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1.  Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus 
Molecular immunology  2012;54(1):23-31.
Systemic lupus erythematosus (SLE) is a prototypic, inflammatory autoimmune disease characterized by significant gender bias. Previous studies have established a role for hormones in SLE pathogenesis, including the sex hormone estrogen. Estrogen regulates gene expression by translocating estrogen receptors (ER) α and β into the nucleus where they induce transcription by binding to estrogen response elements (EREs) of target genes. The ZAS3 locus encodes a signaling and transcriptional molecule involved in regulating inflammatory responses. We show that ZAS3 is significantly up-regulated in SLE patients at both the protein and mRNA levels in peripheral blood mononuclear cells (PBMCs). Furthermore, estrogen stimulates the expression of ZAS3 in vitro in several leukocyte and breast cancer cell lines of both human and murine origin. In vivo estrogen treatment mediates induction of tissue specific ZAS3 expression in several lymphoid organs in mice. Estrogen stimulation also significantly up-regulates ZAS3 expression in primary PBMCs, while treatment with testosterone has no effect. Mechanistically, estrogen induces differential ERα binding to putative EREs within the ZAS3 gene and ERα knockdown with siRNA prevents estrogen induced ZAS3 up-regulation. In contrast, siRNA targeting IFNα has no effect. These data demonstrate that ZAS3 expression is directly regulated by estrogen and that ZAS3 is overexpressed in lupus. Since ZAS3 has been shown to regulate inflammatory pathways, its up-regulation by estrogen could play a critical role in female-biased autoimmune disorders.
PMCID: PMC3913539  PMID: 23178823
Systemic lupus erythematosus; estrogen; ZAS3; autoimmunity
2.  End-Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1 
Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.
APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression.
Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10−9), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10−6). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ~2 years earlier among individuals with APOL1 risk genotypes (P = 0.01).
APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.
PMCID: PMC4002759  PMID: 24504811
3.  High sensitivity C-reactive protein, disease activity and cardiovascular risk factors in systemic lupus erythematosus 
Arthritis care & research  2013;65(3):441-447.
To study the level of high-sensitivity C-reactive protein (hsCRP) and its relationship with disease activity, damage and cardiovascular risk factors in patients with systemic lupus erythematosus (SLE).
Consecutive patients who fulfilled ≥4 ACR criteria for SLE but did not have concurrent infection were recruited. Blood was assayed for hsCRP and disease activity, organ damage of SLE and cardiovascular risk factors were assessed. Linear regression was performed for the relationship among hsCRP, SLE activity, damage and cardiovascular risk factors.
289 patients were studied (94% women; age 39.0±13.1 years; SLE duration 7.8±6.7 years). The mean SLEDAI score was 4.9±5.6 and clinically active SLE was present in 122(42%) patients. The mean hsCRP level was 4.87±12.7mg/L, and 28(23%) patients with active SLE had undetectable hsCRP (<0.3mg/L). Linear regression revealed a significant correlation between hsCRP and musculoskeletal (Beta=0.21), hematological (Beta=0.19), serosal (Beta=0.46) and clinical SLEDAI score (Beta=0.24), adjusting for age, sex, body mass index, creatinine and the use of various medications (p<0.005 in all). Levels of hsCRP correlated significantly with anti-dsDNA titer (Beta=0.33;p<0.001) but not with complement C3 (Beta=0.07;p=0.26). Significantly more patients with hsCRP >3.0mg/L were men and chronic smokers, and had diabetes mellitus, higher atherogenic index and history of arterial thrombosis. hsCRP levels correlated significantly with pulmonary and endocrine damage score.
hsCRP is detectable in 77% of SLE patients with clinically active disease and correlates with SLEDAI scores, particularly serositis and in the musculoskeletal and hematological systems. Elevated hsCRP in SLE is associated with certain cardiovascular risk factors and history of arterial thromboembolism.
