Experimental expression in mice and spontaneous expression in human SLE of polyomavirus T-antigen. A molecular basis for induction of antibodies to DNA and eukaryotic transcription factors.

Rekvig, OP; Moens, Ugo; Sundsfjord, Arnfinn; Bredholt, Geir; Osei, Awuku; Haaheim, Håkon; Traavik, Terje; Arnesen, Egil; Haga, Hans‐Jacob

doi:10.1172/jci119373

Cited by 109 publications

(159 citation statements)

References 45 publications

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“…Direct conjugation of Ag to ODN might unveil unexpected immunogenic aspects of DNA; it has been reported that DNA complexed to proteins or peptides induces the production of lupus-like anti-dsDNA Abs (45)(46)(47), whereas immunization with the DNAprotein complex was reported to attenuate murine lupus despite the induction of pathogenic Abs (48). As discussed above, the reasons for the possible deteriorating effects of autoimmune diseases by CpG-protein conjugates need to be clarified.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Murine Airway Eosinophilia and Th2 Cells by Antigen-Conjugated CpG Oligodeoxynucleotides as a Novel Antigen-Specific Immunomodulator

Shirota

Sano

Kimura

et al. 2000

The Journal of Immunology

154

127

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The characteristic features of bronchial asthma reflect the orchestrated activity of Th2 cells. Oligodeoxynucleotides containing CpG motifs (CpG) have recently been highlighted as an immunomodulator that biases toward a Th1-dominant phenotype. We have previously reported that intratracheal coadministration of CpG and allergen inhibited airway eosinophilia and hyperresponsiveness in a synergistic manner. To substantiate the synergism between CpG and Ag, we introduced a covalently linked conjugate between CpG and Ag and examined the efficacy on airway eosinophilia and Th2 cytokine production. We found that the conjugated form of CpG plus Ag was 100-fold more efficient in regulating airway eosinophilia than the unconjugated mixture. The inhibitory effects lasted for at least 2 mo. The inhibition of airway eosinophilia by the conjugate was Ag specific and associated with an improvement of the airway hyperresponsiveness and the unresponsiveness of the Ag-specific Th2 cells in the regional lymph nodes. The CpG-Ag conjugate was 100-fold more effective than the unconjugated mixture for inducing in vitro Th1 differentiation in an IL-12-dependent manner. Our data show that CpG conjugated to Ag can work as a novel Ag-specific immunomodulator and imply that inhalation of allergen-CpG conjugate could be a desensitization therapy for patients with bronchial asthma.

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Section: Discussionmentioning

confidence: 99%

Regulation of Murine Airway Eosinophilia and Th2 Cells by Antigen-Conjugated CpG Oligodeoxynucleotides as a Novel Antigen-Specific Immunomodulator

Shirota

Sano

Kimura

et al. 2000

The Journal of Immunology

154

127

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“…Serum antibodies against dsDNA were detected and titrated by ELISA exactly as described previously (15,36). An anti-dsDNA mAb was included in each ELISA for intraassay validation (15,36).…”

Section: Methodsmentioning

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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“…An enzyme-linked immunosorbent assay (ELISA) was performed to detect antibodies to nucleosomes, H1, dsDNA, DNase I, type IV collagen, heparan sulfate, and ␣-actinin, as described previously (27)(28)(29)(30). Essentially, microtiter plates (MaxiSorp; Nunc, Copenhagen, Denmark) were coated with nucleosomes (10 g/ml as DNA), dsDNA (10 g/ml), H1 (2 g/ml), heparan sulfate (10 g/ml), ␣-actinin (5 g/ml), DNase I (5 g/ml), and type IV collagen (5 g/ml).…”

Section: Methodsmentioning

confidence: 99%

“…All mAb, serum antibodies, and antibodies eluted from kidneys were diluted 2-fold in PBS-0.02% Tween 20. Relevant control antibodies were included in each ELISA for intraassay validation of results (22,29). The Crithidia luciliae immunofluorescence test (CLIFT) was performed to detect anti-dsDNA antibodies, as previously described (31).…”

Section: Methodsmentioning

confidence: 99%

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Critical comparative analyses of anti–α‐actinin and glomerulus‐bound antibodies in human and murine lupus nephritis

Kalaaji¹,

Sturfelt²,

Mjelle³

et al. 2006

Arthritis & Rheumatism

102

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Objective. Although anti-double-stranded DNA (anti-dsDNA) antibodies are important in lupus nephritis, the question regarding which glomerular structures (␣-actinin, nucleosomes, or others) are recognized by nephritogenic anti-dsDNA antibodies is still controversial. In this study, we determined which glomerular structures are recognized by monoclonal and in vivobound nephritogenic antibodies.Methods.Western blotting was used to analyze the ability of nephritogenic anti-dsDNA antibodies to recognize glomerular and nucleosomal structures. Sera from patients with lupus nephritis, sera from random antinuclear antibody-positive patients, and paired antibodies from sera and kidney eluates from nephritic (NZB ؋ NZW)F 1 mice were analyzed for activity against proteins identified by monoclonal nephritogenic antibodies, and against ␣-actinin, dsDNA, nucleosomes, histone H1, heparan sulfate, DNase I, and type IV collagen. Immunoelectron microscopy was used to determine the glomerular localization of ␣-actinin and in vivo-bound autoantibodies in nephritic (NZB ؋ NZW)F 1 mouse kidneys.Results. Anti-␣-actinin antibodies were observed in human and murine lupus nephritis sera and in sera from patients without systemic lupus erythematosus and were not detected in kidney eluates from nephritic mice. Antibodies to dsDNA and histone H1 were detected in all eluates. Western blot analyses revealed that nephritogenic anti-dsDNA antibodies recognized a 32-kd band, identified as histone H1. Competitive enzyme-linked immunosorbent assay demonstrated that nephritogenic monoclonal antibodies, and dominant antibodies eluted from nephritic kidneys, cross-reacted with dsDNA and H1. This cross-reactive anti-H1 specificity was largely absent in sera from those mice. Immunoelectron microscopic analysis of nephritic (NZB ؋ NZW)F 1 mouse kidneys revealed that antibodies eluted from kidneys, but not anti-␣-actinin antibodies, bound to distinct nephritis-associated electrondense structures linked to glomerular basement membranes. Conclusion.Cross-reactive anti-dsDNA/antihistone H1 antibodies, but not anti-␣-actinin antibodies, are central among those deposited in nephritic glomeruli.

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Experimental expression in mice and spontaneous expression in human SLE of polyomavirus T-antigen. A molecular basis for induction of antibodies to DNA and eukaryotic transcription factors.

Abstract: We have previously demonstrated that experimental expression of the polyomavirus transcription factor T-antigen has the potential to induce anti-DNA antibodies in mice. Two sets of independent evidences are presented here that demonstrate a biological relevance for this model.

Cited by 109 publications

References 45 publications

Regulation of Murine Airway Eosinophilia and Th2 Cells by Antigen-Conjugated CpG Oligodeoxynucleotides as a Novel Antigen-Specific Immunomodulator

Regulation of Murine Airway Eosinophilia and Th2 Cells by Antigen-Conjugated CpG Oligodeoxynucleotides as a Novel Antigen-Specific Immunomodulator

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

Critical comparative analyses of anti–α‐actinin and glomerulus‐bound antibodies in human and murine lupus nephritis

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