title: Circulating Apoptotic Microparticles in Systemic Lupus Erythematosus Patients Drive the Activation of Dendritic Cell Subsets and Prime Neutrophils for NETosis.
abstract: OBJECTIVE
  Circulating chromatin-containing apoptotic material and/or neutrophil extracellular traps (NETs) have been proposed to be an important driving force for the antichromatin autoimmune response in patients with systemic lupus erythematosus (SLE). The aim of this study was to determine the exact nature of microparticles in the circulation of SLE patients and to assess the effects of the microparticles on the immune system.
  
  
  METHODS
  We analyzed microparticles isolated from the plasma of patients with SLE, rheumatoid arthritis (RA), and systemic sclerosis (SSc), as well as from healthy subjects. The effects of the microparticles on blood-derived dendritic cells (DCs) and neutrophils were assessed by flow cytometry, enzyme-linked immunosorbent assay, and immunofluorescence microscopy.
  
  
  RESULTS
  In SLE patients, we identified microparticles that were highly positive for annexin V and apoptosis-modified chromatin that were not present in healthy subjects or in RA or SSc patients. These microparticles were mostly CD31+/CD45- (endothelial), partly CD45+/CD66b+ (granulocyte), and negative for B and T cell markers. Microparticles isolated from the plasma of SLE patients increased the expression of the costimulatory surface molecules CD40, CD80, CD83, and CD86 and the production of proinflammatory cytokines interleukin-6, tumor necrosis factor, and interferon-α by blood-derived plasmacytoid DCs (PDCs) and myeloid DCs (MDCs). SLE microparticles also primed blood-derived neutrophils for NETosis. Microparticles from healthy subjects and from RA or SSc patients exhibited no significant effects on MDCs, PDCs, and NETosis.
  
  
  CONCLUSIONS
  Circulating microparticles in SLE patients include a population of apoptotic cell-derived microparticles that has proinflammatory effects on PDCs and MDCs and enhances NETosis. These results underline the important role of apoptotic microparticles in driving the autoimmune response in SLE patients.
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Dieker
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jurjen
authors.initials: J
authors.lastname: Tel
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Elmar
authors.initials: E
authors.lastname: Pieterse
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Astrid
authors.initials: A
authors.lastname: Thielen
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Nils
authors.initials: N
authors.lastname: Rother
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marinka
authors.initials: M
authors.lastname: Bakker
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Fransen
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Henry B P M
authors.initials: HB
authors.lastname: Dijkman
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jo H
authors.initials: JH
authors.lastname: Berden
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jolanda M
authors.initials: JM
authors.lastname: de Vries
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Luuk B
authors.initials: LB
authors.lastname: Hilbrands
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D065206:Extracellular Traps / Q000276:immunology*; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D016898:Interferon-alpha / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009504:Neutrophils / Q000276:immunology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D000097802:CD83 Antigen
chemical_list: D017304:Annexin A5; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D007136:Immunoglobulins; D016898:Interferon-alpha; D015850:Interleukin-6; D017493:Leukocyte Common Antigens; D008562:Membrane Glycoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D014409:Tumor Necrosis Factor-alpha; D000097802:CD83 Antigen; C504120:CEACAM8 protein, human; C508600:IL6 protein, human; C439524:TNF protein, human; C516769:PTPRC protein, human