title: Insufficient autoantigen presentation and failure of tolerance in a mouse model of rheumatoid arthritis.
abstract: OBJECTIVE
  In the K/BxN mouse model of rheumatoid arthritis, T cells reactive for the self antigen glucose-6-phosphate isomerase (GPI) escape negative selection even though GPI expression is ubiquitous. We sought to determine whether insufficient GPI presentation could account for the failure of negative selection and for the development of arthritis.
  
  
  METHODS
  To increase the antigen presentation of GPI, we generated transgenic mice expressing a membrane-bound form of GPI (mGPI) and crossed them with K/BxN mice. A monoclonal antibody specific for the α-chain of the KRN T cell receptor was generated to examine the fate of GPI-specific T cells.
  
  
  RESULTS
  The mGPI-transgenic mice presented GPI more efficiently and showed a dramatic increase in negative selection and an inhibition of arthritis. Interestingly, thymic negative selection remained incomplete in these mice, and the escaped autoreactive T cells were anergic in the peripheral lymphoid organs, suggesting that enhanced antigen presentation also induces peripheral tolerance. Despite this apparent tolerance induction toward GPI, these mice developed a chronic wasting disease, characterized by colonic inflammation with epithelial dysplasia, as well as a dramatic reduction in Treg cells.
  
  
  CONCLUSIONS
  These data indicate that insufficient autoantigen expression or presentation results in defects of both central and peripheral tolerance in the K/BxN mice. Our findings also support the idea that insufficient autoantigen levels may underlie the development of autoimmunity.
authors.affiliation: University of Chicago, Chicago, Illinois.
authors.forename: Jason
authors.initials: J
authors.lastname: Perera
authors.forename: Xiao
authors.initials: X
authors.lastname: Liu
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Nora E
authors.initials: NE
authors.lastname: Joseph
authors.forename: Liping
authors.initials: L
authors.lastname: Meng
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
authors.forename: Haochu
authors.initials: H
authors.lastname: Huang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017951:Antigen Presentation / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005956:Glucose-6-Phosphate Isomerase / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D016207:Cytokines; D005956:Glucose-6-Phosphate Isomerase; C554960:Gpi1 protein, mouse