Nucleosomes possess a high affinity for glomerular laminin and collagen IV and bind nephritogenic antibodies in murine lupus-like nephritis

Mjelle, Janne Erikke; Rekvig, Ole Petter; Fenton, Kristin Andreassen

doi:10.1136/ard.2007.070482

Cited by 63 publications

(86 citation statements)

References 42 publications

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“…The BIAcore T100 instrument was used for SPR analyses. Type IV collagen and laminin (mainly laminin ␤2 but also ␣1 chains [14]) were immobilized on carboxymethylated dextran-coated sensor chips (CM5; BIAcore, GE Healthcare) as described (14) to target levels of 6,000 and 5,600 response units (RU), respectively. Biotinylated DNA was immobilized on a streptavidin-coated sensor chip (14) to the target level of 940 RU.…”

Section: Methodsmentioning

confidence: 99%

“…Type IV collagen and laminin (mainly laminin ␤2 but also ␣1 chains [14]) were immobilized on carboxymethylated dextran-coated sensor chips (CM5; BIAcore, GE Healthcare) as described (14) to target levels of 6,000 and 5,600 response units (RU), respectively. Biotinylated DNA was immobilized on a streptavidin-coated sensor chip (14) to the target level of 940 RU. Sensor chips, an amine coupling kit, 10ϫ HBS-EPϩ running buffer (1M HEPES, 1.5M NaCl, 30 mM EDTA, and 0.5% v/v Surfactant P20, pH 7.4), regeneration solutions, and immobilization buffers were from BIAcore.…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies have demonstrated that nephritogenic antibodies recognize chromatin fragments (10)(11)(12)(13) which bind glomerular basement membranes (GBMs) and matrix components with high affinity (14). These immune complexes were observed as electron-dense structures in GBMs and the mesangial matrix, and bound IgG was confined to electron-dense structures in both murine (12,14) and human (13) lupus nephritis.…”

mentioning

confidence: 99%

“…These immune complexes were observed as electron-dense structures in GBMs and the mesangial matrix, and bound IgG was confined to electron-dense structures in both murine (12,14) and human (13) lupus nephritis. In vivo bound IgG was not observed in regular glomerular structures (15), although anti-DNA antibodies have been shown to cross-react in vitro with other glomerular antigens (16)(17)(18)(19).…”

mentioning

confidence: 99%

“…Since heparin binds tightly to histone tails and thereby alters the net charge of the nucleosome, heparin may theoretically also inhibit binding of nucleosomecontaining immune complexes to components like laminins and collagens of the GBM and the mesangial matrix (14,32). Thus, heparin may have a 2-sided effect on the role of chromatin fragments in lupus nephritisincreasing their enzymatic sensitivity and inhibiting their binding to glomerular membranes.…”

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confidence: 99%

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Heparin exerts a dual effect on murine lupus nephritis by enhancing enzymatic chromatin degradation and preventing chromatin binding in glomerular membranes

Hedberg¹,

Fismen²,

Fenton³

et al. 2011

Arthritis & Rheumatism

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Objective. Association of nucleosome-IgG immune complexes with glomerular basement membranes (GBMs) is an important event in the development of lupus nephritis. Preventing this binding and/or increasing nuclease sensitivity of nucleosomes may be viable strategies for the prevention of the disease. Theoretically, heparin may alter nucleosomal structure and increase sensitivity to proteinases and nucleases, and may also inhibit binding of nucleosomes and nucleosome-IgG complexes to basement membrane structures. The aim of this study was to investigate whether and eventually how heparin prevents murine lupus nephritis.Methods. Surface plasmon resonance was used to analyze if heparin inhibits binding of nucleosomes to laminin and collagen. The effect of heparin on nucleaseand proteinase-mediated degradation of nucleosomes was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and agarose gel electrophoresis. In vitro results were compared with analyses in vivo in heparin-treated (NZB ؋ NZW)F 1 mice. Anti-doublestranded DNA antibody production, deposition of nucleosome-IgG complexes in GBMs, and development of proteinuria were monitored, and circulating chromatin fragments were quantified using quantitative polymerase chain reaction.Results. In vitro studies demonstrated that heparin increased enzymatic degradation of nucleosomes and almost completely inhibited binding of nucleosomes to laminin and collagen. (NZB ؋ NZW)F 1 mice treated with heparin demonstrated delayed or no antibody production and higher variation of circulating chromatin levels compared with untreated control mice. This effect was accompanied by highly reduced nucleosomeIgG complexes in GBMs and delayed development of nephritis.Conclusion. Increasing the degradation of nucleosomes, reducing their immunogenicity, and preventing binding of nucleosome-IgG complexes in glomeruli together provide an alternative basis for the treatment of lupus nephritis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Heparin exerts a dual effect on murine lupus nephritis by enhancing enzymatic chromatin degradation and preventing chromatin binding in glomerular membranes

