Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease

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• 作者：Eva N Hadaschik (1)
  Xiaoying Wei (1) (2)
  Harald Leiss (3)
  Britta Heckmann (1)
  Birgit Niederreiter (3)
  G眉nter Steiner (3)
  Walter Ulrich (4)
  Alexander H Enk (1)
  Josef S Smolen (3)
  Georg H Stummvoll (3)
  
  1. Department of Dermatology ; University of Heidelberg ; Im Neuenheimer Feld 440 ; 69120 ; Heidelberg ; Germany
  2. Department of Pathology ; Affiliated Zhong-Da Hospital ; Southeast University ; 87 Dingjia Bridge ; Gulou ; 210009 ; Nanjing ; China
  3. Department of Rheumatology ; Medical University of Vienna ; Wahringer Gurtel 18-20 ; 1090 ; Vienna ; Austria
  4. Department of Pathology ; Hietzing Hospital ; Wolkersbergenstrasse 1 ; 1130 ; Vienna ; Austria
  
• 刊名：Arthritis Research & Therapy
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：17
• 期：1
• 全文大小：3,958 KB
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• 刊物主题：Rheumatology; Orthopedics;
• 出版者：BioMed Central
• ISSN：1478-6354

文摘

Introduction 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. Conclusion Our observations support the hypothesis that lupus-like autoimmune features develop in the absence of functional Tregs.