Anti‐DNA Antibodies Cross‐reacting with Laminin Inhibit Trophoblast Attachment and Migration: Implications for Recurrent Pregnancy Loss in SLE Patients

Qureshi, Faisal; Yang, Yan; Jaques, S. M.; Johnson, Matthew P.; Naparstek, Yaakov; Ulmansky, Rina; Schuger, Lucy

doi:10.1111/j.8755-8920.2000.440302.x

Cited by 38 publications

(34 citation statements)

References 24 publications

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“…1 An association between autoantibodies and gestational loss has been identifi ed, especially for antiphospholipid antibodies (APA). Other antibodies such as those against thyroid components, nuclear antigens and deoxyribonucleic acid (DNA) fractions 2 have also been associated with gestational loss and preeclampsia. 3 Venous thrombosis in the mother has been associated with RSA in several series.…”

Section: Introductionmentioning

confidence: 99%

Association of anticardiolipin antibody and C677T in methylenetetrahydrofolate reductase mutation in women with recurrent spontaneous abortions: a new path to thrombophilia?

et al. 2005

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RESULTS: ACA was detected in 11 women with RSA and one fertile woman. Heterozygous C677T was detected in 59 women with RSA and 35 fertile women. Concomitant presence of ACA and C677T was found in eight women with RSA and no fertile women (p < 0.01). DISCUSSION:The meaning of the association between C677T mutation in the MTHFR gene and ACA is still not clear. It is possible that an inherited factor that alone would not strongly predispose a woman to thrombosis could, when associated with an acquired factor, start the process and increase the likelihood of thrombosis expression.CONCLUSIONS: ACA and C677T in the MTHFR gene are statistically associated with RSA. The association of these two conditions is a new fi nding in thrombogenic factors and RSA.

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Section: Introductionmentioning

confidence: 99%

Association of anticardiolipin antibody and C677T in methylenetetrahydrofolate reductase mutation in women with recurrent spontaneous abortions: a new path to thrombophilia?

et al. 2005

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“…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). It is unclear whether antibodies form complexes with chromatin in circulation or in situ in glomeruli.…”

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confidence: 99%

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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“…However, the pathways by which these antibodies act as a pathogenic factor are controversial. Diverse models have been suggested that involve interaction pathways that differ from pure antibody binding to their homologous antigens (dsDNA or nucleosomes [7,[10][11][12][13]), to cross-reactions with glomerular constituents such as ␣-actinin (14,15), laminin (16)(17)(18), mesangial cells (19,20), or mesangial matrix structures (19,21,22). Because one therapeutic strategy may be to inhibit complex formation of antinucleosome antibodies with their glomerular target antigens, it is crucial to determine the nature of these structures.…”

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confidence: 99%

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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Anti‐DNA Antibodies Cross‐reacting with Laminin Inhibit Trophoblast Attachment and Migration: Implications for Recurrent Pregnancy Loss in SLE Patients

Abstract: These studies suggest that anti-DNA antibodies cross-reacting with LNs may play a role in early pregnancy failure in SLE patients by interfering with placental implantation.

Cited by 38 publications

References 24 publications

Association of anticardiolipin antibody and C677T in methylenetetrahydrofolate reductase mutation in women with recurrent spontaneous abortions: a new path to thrombophilia?

Association of anticardiolipin antibody and C677T in methylenetetrahydrofolate reductase mutation in women with recurrent spontaneous abortions: a new path to thrombophilia?

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

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Anti‐DNA Antibodies Cross‐reacting with Laminin Inhibit Trophoblast Attachment and Migration: Implications for Recurrent Pregnancy Loss in SLE Patients

Abstract: These studies suggest that anti-DNA antibodies cross-reacting with LNs may play a role in early pregnancy failure in SLE patients by interfering with placental implantation.

Cited by 38 publications

References 24 publications

Association of anticardiolipin antibody and C677T in methylenetetrahydrofolate reductase mutation in women with recurrent spontaneous abortions: a new path to thrombophilia?

Association of anticardiolipin antibody and C677T in methylenetetrahydrofolate reductase mutation in women with recurrent spontaneous abortions: a new path to thrombophilia?

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

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