded that among the many proteins that appear to play critical roles in this pathology, most of them are either ribosomal proteins, ubiquitination pathway proteins or heat shock proteins. We propose some of the proteins identified in this study to be considered for drug targeting.

Elevated Microparticle Tissue Factor Activity Differentiates Patients With Venous Thromboembolism in Anti-neutrophil Cytoplasmic Autoantibody Vasculitis.

INTRODUCTION: Venous thromboembolism (VTE) is a life-threatening complication of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis whose mechanism remains incompletely elucidated. We tested the hypothesis that elevated microparticle tissue factor activity (MPTFa) or anti-plasminogen antibodies (anti-Plg) may identify patients at risk for VTE. METHODS: In this prospective study, patients were enrolled during active disease and followed longitudinally. Twelve patients who experienced a VTE (VTEpos) were compared with patients without VTE (VTEneg, n = 29) and healthy controls (HC, n = 70). MPTFa, anti-Plg, interleukin-6, high-sensitivity C-reactive protein (hs-CRP), D-dimer, serum creatinine, and serum albumin were assessed. Fisher's exact tests and Wilcoxon tests compared categorical and continuous variables, respectively. Cox regression for time to VTE or last follow-up was performed. RESULTS: VTEpos patients had higher MPTFa (peak median = 14.0, interquartile range = 4.3-36.6) than HC (0, 0-3.5) and VTEneg patients (0, 0-1.4). In time-to-event analysis, MPTFa was associated with VTE when measured during both active disease (hazard ratio [HR]; 95% confidence interval [CI]: 1.04; 1.01-1.08) and remission (1.4; 1.11-1.77). Anti-Plg during remission was also associated with VTE (1.17; 1.03-1.33). Each g/dl decrease of serum albumin was associated with a 4-fold increase in VTE risk (4.4; 1.5-12.9). Adjusting for estimated glomerular filtration rate (eGFR), anti-Plg during remission remained significantly associated with VTE. CONCLUSION: Elevated MPTFa and increased anti-Plg in remission are strong indicators of VTE independent of renal function. Association of anti-Plg during remission with VTE implies hypercoagulability even during disease quiescence. Hypoalbuminemia strongly portends VTE risk, which is a novel finding in ANCA vasculitis. A thrombotic signature would allow improved management of patients to minimize VTE risk and complications of anticoagulation.

Gene-Specific DNA Methylation Changes Predict Remission in Patients with ANCA-Associated Vasculitis.

ANCA-associated vasculitis is an autoimmune condition characterized by vascular inflammation and organ damage. Pharmacologically induced remission of this condition is complicated by relapses. Potential triggers of relapse are immunologic challenges and environmental insults, both of which associate with changes in epigenetic silencing modifications. Altered histone modifications implicated in gene silencing associate with aberrant autoantigen expression. To establish a link between DNA methylation, a model epigenetic gene silencing modification, and autoantigen gene expression and disease status in ANCA-associated vasculitis, we measured gene-specific DNA methylation of the autoantigen genes myeloperoxidase (MPO) and proteinase 3 (PRTN3) in leukocytes of patients with ANCA-associated vasculitis observed longitudinally (n=82) and of healthy controls (n=32). Patients with active disease demonstrated hypomethylation of MPO and PRTN3 and increased expression of the autoantigens; in remission, DNA methylation generally increased. Longitudinal analysis revealed that patients with ANCA-associated vasculitis could be divided into two groups, on the basis of whether DNA methylation increased or decreased from active disease to remission. In patients with increased DNA methylation, MPO and PRTN3 expression correlated with DNA methylation. Kaplan-Meier estimate of relapse revealed patients with increased DNA methylation at the PRTN3 promoter had a significantly greater probability of a relapse-free period (P<0.001), independent of ANCA serotype. Patients with decreased DNA methylation at the PRTN3 promoter had a greater risk of relapse (hazard ratio, 4.55; 95% confidence interval, 2.09 to 9.91). Thus, changes in the DNA methylation status of the PRTN3 promoter may predict the likelihood of stable remission and explain autoantigen gene regulation.

Renoprotection with pituitary adenylate cyclase-activating polypeptide in cyclosporine A-induced nephrotoxicity.

BACKGROUND: Acute and long-term nephrotoxicity is the major dose-limiting factor for cyclosporine A (CsA). We evaluated the protective effects of pituitary adenylate cyclase-activating polypeptide (PACAP)38 on CsA-induced nephrotoxicity in human renal proximal tubule epithelial (human kidney-2) cells and in intact mice. METHODS: Confluent (human kidney-2 cells were exposed to CsA (25-50 µmol/L) in the presence or absence of PACAP38 or vasoactive intestinal peptide (10(-10) to 10(-6) M). For studies in vivo, male BALB/c mice (n = 5 in each group) were given a single intraperitoneal injection of CsA (5 mg/kg body weight). Treatment group received 20 µg of PACAP38 2 hours before exposure to CsA and additional doses daily for 10 days. RESULTS: Cyclosporine A caused oxidative injury, marked morphological alterations, apoptosis, and increased expression of transforming growth factor (TGF)-ß1 in cell cultures. Pituitary adenylate cyclase-activating polypeptide 38 at 10(-8) mol/L restored cell confluency, reduced TGF-ß1 secretion, and preserved cell integrity. In mice, CsA caused tubular injury characterized by loss of tubular epithelial cell brush border membranes, tubular collapse, cellular necrosis, interstitial fibrosis, increased production of TGF-ß1, and elevated serum creatinine (3.39 ± 0.21 vs 0.13 ± 0.02 mg/dL in controls, P < 0.01). Treatment with PACAP38 reduced TGF-ß1 and tumor necrosis factor-α production in kidney, prevented epithelial-mesenchymal transition of the renal cells, and reduced serum creatinine levels to 1.01 ± 0.18 mg/dL, P < 0.01 versus CsA group. CONCLUSIONS: Pituitary adenylate cyclase-activating polypeptide 38 ameliorated renal tubular injury, reduced oxidative injury, and inhibited the expression of TGF-ß1 in CsA-exposed murine kidneys. Pituitary adenylate cyclase-activating polypeptide could be a novel renoprotective and antifibrotic agent for CsA nephrotoxicity.