Nucleosome‐restricted antibodies are detected before anti‐dsdna and/or antihistone antibodies in serum of mrl‐mp lpr/lpr and +/+ mice, and are present in kidney eluates of lupus mice with proteinuria

Amoura, Zahir; Chabre, Henri; Koutouzov, Sophie; Lotton, Chantal; Cabrespines, Alban; Bach, J F; Jacob, Laurent

doi:10.1002/art.1780371118

Cited by 194 publications

(150 citation statements)

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“…Nucleosomes from apoptotic cells are shown to be immunogenic for pathogenic autoantibody-inducing T cells in lupus (7). Antinucleosome antibodies are found to be present before anti-double-stranded DNA and antihistone antibodies in MRL-lpr mice (8). Analysis of the relationship between PCD and autoantibody production would contribute to the elucidation of the mechanisms of autoantibody production in SS.…”

Section: Discussionmentioning

confidence: 99%

Lymphocyte apoptosis and apoptosis‐associated gene expression in Sjögren's syndrome

Ogawa

Dang

Kong

et al. 1996

Arthritis & Rheumatism

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Objective. To study the mechanism and regulation of apoptosis in peripheral blood T and B lymphocytes from patients with Sjögren's syndrome (SS). Methods. The mode of in vitro lymphocyte death in the peripheral blood of patients with SS was determined by fluorescence microscopic analysis, terminal deoxynucleotidyl transferase assay, and DNA fragmentation analysis. Apoptotic cell death of T and B cells was determined at 48 hours of culture by fluorescence‐activated cell sorter analysis of propidium iodidestained cells. Messenger RNA (mRNA) expression of bcl‐2, bcl‐x, bax, and c‐myc in T and B cells was determined by enzyme‐linked immunosorbent assaypolymerase chain reaction (ELISA‐PCR). Expression of bcl‐xL and bcl‐xS was determined by Southern blot analysis of PCR products. Gene expression was calculated as the ratio of each gene message to the message of the GAPDH gene. Bcl‐2 protein levels in SS T cells were determined by ELISA. Results. SS T cells showed increased in vitro apoptosis compared with normal T cells (mean ± SD 12.3 ± 4.5% versus 7.3 ± 2.0%; P < 0.01). Freshly isolated SS T cells showed increased expression of bcl‐2 mRNA compared with normal controls (mean ± SD 1.50 ± 0.65 versus 0.88 ± 0.23; P < 0.05). There was no significant difference in levels of bax or c‐myc mRNA in T cells and B cells between SS patients and normal controls. When SS T lymphocytes were cultured in vitro for 72 hours, Bcl‐2 protein levels decreased with time. Conclusion. SS T cells showed accelerated apoptosis in vitro. Freshly isolated SS T cells had increased expression of bcl‐2. An increase in death‐promoter signals and decrease in death‐suppressor signals in vitro may have been responsible, in part, for the apoptosis in SS T lymphocytes.

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Section: Discussionmentioning

confidence: 99%

Lymphocyte apoptosis and apoptosis‐associated gene expression in Sjögren's syndrome

Ogawa

Dang

Kong

et al. 1996

Arthritis & Rheumatism

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“…Age-matched animals of the same sex (female) were used in each experiment. In the present study, MRLϩ/ϩ mice were classified into three groups, according to their serum autoantibody pattern (as assessed by enzyme-linked immunosorbent assay) during the course of disease; 10-week-old pre-autoimmune mice (antichromatin antibody negative), 20-to 30-week-old (anti-nucleosome antibody positive), and 30-to 40-week-old mice (anti-nucleosome and anti-dsDNA antibody positive) [3].…”

Section: Micementioning

confidence: 99%

“…The in vivo basic unit of chromatin, the nucleosome (composed of a histone octamer wrapped by ϳ160-180 of helical base pairs DNA) appears to play a crucial role in the induction of disease. The detection in murine lupus of nucleosome-specific antibodies before the appearance of antibodies directed against its individual components, dsDNA and histones [2,3], and the presence of nucleosome-specific pathogenic T cells in the periphery of young, pre-autoimmune (NZB ϫ SWR)F1 lupusprone mice [4] indicates early autoimmunization with nucleosomes in murine lupus. Similar observations have been made in lupus patients as nucleosome-specific antibodies are detected with high occurrence (80-90%) [5,6].…”

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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“…The presence of nucleosome-restricted antibodies in sera of patients with SLE was reported previously ( 1 9). In addition, nucleosomes have recently been found to be a major immunogenfor induction of autoantibodies in T cells of lupus-prone mice (8), and antibodies to nucleosomes were detected in plasma of such mice prior to the appearance of anti-dsDNA and anti-histone antibodies (9). These results suggest that antibodies to nucleosomes are specifically related to the pathogenesis of SLE.…”

Section: Discussionmentioning

confidence: 87%

“…Nucleosomes, the unit of DNA-histone complexes, rather than naked DNAor free histones have been detected in plasma ofSLE patients (7). In addition, nucleosomes have recently been found to be a major immunogenfor autoantibody-inducing T cells (8) , and antibodies to nucleosomes have been detected earlier than anti-double-stranded (antidsDNA) and anti-histone antibodies in lupus-prone mice (9). The LE factor is an antibody to DNA-histone complexes, but not to free histones or DNAitself (10, ll demonstrated that the binding between antigens and antibodies is dependent upon the presence of anions with an electrostatic influence (12).…”

Section: Introductionmentioning

confidence: 99%

Detection of Polyanion-Restricted Anti-Histone Antibodies in Patients with Systemic Lupus Erythematosus.

et al. 1997

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The nature of the antibodies responsible for lupus erythematosus (LE) cells in systemic lupus erythematosus (SLE) remains obscure. Weexamined whether polyanion-restricted anti-histone antibodies were present in serum of patients with SLEusing Western blotting analysis. Dextran sulfate or alginate was used as a polyanion compoundin place ofDNA. Antibodies which recognized dextran sulfate-histone complexes were present in serum of patients with SLE (17/34, 50% ). These antibodies were detected in most SLE patients positive for LE cells (17/18, 94%) but not in those negative for LE cells or in patients with other collagen diseases. Similar results were obtained using alginate-histone complexes as antigens for Western blotting analysis. The antibodies to dextran sulfate-histone or alginate-histone complexes in serum of SLEpatients were completely absorbed by treatment of serum with DNA-histone complexes, while they were unaffected by treatment with DNAonly. The presence of antibodies to free histones and dextran sulfate-histone complexes did not seem to be related to the titer of anti-single stranded DNAantibody and anti-double stranded DNAantibody. We demonstrated the presence of polyanion-restricted antibodies in SLE, which may be responsible for the LE factor. (Internal Medicine 36: 781-786, 1997)

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Nucleosome‐restricted antibodies are detected before anti‐dsdna and/or antihistone antibodies in serum of mrl‐mp lpr/lpr and +/+ mice, and are present in kidney eluates of lupus mice with proteinuria

Cited by 194 publications

References 13 publications

Lymphocyte apoptosis and apoptosis‐associated gene expression in Sjögren's syndrome

Lymphocyte apoptosis and apoptosis‐associated gene expression in Sjögren's syndrome

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

Detection of Polyanion-Restricted Anti-Histone Antibodies in Patients with Systemic Lupus Erythematosus.

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