title: FSAP-mediated nucleosome release from late apoptotic cells is inhibited by autoantibodies present in SLE.
abstract: Inefficient clearance of apoptotic cells and the subsequent exposure of the immune system to nuclear contents are crucially involved in the pathogenesis of systemic lupus erythematosus (SLE). Factor VII-activating protease (FSAP) is activated in serum upon contact with dead cells, and releases nucleosomes from late apoptotic cells into the extracellular environment. We investigated whether FSAP-mediated nucleosome release from late apoptotic cells is affected in SLE patients. Nucleosome release in sera of 27 SLE patients and 30 healthy controls was investigated by incubating late apoptotic Jurkat cells with serum and analyzing the remaining DNA content by flow cytometry. We found that nucleosome release in sera of SLE patients with high disease activity was significantly decreased when compared with that in SLE sera obtained during low disease activity or from healthy individuals. Upon removal of IgG/IgM antibodies from SLE sera, nucleosome release was restored. Similarly, monoclonal antinuclear antibodies inhibited nucleosome release in healthy donor serum or by plasma-purified FSAP. This inhibition was lost when Fab fragments were used, suggesting that antigen cross-linking is involved. In conclusion, FSAP-mediated nucleosome release from late apoptotic cells is greatly impaired in SLE patient sera, possibly hampering the clearance of these cells and thereby propagating inflammation.
authors.affiliation: Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Gerben
authors.initials: G
authors.lastname: Marsman
authors.affiliation: Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: Stephan
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Medical Center, University of Groningen, Groningen, The Netherlands.
authors.forename: Karina
authors.initials: K
authors.lastname: de Leeuw
authors.affiliation: Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Bulder
authors.affiliation: Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jessica T
authors.initials: JT
authors.lastname: Ruinard
authors.affiliation: Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: de Jong
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Medical Center, University of Groningen, Groningen, The Netherlands.
authors.forename: Johanna
authors.initials: J
authors.lastname: Westra
authors.affiliation: Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Irene E M
authors.initials: IE
authors.lastname: Bultink
authors.affiliation: Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Voskuyl
authors.affiliation: Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Lucien A
authors.initials: LA
authors.lastname: Aarden
authors.affiliation: Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Luken
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Medical Center, University of Groningen, Groningen, The Netherlands.
authors.forename: Cees G M
authors.initials: CG
authors.lastname: Kallenberg
authors.affiliation: Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.|Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Sacha
authors.initials: S
authors.lastname: Zeerleder
mesh_terms: D000293:Adolescent; D000328:Adult; D000974:Antibodies, Antinuclear / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis / Q000502:physiology; D001323:Autoantibodies / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D007075:Immunoglobulin M / Q000172:deficiency; D007249:Inflammation / Q000209:etiology / Q000276:immunology; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009707:Nucleosomes / Q000276:immunology / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000276:immunology / Q000502:physiology*; D044967:Serum / Q000737:chemistry; D055815:Young Adult
chemical_list: D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D009707:Nucleosomes; C433550:HABP2 protein, human; D012697:Serine Endopeptidases
keywords: Antinuclear antibodies; DAMPs; Factor VII-activating protease; Nucleosomes; Systemic lupus erythematosus