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Large-scale analysis of tumor necrosis factor ? levels in systemic lupus erythematosus.

ABSTRACT: Systemic lupus erythematosus (SLE) disease manifestations are highly variable among patients, and the prevalence of individual clinical features differs significantly by ancestry. Serum tumor necrosis factor ? (TNF?) levels are elevated in some SLE patients and may play a role in disease pathogenesis. The aim of this study was to look for associations between serum TNF? levels, clinical manifestations of SLE, autoantibodies, and serum interferon-? (IFN?) levels in a large multiancestral SLE cohort.We studied serum TNF? levels in 653 SLE patients (214 African Americans, 298 European Americans, and 141 Hispanic Americans). TNF? was measured using an enzyme-linked immunosorbent assay, and IFN? was measured with a functional reporter cell assay. Stratified and multivariate analyses were used to detect associations in each ancestral background separately, with meta-analysis when appropriate.Serum TNF? levels were significantly higher in SLE patients than in non-autoimmune disease controls (P < 5.0 × 10(-3) for each ancestral background). High serum TNF? levels were positively correlated with high serum IFN? levels when tested in the same sample across all ancestral backgrounds (odds ratio range 1.76-1.86, P = 4.8 × 10(-3) by Fisher's combined probability test). While serum TNF? levels alone did not differ significantly among SLE patients of different ancestral backgrounds, the proportion of patients with concurrently high levels of TNF? and IFN? was highest in African Americans and lowest in European Americans (P = 5.0 × 10(-3) ). Serum TNF? levels were not associated with autoantibodies, clinical criteria for the diagnosis of SLE, or age at the time of sampling.Serum TNF? levels are high in many SLE patients, and we observed a positive correlation between serum TNF? and IFN? levels. These data support a role for TNF? in the pathogenesis of SLE across all ancestral backgrounds and suggest important cytokine subgroups within the disease.

SUBMITTER: Weckerle CE

PROVIDER: S-EPMC3396783 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Large-scale analysis of tumor necrosis factor α levels in systemic lupus erythematosus.

Weckerle Corinna E CE Mangale Dorothy D Franek Beverly S BS Kelly Jennifer A JA Kumabe Marissa M James Judith A JA Moser Kathy L KL Harley John B JB Niewold Timothy B TB

Arthritis and rheumatism 20120901 9

<h4>Objective</h4>Systemic lupus erythematosus (SLE) disease manifestations are highly variable among patients, and the prevalence of individual clinical features differs significantly by ancestry. Serum tumor necrosis factor α (TNFα) levels are elevated in some SLE patients and may play a role in disease pathogenesis. The aim of this study was to look for associations between serum TNFα levels, clinical manifestations of SLE, autoantibodies, and serum interferon-α (IFNα) levels in a large multi ...[more]

PMID: 22488302

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Project description:Systemic lupus erythematosus (SLE) is a multifaceted disease characterized by immune dysregulation and unpredictable disease activity. This study sought to evaluate the changes in plasma concentrations of soluble mediators that precede clinically defined disease flares.Fifty-two different soluble mediators, including cytokines, chemokines, and soluble receptors, were examined using validated multiplex bead-based or enzyme-linked immunosorbent assays in plasma from 28 European American patients with SLE who developed disease flare 6 or 12 weeks after a baseline assessment (preflare), 28 matched SLE patients without impending flare (nonflare), and 28 matched healthy controls. In a subset of 13 SLE patients, mediators within samples obtained preceding disease flare were compared with those within samples from the same individual obtained during a clinically stable period without flare.Compared to SLE patients with clinically stable disease, SLE patients with impending flare had significant alterations (P ? 0.01) in the levels of 27 soluble mediators at baseline; specifically, the levels of proinflammatory mediators, including Th1-, Th2-, and Th17-type cytokines, were significantly higher several weeks before clinical flare. Baseline levels of regulatory cytokines, including interleukin-10 and transforming growth factor ?, were higher in nonflare SLE patients, whereas baseline levels of soluble tumor necrosis factor receptor type I (TNFRI), TNFRII, Fas, FasL, and CD40L were significantly higher (P ? 0.002) in preflare SLE patients. The normalized and weighted combined soluble mediator score was significantly higher (P ? 0.0002) in preflare samples from SLE patients compared to samples from the same patients obtained during periods of stable disease.The levels of proinflammatory adaptive cytokines and shed TNF receptors are elevated prior to disease flare, while the levels of regulatory mediators are elevated during periods of stable disease. Alterations in the balance between inflammatory and regulatory mediators may help identify patients at risk of disease flare and help decipher the pathogenic mechanisms of SLE.

Project description:To define the pathogenesis of bone marrow (BM) involvement in systemic lupus erythematosus (SLE).Tumor necrosis factor ? (TNF?) levels, cell death, and cellular damage in BM from SLE patients, controls, and mice with pristane-induced lupus were analyzed using a morphometric technique and immunohistochemistry. The pathogenesis of BM abnormalities was studied in wild-type (WT), TNF?(-/-) , Toll-like receptor-deficient (TLR-7(-/-) ), interferon (IFN)-?/?/? receptor-knockout (IFNAR(-/-) ), and B cell-deficient (?mt) mice treated with pristane. Flow cytometry was used to examine TNF? production (by intracellular staining) and plasma cell/plasmablast development. CXCL12 expression was determined by quantitative polymerase chain reaction.BM from SLE patients exhibited striking death of niche and hematopoietic cells associated with TNF? overproduction. BM from mice with a type I IFN-mediated lupus syndrome induced by pristane showed similar abnormalities. TNF? was produced mainly by BM neutrophils, many with phagocytosed nuclear material (lupus erythematosus cells). TNF? production was abolished in pristane-treated TLR-7(-/-) and ?mt mice but was restored in ?mt mice by infusing normal plasma. Pristane-treated WT and IFNAR(-/-) mice developed anemia, BM hypocellularity, and extramedullary hematopoiesis, which were absent in TLR-7(-/-) and TNF?(-/-) mice. Additionally, the expression of CXCL12, which is produced by stromal cells and mediates homing of hematopoietic cells and plasmablasts, was decreased in BM from pristane-treated WT mice but was normal in BM from pristane-treated TNF?(-/-) mice.Although autoantibodies and glomerulonephritis are type I IFN dependent, lupus-associated BM abnormalities were TLR-7 and TNF? driven but type I IFN independent, suggesting that lupus is a disorder of innate immunity in which TLR-7 activation by phagocytosed nuclei causes relentless type I IFN and TNF? production mediating glomerulonephritis and hematologic involvement, respectively.

Dataset Information

Large-scale analysis of tumor necrosis factor ? levels in systemic lupus erythematosus.

Publications

Large-scale analysis of tumor necrosis factor α levels in systemic lupus erythematosus.

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