Specificity of Monoclonal Anti-nucleosome Auto-antibodies Derived from Lupus Mice

Kramers, Kees; Stemmer, Christian; Monestier, Marc; Vanbruggen, Mcj; RijkeSchilder, Tpm; Hylkema, Machteld N.; Smeenk, R. J. T.; Muller, Sylviane; Berden, J.H.M.

doi:10.1006/jaut.1996.0094

Cited by 35 publications

(28 citation statements)

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“…The initial autoimmune response in these mice occurs months prior to the appearance of serum anti-dsDNA antibodies and is associated with loss of tolerance to histone H2A/H2B/DNA. 59,60 Our results indicating that ERa deficiency is associated with reduced development of anti-H2A/H2B/DNA antibodies in (NZB Â NZW)F 1 females at this early time point suggest that ERa promotes the initial loss of tolerance event The symbols represent mice that were killed when they reached or exceeded 18 months of age. '1' indicates data significantly different than that in ERa þ / þ mice and '2' indicates data significantly different than that in ERa þ /À mice.…”

Section: Discussionmentioning

confidence: 91%

Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice

et al. 2008

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Estrogens promote lupus in humans and some mouse models of this disease. Nonetheless, little is known about the role of estrogen receptors in lupus pathogenesis. Here, we report that in females on the lupus-prone (NZB Â NZW)F 1 background, disruption of estrogen receptor-a (ERa or Esr1) attenuated glomerulonephritis and increased survival. ERa deficiency also retarded development of anti-histone/DNA antibodies, suggesting that ERa promotes loss of immunologic tolerance. Furthermore, ERa deficiency in (NZB Â NZW)F 1 females attenuated the subsequent development of anti-double-stranded DNA (dsDNA) IgG antibodies, which are associated with glomerulonephritis in this model. We provide evidence that ERa may promote lupus, at least in part, by inducing interferon-g, an estrogen-regulated cytokine that impacts this disease. ERa deficiency in (NZB Â NZW)F 1 males increased survival and reduced anti-dsDNA antibodies, suggesting that ERa also modulates lupus in males. These studies demonstrate that ERa, rather than ERb, plays a major role in regulating autoimmunity in (NZB Â NZW)F 1 mice. Furthermore, our results suggest for the first time that ERa promotes lupus, at least in part, by impacting the initial loss of tolerance. These data suggest that targeted therapy disrupting ERa, most likely within the immune system, may be effective in the prevention and/or treatment of lupus.

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Section: Discussionmentioning

confidence: 91%

Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice

et al. 2008

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“…ELISA data 11,13,14,17,18 demonstrate that the chromatin epitope recognized by PL2-6 is a conformational one, involving a ternary complex of H2A, H2B and DNA. Even though the epitope is present in the binary complex of H2A and H2B, reactivity is augmented by complexing with (mixed sequence) DNA on a surface, as in ELISA plates, or in solution.…”

Section: Discussionmentioning

confidence: 97%

“…During prophase the epichromatin epitope is accessible part of a program to analyze the mechanisms underlying autoimmune disorders, several mouse strains have been identified that spontaneously develop SLE and are the source of a number of monoclonal anti-nucleosomal antibodies. 13,14 We have employed some of these mouse monoclonal antibodies (mAbs) to probe nuclear structural domains. Historically, this approach was useful in identifying the histone H3 variants of centromeric regions employing CREST autoantibodies from scleroderma patients.…”

Section: Introductionmentioning

confidence: 99%

“…Most of our current knowledge about the binding specificity of the epichromatin antibody (PL2-6) is derived from ELISA studies. 11,13,14,17,18 We know, based upon ELISA quantitation, that PL2-6 binds strongly to mononucleosomes and to a ternary complex of histones H2A + H2B + DNA, weakly to H2A + H2B and very weakly to H3 + H4 + DNA, individual histones or DNA alone. In the present immunoblotting results with both native Hela and recombinant H2A and H2B.…”

Section: Introductionmentioning

confidence: 99%

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An epichromatin epitope: Persistence in the cell cycle and conservation in evolution

