Serum amyloid P component binds to cell nuclei in vitro and to in vivo deposits of extracellular chromatin in systemic lupus erythematosus.

Breathnach, S.M.; Kofler, Heinz; Sepp, Norbert; Ashworth, J.; Woodrow, David; Pepys, Mark B.; Hintner, Helmut

doi:10.1084/jem.170.4.1433

Cited by 68 publications

(43 citation statements)

References 14 publications

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“…In a recent report (45), Bickerstaff et al showed that in an otherwise healthy strain of mice, targeted deletion of the SAP gene led to the development of antinuclear autoimmunity and severe glomerulonephritis. Like CRP, SAP binds and can solubilize chromatin (46), and it binds to apoptotic and necrotic cells (47,48). Thus, the SLE-like phenotype of SAP-deficient mice was linked to their impaired handling and degradation of chromatin, which allowed for increased anti-DNA responses (45).…”

Section: Discussionmentioning

confidence: 99%

Delayed lupus onset in (NZB × NZW)F₁ mice expressing a human C‐reactive protein transgene

Szalai

Weaver

McCrory

et al. 2003

Arthritis & Rheumatism

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Objective. Human C-reactive protein (CRP) binds apoptotic cells and alters blood clearance of injected chromatin in mice. To test whether CRP participates in the pathogenesis of systemic lupus erythematosus (SLE), we examined disease development in lupusprone (NZB ؋ NZW)F 1 (NZB/NZW) mice expressing a human CRP transgene (hCRPtg/BW).Methods. Mortality was monitored, proteinuria was determined by dipstick, and serum levels of human CRP and anti-double-stranded DNA (anti-dsDNA) were determined by enzyme-linked immunosorbent assay in NZB/NZW and hCRPtg/BW mice. Thin sections of kidneys were analyzed by immunofluorescence microscopy to compare deposition of IgG, IgM, C3, and human CRP, and electron microscopy was used to reveal differences in ultrastructure. In situ hybridization was performed to detect human CRP messenger RNA expression.Results. The hCRPtg/BW mice had less proteinuria and longer survival than NZB/NZW mice. They also had lower IgM and higher IgG anti-dsDNA titers than NZB/NZW mice, although the differences were transient and small. In hCRPtg/BW mice, accumulation of IgM and IgG in the renal glomeruli was delayed, reduced, and more mesangial than in NZB/NZW mice, while end-stage accumulation of IgG, IgM, and C3 in the renal cortex was prevented. There was less glomerular podocyte fusion, basement membrane thickening, mesangial cell proliferation, and occlusion of capillary lumens in hCRPtg/BW mice, but dense deposits in the mesangium were increased. With disease progression in hCRPtg/BW mice, there was little rise in the plasma CRP level, but CRP in the kidneys became increasingly apparent due to local, disease-independent, age-related expression of the transgene.Conclusion. In hCRPtg/BW mice, CRP protects against SLE by increasing blood and mesangial clearance of immune complexes and by preventing their accumulation in the renal cortex.

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Section: Discussionmentioning

confidence: 99%

Delayed lupus onset in (NZB × NZW)F₁ mice expressing a human C‐reactive protein transgene

Szalai

Weaver

McCrory

et al. 2003

Arthritis & Rheumatism

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“…Each subunit monomer has two Ca 2+ -binding sites and shows Ca 2+ -dependent binding to many different ligands, including certain oligosaccharides, glycosaminoglycans (Hamazaki 1987), fibronectin , C-reactive protein (Swanson et al, 1992), aggregated IgG (Brown and Anderson 1993), C1q (Sorensen et al, 1996), complement C4-binding protein (Sorensen et al, 1996), DNA (Pepys and Butler 1987), chromatin (Breathnach et al, 1989), histones (Hicks et al, 1992), and phosphoethanolamine-containing compounds such as phosphatidylethanolamine (Emsley et al, 1994). Interaction with these ligands localises SAP to elastic microfibrils , glomerular and alveolar basement membrane, arterioles, bronchioles, sarcolemma of cardiac and smooth muscle (Dyck et al, 1980), and all forms of amyloid .…”

Section: Serum Amyloid P Componentmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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“…In the presence of calcium ions, SAP can bind to several ligands such as amyloid fibrils of any type (4), agarose (8), heparin and dermatan sulfate (9), C1q (10,11), C4 binding protein (12,13), laminin (14), type V collagen (15), and phosphoethanolaminecontaining compounds such as phosphatidylethanolamine (16,17), DNA (18), chromatin (19,20), and histones (21,22).…”

Section: H Uman Serum Amyloid P Component (Sap)mentioning

confidence: 99%

Chromatin-Independent Binding of Serum Amyloid P Component to Apoptotic Cells

Familian

Zwart

et al. 2001

The Journal of Immunology

111

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Human serum amyloid P component (SAP) is a glycoprotein structurally belonging to the pentraxin family of proteins, which has a characteristic pentameric organization. Mice with a targeted deletion of the SAP gene develop antinuclear Abs, which was interpreted as evidence for a role of SAP in controlling the degradation of chromatin. However, in vitro SAP also can bind to phosphatidylethanolamine, a phospholipid which in normal cells is located mainly in the inner leaflet of the cell membrane, to be translocated to the outer leaflet of the cell membrane during a membrane flip-flop. We hypothesized that SAP, because of its specificity for phosphatidylethanolamine, may bind to apoptotic cells independent of its nuclear binding. Calcium-dependent binding of SAP to early, nonpermeable apoptotic Jurkat, SKW, and Raji cells was indeed observed. Experiments with flip-flopped erythrocytes confirmed that SAP bound to early apoptotic cells via exposed phosphatidylethanolamine. Binding of SAP was stronger to late, permeable apoptotic cells. Experiments with enucleated neutrophils, with DNase/RNase treatment of late apoptotic Jurkat cells, and competition experiments with histones suggested that binding of SAP to late apoptotic cells was largely independent of chromatin. Confocal laser microscopic studies indeed suggested that SAP bound to these apoptotic cells mainly via the blebs. Thus, this study shows that SAP binds to apoptotic cells already at an early stage, which raises the possibility that SAP is involved in dealing with apoptotic cells in vivo.

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Serum amyloid P component binds to cell nuclei in vitro and to in vivo deposits of extracellular chromatin in systemic lupus erythematosus.

Cited by 68 publications

References 14 publications

Delayed lupus onset in (NZB × NZW)F₁ mice expressing a human C‐reactive protein transgene

Delayed lupus onset in (NZB × NZW)F₁ mice expressing a human C‐reactive protein transgene

Extracellular Chaperones and Amyloids

Chromatin-Independent Binding of Serum Amyloid P Component to Apoptotic Cells

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Serum amyloid P component binds to cell nuclei in vitro and to in vivo deposits of extracellular chromatin in systemic lupus erythematosus.

Cited by 68 publications

References 14 publications

Delayed lupus onset in (NZB × NZW)F1 mice expressing a human C‐reactive protein transgene

Delayed lupus onset in (NZB × NZW)F1 mice expressing a human C‐reactive protein transgene

Extracellular Chaperones and Amyloids

Chromatin-Independent Binding of Serum Amyloid P Component to Apoptotic Cells

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Delayed lupus onset in (NZB × NZW)F₁ mice expressing a human C‐reactive protein transgene

Delayed lupus onset in (NZB × NZW)F₁ mice expressing a human C‐reactive protein transgene