title: T cell epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the HLA class II haplotype DRB1*0301/DQB1*0201.
abstract: OBJECTIVE
  T cells are implicated in the production of anti-La/SSB and anti-Ro/SSA autoantibodies commonly associated with the DR3/DQ2 haplotype in systemic lupus erythematosus and Sjögren's syndrome. This study was undertaken to investigate the DR3/DQ2-restricted T cell response to wild-type human La (hLa) and a truncated form of mutant La.
  
  
  METHODS
  Humanized transgenic mice expressing HLA-DRB1*0301/DQB1*0201 (DR3/DQ2) were immunized with recombinant antigen and examined for development of autoantibodies and T cell proliferation against overlapping peptides spanning the La autoantigen. HLA restriction and peptide binding of identified T cell epitopes to DR3 or DQ2 were determined using blocking monoclonal antibodies and a direct binding assay.
  
  
  RESULTS
  DR3/DQ2-transgenic mice generated an unusually rapid class-switched humoral response to hLa with characteristic spreading to Ro 52 and Ro 60 proteins following hLa protein immunization. Seven T cell determinants in hLa were restricted to the HLA-DR3/DQ2 haplotype. Six epitopes tested were restricted to HLA-DR and bound DR3 with semiconserved DR3 binding motifs. No DQ restriction of these epitopes was demonstrable despite efficient DQ binding activity in some cases. No neo-T cell epitopes were identified in mutant La; however, T cells primed with mutant La exhibited a striking increase in proliferation to the epitope hLa(151-168) compared with T cells primed with hLa.
  
  
  CONCLUSIONS
  Multiple DR3-restricted epitopes of hLa have been identified. These findings suggest that truncation of La produced by somatic mutation or possibly granzyme B-mediated cleavage alters the immunodominance hierarchy of T cell responsiveness to hLa and may be a factor in the initiation or maintenance of anti-La autoimmunity.
authors: Bio21 Molecular Science and Biotechnology Institute, and University of Melbourne, Melbourne, Victoria, Australia.
authors: Nadine L
authors: NL
authors: Dudek
authors: Shannon
authors: S
authors: Maier
authors: Zhen-Jun
authors: ZJ
authors: Chen
authors: Philip A
authors: PA
authors: Mudd
authors: Stuart I
authors: SI
authors: Mannering
authors: David C
authors: DC
authors: Jackson
authors: Weiguang
authors: W
authors: Zeng
authors: Catherine L
authors: CL
authors: Keech
authors: Kassie
authors: K
authors: Hamlin
authors: Zi-jian
authors: ZJ
authors: Pan
authors: Karen
authors: K
authors: Davis-Schwarz
authors: Jennifer
authors: J
authors: Workman-Azbill
authors: Michael
authors: M
authors: Bachmann
authors: James
authors: J
authors: McCluskey
authors: A Darise
authors: AD
authors: Farris
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D001324:Autoantigens / Q000235:genetics*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics*; D015870:Gene Expression; D006683:HLA-DQ Antigens / Q000096:biosynthesis*; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000096:biosynthesis*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012261:Ribonucleoproteins / Q000235:genetics*; D000097585:SS-B Antigen
chemical_list: D000974:Antibodies, Antinuclear; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II; D012261:Ribonucleoproteins; D000097585:SS-B Antigen; C069051:HLA-DQB1 antigen; C553502:HLA-DRB1*03:01 antigen