Olins¹,

Langhans²,

Monestier³

et al. 2011

nucleus

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NucleusVolume 2 Issue 1 U2OS and HL-60/S4 cells by deconvolution immunofluorescence microscopy with the aim of searching for chromatin substructures. One anti-nucleosome antibody (PL2-6) specifically stained a chromatin compartment at the periphery of interphase nuclei, as well as staining the surface of mitotic chromosomes. We suggest that this compartment represents a unique surface chromatin conformation, to which we assign the name "epichromatin". Furthermore, we formulate an "epichromatin hypothesis", suggesting that this chromatin may play a crucial role in organizing interphase nuclear architecture, justifying its conservation in the evolution of cell structure. Results

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“…32,33 Briefly, Immulon II 96-well plates (Dynatech, Chantilly, VA) were coated overnight in PBS at 4°C with 5 g/mL immunoglobulin G2a (IgG2a) monoclonal antinucleosome antibody denoted PA-1. The plates were blocked at 37°C for 1 hour with PBS containing 1% bovine serum albumin (BSA; Sigma) and 0.05% Tween 20.…”

Section: Detection Of Nucleosomes In Plasmamentioning

confidence: 99%

Role of macrophages in the generation of circulating blood nucleosomes from dead and dying cells

Jiang

Reich

Pisetsky

2003

Blood

104

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After apoptosis or necrosis, macrophages clear dead cells by phagocytosis. Although this process is efficient, circulating nucleosomes can occur in certain diseases, presumably reflecting either increased production or impaired clearance. To investigate the generation of blood nucleosomes, graded numbers of apoptotic and necrotic cells were administered to healthy mice, and levels of blood nucleosomes and DNA were determined. Using Jurkat cells as a model, nucleosomes and DNA were detected in the blood after the administration of 10 8 apoptotic or necrotic cells per mouse by the intraperitoneal route. The kinetics of the response were similar for both types of cells. The role of macrophages was assessed by eliminating these cells with clodronate liposomes or silica. Although clodronate treatment alone produced a peak level of blood DNA, the subsequent administration of dead cells caused no change in DNA levels. In contrast, silica treatment alone did not elicit a blood DNA response, though this treatment limited the rise in DNA from administered cells. Molecular studies showed that the blood DNA following the administration of apoptotic or necrotic cells arose from the mouse and the Jurkat cells, and its size distribution was consistent with apoptosis. Together, these findings suggest that the generation of blood nucleosomes depends on macrophages, with apoptosis a concomitant of a high burden of dead and dying cells. IntroductionCell death is integral to the biology of the mammalian organism and varies in form and mechanism. Two types of cell death have been broadly defined. Apoptotic or programmed cell death is a regulated and orderly process mediated by a cascade of enzymes that rearrange and degrade cell constituents. Apoptosis occurs in physiologic and pathologic settings and can be triggered by a variety of stimuli that initiate a stereotyped death program. In contrast, necrotic or accidental cell death results from cell injury and is frequently a concomitant of inflammation, whether induced by physical or chemical means. [1][2][3][4] Death by necrosis does not involve the regulated action of enzymes and leads to cellular changes that differ in phenotype and structure from apoptotic death. Although this dichotomy may be an oversimplification, 5,6 it is nevertheless useful in assessing the impact of dead and dying cells on the organism.In addition to their structure and phenotype, apoptotic cells and necrotic cells may differ in their interaction with the immune system. As shown in in vitro studies, apoptotic cells are rapidly engulfed by mononuclear phagocytes that bind an array of cell surface molecules, including phosphatidylserine. Phosphatidylserine appears on the surface of the apoptotic cell with the loss of membrane symmetry. [7][8][9][10][11][12] In addition to signaling uptake by phagocytosis, phosphatidylserine binding may induce an antiinflammatory state because of the production of mediators such as transforming growth factor-␤ (TGF-␤). [13][14][15] Like apoptotic cells, necrotic cells are eng...

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Specificity of Monoclonal Anti-nucleosome Auto-antibodies Derived from Lupus Mice

Cited by 35 publications

References 0 publications

Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice

Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice

An epichromatin epitope: Persistence in the cell cycle and conservation in evolution

Role of macrophages in the generation of circulating blood nucleosomes from dead and dying cells

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