title: Enhanced activation of dendritic cells by autologous apoptotic microvesicles in MRL/lpr mice.
abstract: BACKGROUND
  Systemic lupus erythematosus is associated with a persistent circulation of modified autoantigen-containing apoptotic debris that might be capable of breaking tolerance. We aimed to evaluate apoptotic microvesicles obtained from lupus or control mice for the presence of apoptosis-associated chromatin modifications and for their capacity to stimulate dendritic cells (DC) from lupus and control mice.
  
  
  METHODS
  Apoptotic microvesicles were in vitro generated from splenocytes, and ex vivo isolated from plasma of both MRL/lpr lupus mice and normal BALB/c mice. Microvesicles were analyzed using flow cytometry. Bone marrow-derived (BM)-DC cultured from MRL/lpr or BALB/c mice were incubated with microvesicles and CD40 expression and cytokine production were determined as measure of activation.
  
  
  RESULTS
  Microvesicles derived from apoptotic splenocytes or plasma of MRL/lpr mice contained more modified chromatin compared to microvesicles of BALB/c mice, and showed enhanced activation of DC, either from MRL/lpr or BALB/c mice, and consecutively an enhanced DC-mediated activation of splenocytes. The content of apoptosis-modified chromatin in microvesicles of apoptotic splenocytes correlated with their potency to induce interleukin-6 (IL-6) production by DC. Microvesicle-activated MRL/lpr DC showed a significant higher production of IL-6 and tumor growth factor-β (TGF-β) compared to BALB/c DC, and were more potent in the activation of splenocytes.
  
  
  CONCLUSIONS
  Apoptotic microvesicles from MRL/lpr mice are more potent activators of DC, and DC from MRL/lpr mice appear relatively more sensitive to activation by apoptotic microvesicles. Our findings indicate that aberrations at the level of apoptotic microvesicles and possibly DC contribute to the autoimmune response against chromatin in MRL/lpr mice.
authors.affiliation: Department of Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands. jurgen.dieker@radboudumc.nl.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Dieker
authors.affiliation: Department of Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands. luuk.hilbrands@radboudumc.nl.
authors.forename: Luuk
authors.initials: L
authors.lastname: Hilbrands
authors.affiliation: Department of Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands. astrid_thielen@hotmail.com.
authors.forename: Astrid
authors.initials: A
authors.lastname: Thielen
authors.affiliation: Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands. henry.dijkman@radboudumc.nl.
authors.forename: Henry
authors.initials: H
authors.lastname: Dijkman
authors.affiliation: Department of Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands. jo.berden@radboudumc.nl.
authors.forename: Jo H
authors.initials: JH
authors.lastname: Berden
authors.affiliation: Department of Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands. johan.vandervlag@radboudumc.nl.|Department of Nephrology, Radboud Institute of Molecular Life Sciences, Radboud University Medical Centre, Geert Grooteplein 10, Nijmegen, 6525, GA, The Netherlands. johan.vandervlag@radboudumc.nl.
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D055252:Cell-Derived Microparticles / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D012680:Sensitivity and Specificity
chemical_list: D001324:Autoantigens