title: Mouse dendritic cells matured by ingestion of apoptotic blebs induce T cells to produce interleukin-17.
abstract: OBJECTIVE
  Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of antinuclear autoantibodies. Increased apoptosis and reduced clearance of apoptotic material have been assigned a role in the pathogenesis of SLE, but the underlying mechanisms remain elusive. During apoptosis apoptotic blebs are formed in which autoantigens are clustered. The cellular remnants after blebbing are referred to as apoptotic cell bodies. We undertook this study to compare the effects of apoptotic blebs and apoptotic cell bodies on maturation of dendritic cells (DCs) and their T cell stimulatory capacity in a murine setting.
  
  
  METHODS
  The uptake by DCs of apoptotic blebs and apoptotic cell bodies was analyzed by flow cytometry and confocal microscopy. DC maturation and DC-induced T cell activation were determined by measuring expression of costimulatory molecules using flow cytometry and by measuring production of cytokines using enzyme-linked immunosorbent assay.
  
  
  RESULTS
  DCs internalized apoptotic blebs more efficiently than apoptotic cell bodies. Incubation of DCs with apoptotic blebs resulted in increased CD40 and CD86 expression and increased interleukin-6 (IL-6) and tumor necrosis factor alpha production, while apoptotic cell bodies had no stimulatory effects. Using chloroquine, apoptotic bleb-induced DC maturation was shown to be independent of Toll-like receptors 3, 7, and 9. Interestingly, in cocultures with allogeneic T cells, bleb-matured DCs induced production of IL-2, interferon-gamma, and, in particular, IL-17, suggesting a Th1/Th17 response.
  
  
  CONCLUSIONS
  Apoptotic blebs, in contrast to apoptotic cell bodies, induce DC maturation, thereby providing DCs with increased Th17 cell stimulatory capacity. These data imply that apoptotic bleb-induced DC maturation represents an important driving force in the autoimmune response in SLE.
authors: Department of Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Justin H
authors: JH
authors: Fransen
authors: Luuk B
authors: LB
authors: Hilbrands
authors: Jurjen
authors: J
authors: Ruben
authors: Monique
authors: M
authors: Stoffels
authors: Gosse J
authors: GJ
authors: Adema
authors: Johan
authors: J
authors: van der Vlag
authors: Jo H
authors: JH
authors: Berden
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001324:Autoantigens / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D022081:Cell Surface Extensions / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D018613:Microscopy, Confocal; D010587:Phagocytosis; D015363:Quinolones / Q000633:toxicity; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: C120195:4-nitroquinolone-1-oxide; D001324:Autoantigens; D020381:Interleukin-17; D015363:Quinolones; D015112:4-Nitroquinoline-1-oxide