Circulating plasma levels of nucleosomes in patients with systemic lupus erythematosus. Correlation with serum antinucleosome antibody titers and absence of clear association with disease activity

Amoura, Zahir; Piette, Jean‐Charles; Chabre, Henri; Cacoub, Patrice; Papo, Thomas; Wechsler, B.; Bach, Jean‐François; Koutouzov, Sophie

doi:10.1002/art.1780401217

Cited by 167 publications

(134 citation statements)

References 41 publications

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“…The DNA in SLE IIF could be of exogenous microbial origin or could be derived from endogenous dying cells. The latter possibility is supported by the presence of elevated levels of circulating apoptotic cells and DNA in the form of nucleosomes (25,26), an increased rate of apoptosis (27)(28)(29), and decreased clearance of apoptotic cells in SLE patients (30). We were also able to demonstrate that apoptotic cells combined with IgG purified from serum of SLE patients (SLE IgG) triggered IFN␣ production in normal peripheral blood mononuclear cells (PBMCs) (31).…”

mentioning

confidence: 79%

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

Lövgren

Eloranta

Båve

et al. 2004

Arthritis & Rheumatism

504

411

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Objective. To investigate the release of interferon-␣ (IFN␣)-inducing material by necrotic or apoptotic cells, its properties, and the necessity of autoantibodies from systemic lupus erythematosus (SLE) patients for the interferogenic activity.Methods. U937 monocytic leukemia cells or peripheral blood mononuclear cells (PBMCs) were rendered necrotic by freeze-thawing or apoptotic by treatment with ultraviolet light. Cell culture supernatants from these cells and IgG from SLE patients (SLE IgG) were added to cultures of normal PBMCs or purified plasmacytoid dendritic cells (PDCs). The importance of nucleic acids for IFN␣ induction was investigated by RNase and DNase treatment. The IFN␣ levels were measured by immunoassay.Results. Both necrotic and apoptotic U937 cells released material that, combined with SLE IgG, induced IFN␣ production in PDCs. The release from apoptotic cells occurred with a 16-hour delay, in late apoptosis. Also, normal PBMCs released IFN␣-inducing material, but only during necrosis. The interferogenic activity of the necrotic material required the presence of RNA, while both RNA and DNA were important in the apoptotic material. In both cases, the presence of SLE IgG was necessary, and its activity correlated with the presence of antibodies to RNA-binding proteins, but not anti-DNA antibodies.Conclusion. Necrotic and late apoptotic cells release material that, combined with SLE IgG, induces production of IFN␣ in PDCs. The IFN␣ inducers probably consist of immune complexes (ICs) containing RNA and possibly DNA as essential interferogenic components. The presence of such interferogenic ICs could explain the ongoing production of IFN␣ in SLE and could be of etiopathogenic importance.

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mentioning

confidence: 79%

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

Lövgren

Eloranta

Båve

et al. 2004

Arthritis & Rheumatism

504

411

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“…Indeed, high levels of circulating nucleosomes have been found in some patients with SLE (41). High titers of IgG against nucleosomal antigens were also found in 2 patients with a heterozygous nonsense mutation in exon 2 of DNase I (42).…”

Section: Discussionmentioning

confidence: 99%

Cooperation between C1q and DNase I in the clearance of necrotic cell–derived chromatin