PMCID: PMC3528823  PMID: 22949303
C-reactive protein; acute phase; disease activity; cardiovascular; damage; outcome
4.  A polymorphism in the type one complement receptor (CR1) involves an additional cysteine within the C3b/C4b binding domain that inhibits ligand binding 
Molecular immunology  2007;44(14):3510-3516.
The type one complement receptor (CR1) contains a variable number of binding domains for C3b and C4b, formed through a nearly identical set of repeating units known as short consensus repeats (SCRs). Each SCR contains 4 cysteines that, by forming two disulfide bonds, impart a conformation critical for function. In this study, we identified a CR1 single nucleotide polymorphism (1597C>T) that results in an additional cysteine (483R>C) in SCR 8 of the N-terminal C3b/C4b binding domain, and occurring sporadically in corresponding SCRs of other repeated C3b/C4b binding domains. The normal carrier frequency for 483-C was 6.3% in 175 African Americans, and 2.4% in 153 Caucasians. In expression constructs containing one C3b/C4b binding domain, the 483-C residue reduced binding to C3b, C3bi, and C4b by over 80% (each p < 0.0001), versus the wildtype construct. Full-length CR1 from 483-C carriers also exhibited reduced binding to C3b and C4b, although the effect was influenced by the total number of binding domains present. Race-matched comparisons between SLE patients (86 African Americans, 228 Caucasians) and the normal cohort showed that 483-C carrier status alone is not a risk factor for SLE or lupus nephritis. The physiological role of this polymorphism remains to be determined.
PMCID: PMC1978224  PMID: 17467802
CR1; polymorphism; complement; SLE
Arthritis and rheumatism  2011;63(7):2031-2037.
The published criteria for the proteinuria increase that constitutes a proteinuric flare in lupus glomerulonephritis (SLE GN) vary widely, likely because they are largely based on expert opinion. Ideally, the threshold for proteinuric flare should be set sufficiently high so that spontaneous variation in proteinuria does not likely explain the increase, but not so high that the patient is needlessly exposed to prolonged heavy proteinuria before a flare is declared and therapy is increased. Here we describe an evidence-based approach to setting the threshold for proteinuric flare based on quantifying the spontaneous variation in urine protein/creatinine (P/C) ratio of SLE GN patients who are not experiencing SLE flare.
SLE GN patients (N = 71) followed in the Ohio SLE Study (OSS) were tested at pre-specified bimonthly intervals within windows of ± 1 week, median follow-up > 44 mo, visit compliance > 90%. To assess spontaneous P/C ratio variation under no-flare conditions, we excluded P/C ratios measured within ± 4 month of renal flare.
For those with mean no-flare P/C ratios ≤ 0.5, the published flare thresholds are set well above the 99% confidence interval (CI) of the no-flare P/C ratios. The opposite is seen in those with patients whose mean no-flare P/C ratios ≥ 1.0.
Current thresholds for proteinuric flare appear to be set either too high or too low. A randomized trial would be needed to test whether re-setting the thresholds would result in faster remission, less therapy, and less chronic kidney disease.
PMCID: PMC3117977  PMID: 21400484
6.  Random Spot Urine Protein/Creatinine Ratio Is Unreliable for Estimating 24-Hour Proteinuria in Individual Systemic Lupus Erythematosus Nephritis Patients 
Nephron. Clinical Practice  2009;113(3):c177-c182.
Recently the American Rheumatologic Association (ARA) recommended random spot urine protein/creatinine ratio (P/C) to monitor systemic lupus erythematosus (SLE) glomerulonephritis (GN). Shortly afterward, 2 works were published, designated Study 1 and Study 2, which are the only studies to test spot P/C in SLE GN. Here we evaluate Study 1 and Study 2, which came to different conclusions.
Study 1 compared spot P/C to the P/C of intended 24-hour collections >50% complete, which reliably estimates 24-hour proteinuria. Study 2 compared spot P/C to the protein content of intended 24-hour collections >80% complete. To compare studies, Study 2 data were converted to P/C ratios.
