Dysregulation of Tumor Necrosis Factor Alpha-Induced Protein 3 mRNA Expression in Lupus Nephritis in Relation to Clinic-pathologic Characteristics and Disease Activity of Systemic Lupus Erythematosus (original) (raw)
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Bulletin of Egyptian Society for Physiological Sciences
Background: Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by complex clinical manifestations and chronic inflammatory processes with failure of immunoregulatory mechanisms. Kidney is one of the most commonly affected organs. Considering the morbidity associated with SLE and particularly with lupus nephritis (LN), it is important to identify novel biomarkers of disease activity which could aid in the detection and assessment of flares and degree of activity. At present, activity of SLE is assessed based on clinical symptoms and biochemical parameters such as autoantibody (e.g antinuclear antibody (ANA)) and serum complement. However, these biomarkers are not specific for evaluating renal activity. Renal biopsy is the gold standard for assessment of kidney damage and disease activity, but its usage is restricted as it is an invasive procedure. Aim of the work: In the present study, plasma level of advanced oxidation protein products (AOPPs) and peripheral blood mononuclear cells nuclear factor-κB (PBMCs NF-κB) level as well as serum levels of fetuin-A, 25-hydroxyvitamin D (25OHD), calcium (Ca), inorganic phosphate were studied as novel biomarkers of LN activity and progression. Methods: The study included 30 SLE female patients, 15 without nephritis (group II) and 15 with nephritis (group III), in addition to 15 agematched healthy controls (group I). Overnight fasting blood was collected from all subjects for measurement of plasma AOPPs level, PBMCs NF-κB level and serum fetuin-A level, 25OHD level, Ca and inorganic phosphate levels as well as calculation of calcification risk index (CRI). Results: Plasma AOPPs, PBMCs NF-κB, serum inorganic phosphate levels and CRI were significantly higher in SLE patients (group II) than age-matched healthy controls (group I) (p<0.05) with the highest level in patients with LN (group III) meanwhile, serum fetuin-A and 25OHD levels were significantly lower in SLE patients than age-matched healthy controls (p<0.05) with the lowest level in LN patient group. In addition plasma AOPPs, PBMCs NF-κB levels and CRI showed significantly positive correlation meanwhile, fetuin-A and 25OHD levels showed significantly negative correlation with serum creatinine, 24 hours urinary albumin, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), ANA, anti double stranded DNA (Anti-dsDNA) antibodies levels and SLE disease activity index (SLEDAI). Conclusions: In SLE patients, high PBMCs NF-κB and plasma AOPPs levels as well as CRI while low levels of fetuin-A and 25OHD were related to disease activity and progression.
Genes and Immunity, 2009
TNFAIP3 encodes the ubiquitin modifying enzyme, A20, a key regulator of inflammatory signaling pathways. We previously reported association between TNFAIP3 variants and systemic lupus erythematosus (SLE). In order to further localize the risk variant(s), we performed a metaanalysis using genetic data available from two Caucasian case/control datasets (1453 total cases, 3381 total controls) and 713 SLE trio families. The best result was found at rs5029939 (P = 1.67 × 10 −14 , OR = 2.09, 95% CI 1.68-2.60). We then imputed SNPs from the CEU Phase II HapMap using genotypes from 431 SLE cases and 2155 controls. Imputation identified eleven SNPs in addition to three observed SNPs, which together, defined a 109 kb SLE risk segment surrounding TNFAIP3. When evaluating whether the rs5029939 risk allele was associated with SLE clinical manifestations, we observed that heterozygous carriers of the TNFAIP3 risk allele at rs5029939 have a two-fold increased risk of developing renal or hematologic manifestations compared to homozygous non-risk subjects. In summary, our study strengthens the genetic evidence that variants in the region of TNFAIP3 influence risk for SLE, particularly in patients with renal and hematologic manifestations, and narrows the risk effect to a 109 kb DNA segment that spans the TNFAIP3 gene.
Analysis of TNF-like weak inducer of apoptosis for detecting lupus nephritis
Comparative Clinical Pathology, 2022
Lupus is an autoimmune disease that has various manifestations in various organs. One of the manifestations of lupus is lupus nephritis (LN), which often causes kidney failure and death. Cytokines play an essential role in the pathogenesis of LN and might be helpful for LN biomarkers. This study aimed to evaluate urine TNF-like weak inducer of apoptosis (TWEAK) for detecting LN since this is not an invasive procedure and is more cost-effective. The gold standard procedure for diagnosing LN needs a biopsy of the kidney. However, the procedure is invasive, high cost, and takes time. Thus, a biomarker from urine is needed for early diagnosis of LN. This research conducted was cross-sectional. The total participants were 57, consisting of 29 lupus nephritis and 28 lupus without nephritis. TWEAK levels were determined by ELISA method; urine protein, urine erythrocyte, and leukocyte were examined by a urine autoanalyzer. Statistical analysis using Mann-Whitney, Spearman correlation, Kruskal-Wallis, ROC curve analysis, and a 2 × 2 contingency table. This study showed a significant difference in TWEAK levels between lupus nephritis and lupus without nephritis (p < 0.05), but no significant difference between TWEAK level and renal domain scores of SLEDAI. There were significant correlations between TWEAK level and urine erythrocyte and urine protein, but there was no significant correlation with urine leukocytes. The sensitivity and specificity of TWEAK for determining LN were 72.4% and 72.5%, respectively, with AUC 0.77. TWEAK had a good diagnostic test for detecting lupus nephritis and substantially correlated with urine erythrocyte and urine protein.
