Renal expression of polyomavirus large T antigen is associated with nephritis in human systemic lupus erythematosus

Fenton, Kristin Andreassen; Mjelle, Janne Erikke; Jakobsen, Søren; Olsen, Randi; Rekvig, Ole Petter

doi:10.1016/j.molimm.2008.03.001

Cited by 13 publications

(17 citation statements)

References 34 publications

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“…In experimental lupus-prone mice, animals with BK infection developed clinical signs of SLE earlier and more severe than those without BK infec- tion did (Fredriksen et al 1994). Although BK reactivation can break immunologic tolerance to autoantigens resulting in the production of autoantibodies in children and in many animal models (Flaegstad et al 1988;Fredriksen et al 1993;Fenton et al 2008), the frequency of positive antidsDNA and severe nephritis did not differ between patients with and without BK viruria in our study. The clinical significance of BK reactivation in pediatric patients with SLE requires further investigation.…”

Section: Azathioprinecontrasting

confidence: 49%

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Polyomavirus Reactivation in Pediatric Patients with Systemic Lupus Erythematosus

Rianthavorn

Posuwan

Payungporn

et al. 2012

Tohoku J. Exp. Med.

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Polyomavirus (PyV) infection usually persists without any symptoms in normal individuals. In immunocompromised patients including patients with systemic lupus erythematosus (SLE), PyV reactivation occurs with a high prevalence and can cause severe clinical complications. In this study, reactivation of six PyV [JC, BK, WU, KI, merkel cell (MC) and trichodysplasia spinulosa (TS)] was investigated in terms of prevalence, clinical implications and correlation with urine transforming growth factor (TGF)-β1 expression in 50 SLE patients aged less than 18 years. Clinical characteristics were obtained from medical record review. PyV viruria was assessed by nested polymerase chain reaction. Urine TGF-β1 was measured with ELISA. The mean age was 13 ± 2.8 years. The prevalence of JC and BK viruria was 16% and 32%, respectively. WU, KI, MC and TS were not isolated from any urine specimens. Co-reactivation of 2 PyV was not detected. Urine TGF-β1 levels in patients with JC viruria, with BK viruria and without PyV viruria were 0.27 ± 0.09, 0.10 ± 0.05 and 0.13 ± 0.09 ng/mg of urine creatinine, respectively. Cumulative doses of cyclophosphamide per body weight and urine TGF-β1 levels were higher in JC viruria than in other groups (p < 0.05). The prevalence of JC and BK reactivation was higher in pediatric patients with SLE than in the normal population. JC reactivation in pediatric patients with SLE was correlated with the administration of high-dose cyclophosphamide and increased urine TGF-β1 levels. Surveillance of JC reactivation is recommended in pediatric patients with chronic and severe SLE receiving high-dose cyclophosphamide.

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Section: Azathioprinecontrasting

confidence: 49%

“…Several studies have demonstrated that a break of immunologic tolerance to selfantigens leading to the production of anti-double stranded DNA antibody (anti-dsDNA) can be induced by PyV reactivation (Flaegstad et al 1988;Fenton et al 2008). The presence of anti-dsDNA is tightly correlated with SLE relapse and nephritis (Flaegstad et al 1988).…”

mentioning

confidence: 99%

Polyomavirus Reactivation in Pediatric Patients with Systemic Lupus Erythematosus

Rianthavorn

Posuwan

Payungporn

et al. 2012

Tohoku J. Exp. Med.

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“…Baseline data for the SLE patients are presented in Figure 3. The glomeruli from the Wegener kidney were devoid of glomerular chromatin-IgG deposits, and the patient did not produce anti-dsDNA antibodies [55].…”

Section: Methodsmentioning

confidence: 86%

Renal Dnase1 Enzyme Activity and Protein Expression Is Selectively Shut Down in Murine and Human Membranoproliferative Lupus Nephritis

