Increased Excretions of β&lt;sub&gt;2&lt;/sub&gt;-Microglobulin, IL-6, and IL-8 and Decreased Excretion of Tamm-Horsfall Glycoprotein in Urine of Patients with Active Lupus nephritis

Tsai, Chang-Youh; Wu, Tsai-Hung; Yu, Chia‐Li; Lu, Jie; Tsai, Ying-Yang

doi:10.1159/000045663

Cited by 145 publications

(116 citation statements)

References 28 publications

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“…uMCP-1 increased significantly at renal flare despite moderate to intense immunosuppression (prednisone, mycophenolate mofetil, azathioprine, or cyclophosphamide) before chemokine measurement, suggesting that uMCP-1 is a robust marker of SLE activity that is valid in patients who have chronic disease and are on long-term therapy. However, this background of immunosuppression may partially account for the fact that uIL-8 did not significantly increase at flare, in contrast to other investigations that measured uIL-8 in untreated SLE patients (7,10,11).…”

Section: Discussioncontrasting

confidence: 73%

Urine Chemokines as Biomarkers of Human Systemic Lupus Erythematosus Activity

Rovin¹,

Song²,

Birmingham³

et al. 2005

Journal of the American Society of Nephrology

240

211

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The purpose of this study was to evaluate urine monocyte chemoattractant protein-1 (MCP-1) and IL-8 as biomarkers of SLE flare. Urine was collected every 2 mo from patients who were followed prospectively in the Ohio SLE Study. Renal and nonrenal flares were identified and MCP-1 and IL-8 were measured by specific ELISA in samples that were collected at flare. When available, MCP-1 and IL-8 were also measured in urine samples before and after flare. For comparison, MCP-1 and IL-8 were measured in the urine of healthy individuals and in renal and nonrenal SLE patients with stable disease activity (disease controls). Most patients were receiving maintenance immunosuppressive therapy before flare. At renal flare, mean urine MCP-1 (uMCP-1) was significantly greater than uMCP-1 at nonrenal flare and from healthy volunteers and renal disease controls. The level of uMCP-1 correlated with the increase in proteinuria at flare and was higher in patients with proliferative glomerulonephritis and in patients with impaired renal function. Urine MCP-1 was increased beginning 2 to 4 mo before flare. Patients who responded to therapy showed a slow decline in uMCP-1 over several months, whereas nonresponders had persistently high uMCP-1. In contrast, uIL-8 did not change with disease activity and was not elevated at renal or nonrenal flare compared with disease controls. In conclusion, uMCP-1 but not uIL-8 is a sensitive and specific biomarker of renal SLE flare and its severity, even in patients who receive significant immunosuppressive therapy. Persistently elevated uMCP-1 after treatment may indicate ongoing kidney injury that may adversely affect renal prognosis. S ubstantial animal and human evidence suggests that chemokines, in particular monocyte chemoattractant protein-1 (MCP-1) and IL-8, contribute to kidney injury in the glomerulonephritis (GN) of SLE (reviewed in 1,2). In murine models of SLE GN, genetic deletion or pharmacologic blockade of MCP-1 attenuates glomerular and interstitial inflammation and reduces kidney damage (3-5). In humans with SLE GN, MCP-1 and IL-8 are expressed in the kidneys, and their transcripts can be detected by in situ hybridization, confirming intrarenal chemokine production (6 -8). Furthermore, urine MCP-1 and IL-8 (uMCP-1, uIL-8) levels are increased in SLE patients during active renal disease and in some reports decrease with treatment-induced disease remission (6,7,9 -11). Thus, uMCP-1, uIL-8, or both may be clinically relevant biomarkers of SLE GN. To date, however, the association of urine chemokines with renal and nonrenal SLE activity has not been examined rigorously through serial measurement of chemokine levels before, during, and after disease flares. This study was undertaken to investigate the relationship of uMCP-1 and uIL-8 to the onset, severity, and resolution of SLE flare in a cohort of well-characterized patients who were followed in the Ohio SLE Study (OSS), a prospective longitudinal investigation of risk factors for SLE flare in patients with renal or nonrenal SLE. Mate...