Hedberg¹,

Fismen²,

Fenton³

et al. 2011

Arthritis & Rheumatism

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Reduced fragmentation of apoptotic chromatin is associated with nephritis in lupus‐prone (NZB × NZW)F₁ mice

Zykova¹,

Seredkina²,

Benjaminsen³

et al. 2008

Arthritis & Rheumatism

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Objective. Antinucleosome autoantibodies are pathogenic factors in lupus nephritis. Defects in apoptotic pathways may result in increased levels of apoptotic nucleosomes. The objectives of this study were 1) to determine whether low molecular weight oligonucleosomes are present in the kidneys of autoimmune (NZB ؋ NZW)F 1 mice, 2) to analyze whether the presence of glomerular membrane-associated TUNELpositive electron-dense structures reflect the existence of low molecular weight oligonucleosomes, and 3) to determine an eventual temporal relationship between glomerular electron-dense structures, oligonucleosomes, and proteinuria in these mice.Methods. DNA was isolated from mouse 111s34 hybridoma cells and from the kidneys of normal BALB/c mice in which apoptosis was induced by camptothecin and from the kidneys of (NZB ؋ NZW)F 1 mice at ages 4 weeks, 8 weeks, 20 weeks, and >26 weeks (nephritic mice). The DNA fragmentation pattern was determined with an Agilent bioanalyzer. An electron microscopybased TUNEL assay was performed to detect apoptotic chromatin in glomerular membranes, and immunoelectron microscopy was used to determine antibody binding. Transcription levels for nucleases associated with apoptosis and necrosis were determined by real-time polymerase chain reaction.Results. DNA from camptothecin-treated cell lines and BALB/c mouse kidneys, but not that from untreated (NZB ؋ NZW)F 1 mouse kidneys, demonstrated DNA cleavage consistent with apoptotic fragmentation. DNA from (NZB ؋ NZW)F 1 mice was devoid of apoptotic fragmentation, irrespective of the age of the mice, whereas TUNEL-positive chromatin particles were detected in glomerular membranes in nephritic mice. Renal DNase I transcription was reduced in nephritic mice. Nucleosomal DNA fragmentation in response to camptothecin exposure was highly reduced in (NZB ؋ NZW)F 1 mouse kidneys compared with that in their normal counterparts.Conclusion. The results of this study demonstrate that TUNEL-positive chromatin particles are deposited in the glomeruli of nephritic (NZB ؋ NZW)F 1 mice, due to reduced fragmentation and clearance of chromatin.

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Glomerular targets of nephritogenic autoantibodies in systemic lupus erythematosus

Bavel¹,

Fenton²,

Rekvig³

et al. 2008

Arthritis & Rheumatism

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Nucleosomes possess a high affinity for glomerular laminin and collagen IV and bind nephritogenic antibodies in murine lupus-like nephritis

Abstract: Collectively, these results provide firm evidence that dominant target structures for nephritogenic autoantibodies are constituted by TUNEL-positive chromatin associated with glomerular capillary and mesangial matrix membranes at high affinity.

Cited by 63 publications

References 42 publications

Heparin exerts a dual effect on murine lupus nephritis by enhancing enzymatic chromatin degradation and preventing chromatin binding in glomerular membranes

Heparin exerts a dual effect on murine lupus nephritis by enhancing enzymatic chromatin degradation and preventing chromatin binding in glomerular membranes

Reduced fragmentation of apoptotic chromatin is associated with nephritis in lupus‐prone (NZB × NZW)F₁ mice

Glomerular targets of nephritogenic autoantibodies in systemic lupus erythematosus

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Nucleosomes possess a high affinity for glomerular laminin and collagen IV and bind nephritogenic antibodies in murine lupus-like nephritis

Abstract: Collectively, these results provide firm evidence that dominant target structures for nephritogenic autoantibodies are constituted by TUNEL-positive chromatin associated with glomerular capillary and mesangial matrix membranes at high affinity.

Cited by 63 publications

References 42 publications

Heparin exerts a dual effect on murine lupus nephritis by enhancing enzymatic chromatin degradation and preventing chromatin binding in glomerular membranes

Heparin exerts a dual effect on murine lupus nephritis by enhancing enzymatic chromatin degradation and preventing chromatin binding in glomerular membranes

Reduced fragmentation of apoptotic chromatin is associated with nephritis in lupus‐prone (NZB × NZW)F1 mice

Glomerular targets of nephritogenic autoantibodies in systemic lupus erythematosus

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Reduced fragmentation of apoptotic chromatin is associated with nephritis in lupus‐prone (NZB × NZW)F₁ mice