Gaipl¹,

Beyer²,

Heyder³

et al. 2004

Arthritis & Rheumatism

105

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Objective. The efficient uptake of dying cells by phagocytes is essential to the avoidance of chronic inflammation. Some human autoimmune responses are thought to be driven by autoantigens from apoptotic or necrotic cells. We analyzed the role of C1q and DNase I in the disposal of necrotic cell-derived chromatin because deficiencies in these serum factors predispose to the development of systemic autoimmune disorders, such as systemic lupus erythematosus.Methods. Human necrotic peripheral blood lymphocytes were incubated in cell culture medium supplemented with various sera or serum components. Chromatin degradation was monitored by measuring the residual DNA content by flow cytometry. The uptake of necrotic cell-derived nuclei was analyzed by in vitro phagocytosis assays.Results. Reconstitution of C1q-depleted serum with C1q strongly increased its ability to degrade necrotic cell-derived chromatin. Although C1q itself displayed no DNase activity, it strongly augmented the activity of serum DNase I. Whereas an excess of recombinant DNase I degraded chromatin in the absence of C1q, efficient uptake of the predigested material by monocyte-derived phagocytes required the presence of C1q. These data show that C1q and DNase I cooperate in the degradation of chromatin from necrotic cells. Furthermore, C1q was found to be necessary for effective uptake of degraded chromatin by monocyte-derived phagocytes.Conclusion. C1q or DNase I deficiencies may precipitate autoimmunity in humans by a mechanism similar to that of other molecules that are involved in the safe, efficient, and rapid disposal of dying cells.

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“…Our data show that there does not appear to be any intrinsic functional defect of macrophages from young MRLϩ/ϩ mice to recognize and phagocytose apoptotic thymocytes. It is interesting to note that we found that challenge of macrophages from young MRLϩ/ϩ mice with nucleosomes (as a mimic of in vivo increased cell apoptosis in lupus) [18][19][20][21][22] markedly reduced their ability to phagocytose apoptotic cells. The inhibitory effect elicited by nucleosomes was almost achieved with low concentrations of the autoantigen, and was not a consequence of any cytotoxic effect.…”

Section: Discussionmentioning

confidence: 99%

“…Increased rates of spontaneous cell apoptosis in vitro have been detected both in human and mouse models of SLE [18][19][20]. Thus, these defects in apoptosis could account for the presence of the elevated concentrations of nucleosomes found in the circulation of lupus patients [21,22]. This increase of nucleosomes might be further augmented in lupus patients if cells dying by apoptosis failed to undergo surface changes recognized by phagocytes or if there were an intrinsic defect in the capacity of the macrophages from affected individuals to clear apoptotic cells.…”

Section: Introductionmentioning

confidence: 99%

Nucleosomes inhibit phagocytosis of apoptotic thymocytes by peritoneal macrophages from MRL+/+ lupus-prone mice

Laderach

Bach

Koutouzov

1998

Journal of Leukocyte Biology

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The nucleosome, the basic structure of chromatin and normal product of cell apoptosis, plays a pivotal role both in the induction and the pathogenesis of systemic lupus erythematosus (SLE). Nucleosomes have been found to circulate at high levels in patients with SLE and apoptosis of lymphoid cells is increased during human and murine lupus. In this study, we examined the presence of possible defects in clearance mechanisms of apoptotic cells in murine lupus, and questioned further whether nucleosomes could compromise this phagocytic process. There did not appear to be any intrinsic functional defect of macrophages from young MRL؉/؉ lupus-prone mice to recognize and phagocytose apoptotic thymocytes. Nucleosomes, as a mimic of increased cell apoptotsis in vivo, induced a strong, dose-dependent, inhibition of phagocytosis of apoptotic thymocytes by young, pre-autoimmune, macrophages of MRL؉/؉ mice, whereas macrophages of non-autoimmune C3H mice only exhibited a trend to inhibition. The nucleosome-elicited inhibitory effect persisted during the development of the autoimmune response and appeared to be specific for the molecular mechanisms involved in macrophage phagocytosis of apoptotic cells. Our data suggest that nucleosome elicited inhibition of phagocytosis of apoptotic cells by MRL؉/؉ macrophages before the onset of the autoimmune response contribute, in a positive loop, to sustain and/or augment the levels of circulating (and potentially immunogenic) nucleosomes in lupus. J. Leukoc. Biol. 64: 774-780; 1998.

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Circulating plasma levels of nucleosomes in patients with systemic lupus erythematosus. Correlation with serum antinucleosome antibody titers and absence of clear association with disease activity

Cited by 167 publications

References 41 publications

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

Cooperation between C1q and DNase I in the clearance of necrotic cell–derived chromatin

Nucleosomes inhibit phagocytosis of apoptotic thymocytes by peritoneal macrophages from MRL+/+ lupus-prone mice

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