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Section: Discussioncontrasting

confidence: 73%

Urine Chemokines as Biomarkers of Human Systemic Lupus Erythematosus Activity

Rovin¹,

Song²,

Birmingham³

et al. 2005

Journal of the American Society of Nephrology

240

211

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“…For example, in experimental IC glomerulonephritis, monocytes infiltrating the kidneys secrete IL-1, which can trigger TNF-a secretion and lead to tissue injury (48). Additionally, urinary levels of IL-6 and IL-8 were higher in patients suffering from lupus nephritis compared with patients without renal involvement or healthy controls, suggesting local production of these particular cytokines (49). Furthermore, analysis of isolated cell populations from nephritic mouse kidneys during flares demonstrated increased expression levels of IL-1, IL-6, IL-10, and TNF-a in gene-expression arrays (43).…”

Section: Discussionmentioning

confidence: 99%

Anti-C1q Autoantibodies from Systemic Lupus Erythematosus Patients Induce a Proinflammatory Phenotype in Macrophages

Thanei

Trendelenburg

2016

The Journal of Immunology

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Anti-C1q autoantibodies (anti-C1q) are frequently found in patients with systemic lupus erythematosus (SLE) and correlate with the occurrence of proliferative lupus nephritis. A previous study of anti-C1q in experimental lupus nephritis demonstrated an important role for FcγRs in the pathogenesis of lupus nephritis, suggesting a direct effect on phagocytes. Therefore, we developed an in vitro model to study the effect of SLE patient–derived anti-C1q bound to immobilized C1q (imC1q) on human monocyte-derived macrophages (HMDMs) obtained from healthy donors and SLE patients. HMDMs were investigated by analyzing the cell morphology, LPS-induced cytokine profile, surface marker expression, and phagocytosis rate of apoptotic Jurkat cells. Morphologically, bound anti-C1q induced cell aggregations of HMDMs compared with imC1q or IgG alone. In addition, anti-C1q reversed the effect of imC1q alone, shifting the LPS-induced cytokine release toward a proinflammatory response. FcγR-blocking experiments revealed that the secretion of proinflammatory cytokines was mediated via FcγRII. The anti-C1q–induced inflammatory cytokine profile was accompanied by a downregulation of CD163 and an upregulation of LPS-induced CD80, CD274, and MHC class II. Finally, HMDMs primed on bound anti-C1q versus imC1q alone displayed a significantly lower phagocytosis rate of early and late apoptotic cells accompanied by a reduced Mer tyrosine kinase expression. Interestingly, anti-C1q–dependent secretion of proinflammatory cytokines was similar in SLE patient–derived cells, with the exception that IL-10 was slightly increased. In conclusion, anti-C1q induced a proinflammatory phenotype in HMDMs reversing the effects of imC1q alone. This effect might exacerbate underlying pathogenic mechanisms in lupus nephritis.

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“…Increased secretion of IL-8 by lupus DCs could potentially contribute to tissue damage, as this cytokine has been proposed to play an important role in the development of lupus nephritis (61)(62)(63)(64) and has been found to be elevated in lupus patients with CNS involvement (65). IL-8 is produced by numerous cell types, including monocytes/macrophages and DCs (64,66,67).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Phenotype and Function of Myeloid Dendritic Cells in Systemic Lupus Erythematosus

Ding

Mehta

McCune

et al. 2006

The Journal of Immunology

132

106

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Systemic lupus erythematosus (SLE) is characterized by a systemic autoimmune response with profound and diverse T cell changes. Dendritic cells (DCs) are important orchestrators of immune responses and have an important role in the regulation of T cell function. The objective of this study was to determine whether myeloid DCs from individuals with SLE display abnormalities in phenotype and promote abnormal T cell function. Monocyte-derived DCs and freshly isolated peripheral blood myeloid DCs from lupus patients displayed an abnormal phenotype characterized by accelerated differentiation, maturation, and secretion of proinflammatory cytokines. These abnormalities were characterized by higher expression of the DC differentiation marker CD1a, the maturation markers CD86, CD80, and HLA-DR, and the proinflammatory cytokine IL-8. In addition, SLE patients displayed selective down-regulation of the maturation marker CD83 and had abnormal responses to maturation stimuli. These abnormalities have functional relevance, as SLE DCs were able to significantly increase proliferation and activation of allogeneic T cells when compared with control DCs. We conclude that myeloid DCs from SLE patients display significant changes in phenotype which promote aberrant T cell function and could contribute to the pathogenesis of SLE and organ damage.

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Increased Excretions of β<sub>2</sub>-Microglobulin, IL-6, and IL-8 and Decreased Excretion of Tamm-Horsfall Glycoprotein in Urine of Patients with Active Lupus nephritis

Cited by 145 publications

References 28 publications

Urine Chemokines as Biomarkers of Human Systemic Lupus Erythematosus Activity

Urine Chemokines as Biomarkers of Human Systemic Lupus Erythematosus Activity

Anti-C1q Autoantibodies from Systemic Lupus Erythematosus Patients Induce a Proinflammatory Phenotype in Macrophages

Aberrant Phenotype and Function of Myeloid Dendritic Cells in Systemic Lupus Erythematosus

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