2010

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BackgroundDeposition of chromatin-IgG complexes within glomerular membranes is a key event in the pathogenesis of lupus nephritis. We recently reported an acquired loss of renal Dnase1 expression linked to transformation from mild to severe membranoproliferative lupus nephritis in (NZBxNZW)F1 mice. As this may represent a basic mechanism in the progression of lupus nephritis, several aspects of Dnase1 expression in lupus nephritis were analyzed.Methodology/Principal FindingsTotal nuclease activity and Dnase1 expression and activity was evaluated using in situ and in vitro analyses of kidneys and sera from (NZBxNZW)F1 mice of different ages, and from age-matched healthy controls. Immunofluorescence staining for Dnase1 was performed on kidney biopsies from (NZBxNZW)F1 mice as well as from human SLE patients and controls. Reduced serum Dnase1 activity was observed in both mesangial and end-stage lupus nephritis. A selective reduction in renal Dnase1 activity was seen in mice with massive deposition of chromatin-containing immune complexes in glomerular capillary walls. Mice with mild mesangial nephritis showed normal renal Dnase1 activity. Similar differences were seen when comparing human kidneys with severe and mild lupus nephritis. Dnase1 was diffusely expressed within the kidney in normal and mildly affected kidneys, whereas upon progression towards end-stage renal disease, Dnase1 was down-regulated in all renal compartments. This demonstrates that the changes associated with development of severe nephritis in the murine model are also relevant to human lupus nephritis.Conclusions/SignificanceReduction in renal Dnase1 expression and activity is limited to mice and SLE patients with signs of membranoproliferative nephritis, and may be a critical event in the development of severe forms of lupus nephritis. Reduced Dnase1 activity reflects loss in the expression of the protein and not inhibition of enzyme activity.

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“…Accumulation of chromatin fragments in the GBM correlates in time with the loss of expression of the most important renal endonuclease (that is, DNaseI), and this result suggests a renal origin of the chromatin fragments. The fact that chromatin found in the GBM in human lupus nephritis can contain the polyomavirus BK large T antigen (95,96) also suggests a renal origin, since the BK virus possesses a selective tropism for tubular cells (97).…”

Section: Origin Of Exposed Glomerular Chromatinmentioning

confidence: 99%

Lupus Nephritis: Enigmas, Conflicting Models and an Emerging Concept

Seredkina

Vlag

Berden

et al. 2013

Mol Med

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Autoantibodies to components of chromatin, which include double-stranded DNA (dsDNA), histones and nucleosomes, are central in the pathogenesis of lupus nephritis. How anti-chromatin autoantibodies exert their nephritogenic activity, however, is controversial. One model assumes that autoantibodies initiate inflammation when they cross-react with intrinsic glomerular structures such as components of membranes, matrices or exposed nonchromatin ligands released from cells. Another model suggests glomerular deposition of autoantibodies in complex with chromatin, thereby inducing classic immune complex-mediated tissue damage. Recent data suggest acquired error of renal chromatin degradation due to the loss of renal DNasel enzyme activity is an important contributing factor to the development of lupus nephritis in lupus-prone (NZBxNZW)F1 mice and in patients with lupus nephritis. Down-regulation of DNasel expression results in reduced chromatin fragmentation and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals who produce IgG anti-chromatin autoantibodies. The main focus of the present review is to discuss whether exposed chromatin fragments in glomeruli are targeted by potentially nephritogenic anti-dsDNA autoantibodies or if the nephritogenic activity of these autoantibodies is explained by cross-reaction with intrinsic glomerular constituents or if both models coexist in diseased kidneys. In addition, the role of silencing of the renal DNasel gene and the biological consequences of reduced chromatin fragmentation in nephritic kidneys are discussed.

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Renal expression of polyomavirus large T antigen is associated with nephritis in human systemic lupus erythematosus

Cited by 13 publications

References 34 publications

Polyomavirus Reactivation in Pediatric Patients with Systemic Lupus Erythematosus

Polyomavirus Reactivation in Pediatric Patients with Systemic Lupus Erythematosus

Renal Dnase1 Enzyme Activity and Protein Expression Is Selectively Shut Down in Murine and Human Membranoproliferative Lupus Nephritis

Lupus Nephritis: Enigmas, Conflicting Models and an Emerging Concept

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