Study 1 and Study 2 were found to be in agreement. Both showed that spot P/C and 24-hour P/C were highly correlated, but only when compared over the entire P/C range (0–8.0) (r = 0.842). Over the P/C range 0.5–3.0 (the most common P/C range encountered in SLE GN), correlation was present, but concordance was poor, rendering random P/C ratio unreliable.
Random spot P/C ratio is unreliable for detecting moderate proteinuria change. For example, random spot P/C would not reliably diagnose British Isles Lupus Assessment Group (BILAG) Category A or B proteinuric flares.
PMCID: PMC2821433  PMID: 19672116
SLE glomerulonephritis; Proteinuria; SLE flare
7.  Mathematical framework for human SLE Nephritis: disease dynamics and urine biomarkers 
Although the prognosis for Lupus Nephritis (LN) has dramatically improved with aggressive immunosuppressive therapies, these drugs carry significant side effects. To improve the effectiveness of these drugs, biomarkers of renal flare cycle could be used to detect the onset, severity, and responsiveness of kidney relapses, and to modify therapy accordingly. However, LN is a complex disease and individual biomarkers have so far not been sufficient to accurately describe disease activity. It has been postulated that biomarkers would be more informative if integrated into a pathogenic-based model of LN.
This work is a first attempt to integrate human LN biomarkers data into a model of kidney inflammation. Our approach is based on a system of differential equations that capture, in a simplified way, the complexity of interactions underlying disease activity. Using this model, we have been able to fit clinical urine biomarkers data from individual patients and estimate patient-specific parameters to reproduce disease dynamics, and to better understand disease mechanisms. Furthermore, our simulations suggest that the model can be used to evaluate therapeutic strategies for individual patients, or a group of patients that share similar data patterns.
We show that effective combination of clinical data and physiologically based mathematical modeling may provide a basis for more comprehensive modeling and improved clinical care for LN patients.
PMCID: PMC2877652  PMID: 20478032
8.  Biomarker Discovery for Lupus Nephritis Through Longitudinal Urine Proteomics 
Kidney international  2008;74(6):799-807.
Lupus nephritis is a frequent and serious complication of systemic lupus erythematosus (SLE). Treatment often requires the use of immunosuppression, and may be associated with severe side effects. The ability to predict relapse, relapse severity, and recovery could be used to more effectively implement therapy and reduce toxicity. We postulated that a proteomic analysis of the low-molecular weight urine proteome using serial urine samples obtained before, during, and after SLE nephritis flares would demonstrate potential biomarkers of SLE renal flare. This study was undertaken to test our hypothesis.
Urine from 25 flare cycles of 19 WHO Class III, IV, and V SLE nephritis patients was used. Urine samples included a baseline, and pre-flare, flare, and post-flare specimens. The urines were fractionated to remove proteins larger than 30 kDa, and spotted onto weak cation exchanger (CM10) protein chips for analysis by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS).
SELDI-TOF MS screening showed 176 protein ions between 2-20 kDa of which 27 were found to be differentially-expressed between specific flare intervals. On-chip peptide sequencing by integrated tandem mass spectrometry was used to positively identify selected differentially-expressed protein ions. The identified proteins included the 20 and 25 amino acid isoforms of hepcidin, a fragment of α1-antitrypsin, and an albumin fragment. Hepcidin 20 increased 4 months pre-flare and returned to baseline at renal flare, whereas hepcidin 25 decreased at renal flare and returned to baseline 4 months post-flare.
Using SELDI-TOF urine protein profiling in lupus nephritis, several candidate biomarkers of renal flare were found. To verify these candidates as true biomarkers, further identification and validation are needed in an independent SLE cohort.
PMCID: PMC2614389  PMID: 18596723
lupus nephritis; biomarker; SELDI

Results 1-8 (8)