Urinary cytokines and mRNA expression as biomarkers of disease activity in lupus nephritis
Lupus, 2018
Introduction: Renal involvement is one of the most serious manifestations of systemic lupus erythematosus, but non-invasive assessment of inflammatory response in kidneys is challenging. In this study we aimed to validate markers of active lupus nephritis (LN) using urine immune profiling. Methods: Urine and serum cytokines (17-plex array) and urine mRNA expression ($40 immune and glomerular injury genes) were measured in LN patients with active disease (n ¼ 17) during remission (n ¼ 16) and in healthy subjects (n ¼ 18). Results: Urine and serum levels of CCL2, CCL5 and CXCL10 were elevated in active LN as compared with disease remission (best discrimination for urine CXCL10 and CCL2) and correlated with LN activity. In the active disease, urinary cell transcriptome showed marked upregulation of proinflammatory cytokines (e.g. TNF, CCL2, CCL5, CXCL10), and type-1 immunity-related genes (e.g. CD3G, CD4, TBX21, IFNG). An active pattern of gene expression was also observed in four patients in remission, who had moderately increased urinary leucocyte count. Two patients from this group developed renal exacerbation during the following 3 months. Markers of type-17 immune axis (e.g. IL-17A) were not significantly increased in active LN. Conclusions: Active LN patients were characterized by marked increase of proinflammatory mediators in the urine. Urine cytokines (CCL2 and CXCL10) and type-1 T-cell-related gene markers in the urine sediment had similar diagnostic performance in detection of active LN. Lupus (2018) 0, 1-12.
Clinical Proteomics
Background: Systemic lupus erythematosus (SLE) is a remarkably heterogeneous autoimmune disease. Despite tremendous efforts, our knowledge of serum protein patterns in severe SLE phenotypes is still limited. We investigated the serum protein pattern of SLE, with special emphasis on irreversible organ damage and active lupus nephritis (LN) as assessed by renal Systemic Lupus Erythematosus Disease Activity Index. Methods: We used proximity extension immunoassay (PEA, Proseek Multiplex, Olink) to assess the serum levels of ninety-two inflammation-related proteins in Czech patients with SLE (n = 75) and age-matched healthy control subjects (n = 23). Subgroup analysis was carried out on the basis of organ damage (with/without, 42/33) and biopsyproven LN (with/without, 27/48; active LN, n = 13; inactive LN, n = 14). Results: Of thirty deregulated proteins between SLE and the healthy controls (P corr < 0.05), the top upregulated proteins in SLE were sirtuin 2, interleukin 18 (IL18), and caspase 8 (P corr < 0.0006). Of these, sirtuin 2 and caspase 8 had not yet been reported with SLE. Elevated levels of IL8, CCL2/MCP1, CCL11, and MMP10 (P corr < 0.05) were detected in patients with organ damage for which the serum levels of CCL11 and MMP10 were particularly informative in organ damage prediction. Comparing patients based on LN, elevated levels of CSF1, sIL15RA, sCD40, sCX3CL1, caspase 8, sIL18R1, bNGF, and GDNF (P corr < 0.05) were detected in active LN. Except GDNF, all LN-associated markers showed usefulness in prediction of active renal disease. Conclusions: This highly sensitive PEA analysis identified the serum pattern of SLE, organ damage, and active LN, with many novel candidate proteins detected. Their exact role and suitability as biomarkers in SLE deserve further investigation.
