title: Sialic acid-binding immunoglobulin-type lectin H-positive plasmacytoid dendritic cells drive spontaneous lupus-like disease development in B6.Nba2 mice.
abstract: OBJECTIVE
  Patients with systemic lupus erythematosus (SLE) often present with elevated levels of interferon-α (IFNα) in serum. Plasmacytoid dendritic cells (pDCs) have been suggested to be the primary source of IFNα in SLE due to their capacity to produce high levels of IFNα. During viral infection, a subset of pDCs expressing sialic acid-binding immunoglobulin-type lectin H (Siglec H) produces the majority of pDC-derived IFNα. The aim of this study was to provide evidence that Siglec H-positive pDCs are pathogenic in the IFNα-dependent B6.Nba2 mouse model of lupus.
  
  
  METHODS
  B6.Nba2 blood dendritic cell antigen 2 (BDCA-2)-diphtheria toxin receptor (DTR)-transgenic (Tg) mice were treated intraperitoneally with DT 3 times weekly starting at 4 weeks or 12 weeks of age and analyzed at 12 weeks and 18 weeks of age, respectively. Lupus-like disease development was measured by the presence of elevated levels of autoantibodies in serum (as determined by enzyme-linked immunosorbent assay), increased expression of IFN-inducible genes (as determined by real-time reverse transcription-polymerase chain reaction), increased IgG immune complex deposition in kidney glomeruli (as determined by immunofluorescence staining), spontaneous lymphocyte activation, and differentiation of B cells into antibody-producing plasma cells (as determined by flow cytometry).
  
  
  RESULTS
  B6.Nba2 mice in which Siglec H-positive pDCs were depleted for 6-8 weeks displayed reduced levels of IFNα-induced gene transcripts and decreased anti-chromatin autoantibody levels in serum, and significantly fewer activated splenic T cells and B cells, germinal center B cells, follicular helper T cells, and splenic plasma cells. In 18-week-old mice, IgG immune complex deposition in kidney glomeruli was similarly reduced.
  
  
  CONCLUSIONS
  The development of lupus-like disease in congenic B6.Nba2 mice depends on Siglec H-positive pDCs. We suggest that depletion of Siglec H-positive pDCs represents a novel cellular target in SLE.
authors.affiliation: Lerner Research Institute, Cleveland Clinic Foundation, and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Davison
authors.forename: Trine N
authors.initials: TN
authors.lastname: Jørgensen
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002843:Chromatin / Q000276:immunology; D003713:Dendritic Cells / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D018858:Germinal Center / Q000276:immunology; D016898:Interferon-alpha / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000378:metabolism*; D013154:Spleen / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001323:Autoantibodies; D002843:Chromatin; D016898:Interferon-alpha; D063265:Sialic Acid Binding Immunoglobulin-like Lectins