title: Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease.
abstract: BACKGROUND
  Scurfy mice are deficient in regulatory T cells (Tregs), develop a severe, generalized autoimmune disorder that can affect almost every organ and die at an early age. Some of these manifestations resemble those found in systemic lupus erythematosus (SLE). In addition, active SLE is associated with low Treg numbers and reduced Treg function, but direct evidence for a central role of Treg malfunction in the pathophysiology of lupus-like manifestations is still missing. In the present study, we characterize the multiorgan pathology, autoantibody profile and blood count abnormalities in scurfy mice and show their close resemblances to lupus-like disease.
  
  
  METHODS
  Scurfy mice have dysfunctional Tregs due to a genetic defect in the transcription factor Forkhead box protein 3 (Foxp3). We analyzed skin, joints, lung and kidneys of scurfy mice and wild-type (WT) controls by conventional histology and immunofluorescence (IF) performed hematological workups and tested for autoantibodies by IF, immunoblotting and enzyme-linked immunosorbent assay. We also analyzed the intestines, liver, spleen and heart, but did not analyze all organs known to be affected in scurfy mice (such as the testicle, the accessory reproductive structures, the pancreas or the eyes). We transferred CD4+ T cells of scurfy or WT mice into T cell-deficient B6/nude mice.
  
  
  RESULTS
  We confirm previous reports that scurfy mice spontaneously develop severe pneumonitis and hematological abnormalities similar to those in SLE. We show that scurfy mice (but not controls) exhibited additional features of SLE: severe interface dermatitis, arthritis, mesangioproliferative glomerulonephritis and high titers of anti-nuclear antibodies, anti-double-stranded DNA antibodies, anti-histone antibodies and anti-Smith antibodies. Transfer of scurfy CD4+ T cells (but not of WT cells) induced autoantibodies and inflammation of lung, skin and kidneys in T cell-deficient B6/nude mice.
  
  
  CONCLUSIONS
  Our observations support the hypothesis that lupus-like autoimmune features develop in the absence of functional Tregs.
authors.affiliation: Department of Dermatology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany. eva.hadaschik@med.uni-heidelberg.de.
authors.forename: Eva N
authors.initials: EN
authors.lastname: Hadaschik
authors.affiliation: Department of Dermatology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany. xiaoying.wei@med.uni-heidelberg.de.|Department of Pathology, Affiliated Zhong-Da Hospital, Southeast University, 87 Dingjia Bridge, Gulou, 210009, Nanjing, China. xiaoying.wei@med.uni-heidelberg.de.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Rheumatology, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria. harald.leiss@meduniwien.ac.at.
authors.forename: Harald
authors.initials: H
authors.lastname: Leiss
authors.affiliation: Department of Dermatology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany. britta.heckmann@med.uni-heidelberg.de.
authors.forename: Britta
authors.initials: B
authors.lastname: Heckmann
authors.affiliation: Department of Rheumatology, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria. birgit.niederreiter@meduniwien.ac.at.
authors.forename: Birgit
authors.initials: B
authors.lastname: Niederreiter
authors.affiliation: Department of Rheumatology, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria. guenter.steiner@meduniwien.ac.at.
authors.forename: Günter
authors.initials: G
authors.lastname: Steiner
authors.affiliation: Department of Pathology, Hietzing Hospital, Wolkersbergenstrasse 1, 1130, Vienna, Austria. walter.ulrich@wienkav.at.
authors.forename: Walter
authors.initials: W
authors.lastname: Ulrich
authors.affiliation: Department of Dermatology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany. alexander.enk@med.uni-heidelberg.de.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Enk
authors.affiliation: Department of Rheumatology, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria. josef.smolen@wienkav.at.
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.affiliation: Department of Rheumatology, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria. georg.stummvoll@meduniwien.ac.at.
authors.forename: Georg H
authors.initials: GH
authors.lastname: Stummvoll
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004247:DNA / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D006657:Histones / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006657:Histones; D004247:DNA