Altered Expression of TNF-α Signaling Pathway Proteins in Systemic Lupus Erythematosus
The Journal of Rheumatology, 2010
Objective. To investigate the expression of tumor necrosis factor receptors (TNFR1 and TNFR2) and adapter proteins (TRADD, RIP, and TRAF2) in peripheral blood mononuclear cell (PBMC) subsets from patients with systemic lupus erythematosus (SLE). Methods. PBMC were isolated from 45 SLE patients and 25 controls, and stained with labeled antibodies that enabled identification of various T cell, B cell, and monocyte subpopulations. Expression of TNF-related signaling molecules was measured by staining with labeled antibodies either directly or following fixation and permeabilization. Apoptosis was quantified using an anti-active caspase 3 antibody. RNA expression of TNF-related signaling molecules was assessed by quantitative RT-PCR and serum levels of TNF-α by ELISA. Results. SLE patients had increased levels of TNFR1, TNFR2, and TRAF2, together with decreased levels of RIP, on various B, CD4+ T, and CD8+ T cell subsets as compared to controls. This altered expression was seen in both naive and memory subpopulations, and reflected altered staining of the whole population rather than a subset of cells that were activated. The levels of these molecules were not significantly correlated with serum TNF-α levels or their RNA expression in whole peripheral blood. TNFR1 and TNFR2 expression was negatively correlated with disease activity. There was no association between the proportion of apoptotic cells in any of the subpopulations and serum TNF-α levels or expression of TNF-related signaling molecules. Conclusion. Patients with SLE had altered expression of TNF-related signaling molecules, suggesting that there may be an imbalance in TNF-α signaling favoring cellular activation as opposed to proapoptotic pathways.
Serum and urinary cytokine levels of SLE patients
Die Pharmazie, 2012
Systemic lupus erythematosus (SLE) is a chronic, relapsing, polysystemic autoimmune disease with various clinical signs. The prognosis of SLE patients is influenced by neuropsychiatric and renal involvement. Lupus nephritis (LN) is present in 40-60% of patients. Classical laboratory parameters are not sensitive and specific in prediction renal flares, over the last few years there has been a growing interest in searching novel lupus biomarkers predicting future flares. Our goal was to detect serum and urinary level of cytokines in 36 patients with lupus nephritis (34 female and 2 male, mean age: 43.36 +/- 11.53 years), 23 patients with SLE without renal involvement (19 women and 4 men, mean age: 54 +/- 8.71) (both groups followed by the 3rd Department of Internal Medicine, Division of Clinical Immunology, University of Debrecen) and 30 healthy controls (23 female and 7 male, mean age: 45.5 +/- 12.4). Serum IL-1 (interleukin), IL-2 (both p < 0.05), IL-6, IL-13 and IFN-gamma (p <...
Imbalance of Th1/Th2 transcription factors in patients with lupus nephritis
Rheumatology (Oxford, England), 2006
Systemic lupus erythematosus (SLE) is characterized by the aberrant activation of T lymphocytes. Since T-bet and GATA-3 are the principal transcription factors for the differentiation of type-1 and type-2 helper T lymphocytes, respectively, we studied their mRNA expression in the urinary sediment of SLE patients and compared this with their urinary and intra-renal protein expression. We studied 100 SLE patients and 10 healthy subjects. Urinary mRNA expression of T-bet and GATA-3 were studied by the real-time quantitative polymerase chain reaction. Intra-renal and urinary expressions of T-bet and GATA-3 were studied by immunohistochemistry and western blotting, respectively. The urinary mRNA and protein expressions of T-bet were significantly higher in SLE patients with active nephritis than those with inactive disease (mRNA: P < 0.001; protein: P = 0.004). The urinary mRNA expression of T-bet correlated with the SLE disease activity index (SLEDAI) score (r = 0.55, P < 0.001) a...
Nephrology Dialysis Transplantation, 2006
Background. Previous studies have shown that messenger RNA (mRNA) expression of target genes is increased in the urinary sediment of patients with active lupus. We study the effect of immunosuppressive therapy on the urinary gene expression profile in patients with active lupus nephritis. Method. We recruited nine patients with active systemic lupus erythematosus (SLE) and renal disease, and required corticosteroid, with or without cytotoxic treatment. They were followed for 6 months, urine samples were collected at 0, 4, 12 and 24 weeks and gene expression profile was determined by polymerase chain reactions. The pattern of gene expression was compared to clinical parameters of therapeutic response. Results. Amongst the target genes studied, there was a progressive decline in the urinary expression of T-bet, interleukin (IL)-10, transforming growth factor-beta (TGF-b), monocyte chemoattractant protein-1 (MCP-1), and interferon-gamma (IFN-g) after immunosuppressive treatment, although the change of IFN-g was not statistically significant. The time course of their urinary expression was parallel to the systemic activity as reflected by the systemic lupus erythematosus disease activity index (SLEDAI). Throughout the study period, the SLEDAI score correlated significantly with the expressions of IFN-g (r ¼ 0.43, P ¼ 0.009), T-bet (r ¼ 0.40, P ¼ 0.016), TGF-b (r ¼ 0.51, P ¼ 0.002) and MCP-1 (r ¼ 0.38, P ¼ 0.022). The anti-double strand(anti-ds)DNA antibody titer correlated significantly with the expressions of IFN-g (r ¼ 0.45, P ¼ 0.009), T-bet (r ¼ 0.37, P ¼ 0.034), IL-10 (r ¼ 0.59, P<0.001), TGF-b (r ¼ 0.44, P ¼ 0.010) and MCP-1