Anti–double‐stranded DNA antibodies, nucleosomes, and systemic lupus erythematosus: A time for new paradigms?

Rekvig, Ole Petter; Nossent, Jiri

doi:10.1002/art.10739

Cited by 92 publications

(93 citation statements)

References 134 publications

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“…Most studies link lupus nephritis to the presence of nephritogenic high avidity anti-dsDNA Ab as detected by C. luciliae immunofluorescence or the Farr radioactivity assay [28][29][30] . Anti-dsDNA Ab are, however, often present long before SLE is clinically apparent and they gradually obtain their nephritogenic potential through repeated antigenic stimulation 28,31,32 . Several short-term prospective studies have shown that intensive anti-dsDNA Ab surveillance can help prevent disease flares such as lupus nephritis 33,34 .…”

Section: Discussionmentioning

confidence: 99%

The Influence of the 1997 Updated Classification Criteria for Systemic Lupus Erythematosus: Epidemiology, Disease Presentation, and Patient Management

Eilertsen¹,

Becker-Merok²,

Nossent³

2009

J Rheumatol

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ABSTRACT. Objective. The 1997 update of the American College of Rheumatology classification criteria (ACR97) for systemic lupus erythematosus (SLE) has not been validated. We determined to what extent their introduction influenced the epidemiology and clinical characteristics of the disease in northern Norway. Methods. Annual incidence and point-prevalence rates, clinical manifestations, and outcome were determined in an inception cohort of patients with SLE in northern Norway, included between 1996 and 2006, using ACR97 criteria (97acr). These findings were compared with a cohort from the same area enrolled 1978-1995 using the 1982 revised criteria ACR82 (82acr). Results. The mean annual incidence of SLE was 3.00 for cohort 97acr (n = 58) versus 2.63 for cohort 82acr (n = 81) (p = 0.5). All patients in the 97acr cohort also fulfilled the 1982 criteria; however, significantly fewer patients presented with discoid rash [odds ratio (OR) 0.31)], arthritis (OR 0.24), renal (OR 0.28) or hematological disorder (OR 0.27), and significantly more with anti-dsDNA (OR 2.57) and antiphospholipid antibodies (OR 27.9). Initial treatment with intravenous pulse methylprednisolone (OR 9.23), azathioprine (OR 6.32), and low-dose aspirin (OR 20.9) was increased in cohort 97acr. Five-(95.2%) and 10-year survival (91.9%) rates were also improved for cohort 97acr. Conclusion. The ACR97 criteria set has construct validity compared to the ACR82 criteria set. SLE incidence remains unchanged in northern Norway, but a significant reduction of renal disease and further improvements in survival rates occurred simultaneously with increased serological surveillance with ELISA-based assays and early immunosuppressive and anticoagulant therapy.

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Section: Discussionmentioning

confidence: 99%

The Influence of the 1997 Updated Classification Criteria for Systemic Lupus Erythematosus: Epidemiology, Disease Presentation, and Patient Management

Eilertsen¹,

Becker-Merok²,

Nossent³

2009

J Rheumatol

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“…Although we have gained insight into requirements for the experimental induction of antibodies to dsDNA (4)(5)(6), the molecular and cellular bases for their generation in SLE are still poorly understood (6)(7)(8). It is believed, however, that the release of apoptotic nucleosomes is central in the immunization process in vivo.…”

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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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“…The presence of pathogenic autoantibody-inducing Th cells specific for chromatin subparticles or histones has also been described in patients with lupus as well as in lupus mice (23)(24)(25). The origin of signals giving rise to their stimulation is still speculative (26). Using overlapping histone peptides covering the four core histones, H2A, H2B, H3, and H4, autoreactive Th cells were characterized at the level of epitopes in normal and (SWR ϫ New Zealand Black (NZB))F 1 (SNF 1 ; haplotype H-2 d/q ) lupus mice as well as in patients with lupus.…”

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confidence: 99%

CD4+ T Cells from (New Zealand Black × New Zealand White)F1 Lupus Mice and Normal Mice Immunized Against Apoptotic Nucleosomes Recognize Similar Th Cell Epitopes in the C Terminus of Histone H3

Fournel

Neichel

Dali

et al. 2003

The Journal of Immunology

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We have previously reported that peptide 88-99 of histone H4 represents a minimal T cell epitope recognized by Th cells from nonautoimmune BALB/c (H-2d/d) mice immunized with nucleosomes. In this study, we tested a panel of overlapping peptides spanning the whole sequences of H4 and H3 for recognition by CD4+ T cells from unprimed (New Zealand Black (NZB) × New Zealand White (NZW))F1 lupus mice (H-2d/z). None of the 11 H4 peptides was recognized by CD4+ T cells from (NZB × NZW)F1 mice. In contrast, these cells proliferated and secreted IL-2, IL-10, and IFN-γ upon ex vivo stimulation with H3 peptides representing sequences 53-70, 64-78, and 68-85. Peptides 56-73 and 61-78 induced the production of IFN-γ and IL-10, respectively, without detectable proliferation, suggesting that they may act as partial agonist of the TCR. Th cells from unprimed BALB/c mice and other lupus-prone mice such as SNF1 (H-2d/q) and MRL/lpr (H-2k/k) mice did not recognize any peptides present within the H3 region 53-85. We further demonstrated that immunization of normal BALB/c mice with syngeneic liver nucleosomes and spleen apoptotic cells, but not with nonapoptotic syngeneic cells, induced Th cell responses against several peptides of the H3 region 53-85. Moreover, we found that this conserved region of H3, which is accessible at the surface of nucleosomes, is targeted by Abs from (NZB × NZW)F1 mice and lupus patients, and contains motifs recognized by several distinct HLA-DR molecules. It might thus be important in the self-tolerance breakdown in lupus.

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Anti–double‐stranded DNA antibodies, nucleosomes, and systemic lupus erythematosus: A time for new paradigms?

Cited by 92 publications

References 134 publications

The Influence of the 1997 Updated Classification Criteria for Systemic Lupus Erythematosus: Epidemiology, Disease Presentation, and Patient Management

The Influence of the 1997 Updated Classification Criteria for Systemic Lupus Erythematosus: Epidemiology, Disease Presentation, and Patient Management

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

CD4+ T Cells from (New Zealand Black × New Zealand White)F1 Lupus Mice and Normal Mice Immunized Against Apoptotic Nucleosomes Recognize Similar Th Cell Epitopes in the C Terminus of Histone H3

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Anti–double‐stranded DNA antibodies, nucleosomes, and systemic lupus erythematosus: A time for new paradigms?

Cited by 92 publications

References 134 publications

The Influence of the 1997 Updated Classification Criteria for Systemic Lupus Erythematosus: Epidemiology, Disease Presentation, and Patient Management

The Influence of the 1997 Updated Classification Criteria for Systemic Lupus Erythematosus: Epidemiology, Disease Presentation, and Patient Management

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

CD4+ T Cells from (New Zealand Black × New Zealand White)F1 Lupus Mice and Normal Mice Immunized Against Apoptotic Nucleosomes Recognize Similar Th Cell Epitopes in the C Terminus of Histone H3

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