title: The role of glutamic or aspartic acid in position four of the epitope binding motif and thyrotropin receptor-extracellular domain epitope selection in Graves' disease.
abstract: BACKGROUND
  Development of Graves' disease (GD) is related to HLA-DRB1*0301 (DR3),and more specifically to arginine at position 74 of the DRB1 molecule. The extracellular domain (ECD) of human TSH receptor (hTSH-R) contains the target antigen.
  
  
  OBJECTIVE
  We analyzed the relation between hTSH-R-ECD peptides and DR molecules to determine whether aspartic acid (D) or glutamic acid (E) at position four in the binding motif influenced selection of functional epitopes.
  
  
  RESULTS
  Peptide epitopes from TSH-R-ECD with D or E in position four (D/E+) had higher affinity for binding to DR3 than peptides without D/E (D/E-) (IC(50) 29.3 vs. 61.4, P = 0.0024). HLA-DR7, negatively correlated with GD, and DRB1*0302 (HLA-DR18), not associated with GD, had different profiles of epitope binding. Toxic GD patients who are DR3+ had higher responses to D/E+ peptides than D/E- peptides (stimulation index 1.42 vs. 1.22, P = 0.028). All DR3+ GD patients (toxic + euthyroid) had higher responses, with borderline significance (Sl; 1.32 vs. 1.18, P = 0.051). Splenocytes of DR3 transgenic mice immunized to TSH-R-ECD responded to D/E+ peptides more than D/E- peptides (stimulation index 1.95 vs. 1.69, P = 0.036). Seven of nine hTSH-R-ECD peptide epitopes reported to be reactive with GD patients' peripheral blood mononuclear cells contain binding motifs with D/E at position four.
  
  
  CONCLUSIONS
  TSH-R-ECD epitopes with D/E in position four of the binding motif bind more strongly to DRB1*0301 than epitopes that are D/E- and are more stimulatory to GD patients' peripheral blood mononuclear cells and to splenocytes from mice immunized to hTSH-R. These epitopes appear important in immunogenicity to TSH-R due to their favored binding to HLA-DR3, thus increasing presentation to T cells.
authors.affiliation: Department of Cellular and Molecular Biology, University of Rhode Island, 80 Washington Street, Providence, Rhode Island 02903, USA.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Inaba
authors.forename: William
authors.initials: W
authors.lastname: Martin
authors.forename: Matt
authors.initials: M
authors.lastname: Ardito
authors.forename: Anne Searls
authors.initials: AS
authors.lastname: De Groot
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: De Groot
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017951:Antigen Presentation; D001224:Aspartic Acid / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005110:Extracellular Space / Q000276:immunology*; D018698:Glutamic Acid / Q000276:immunology*; D006111:Graves Disease / Q000276:immunology*; D006680:HLA Antigens / Q000378:metabolism; D006684:HLA-DR Antigens / Q000276:immunology / Q000378:metabolism; D015803:HLA-DR3 Antigen / Q000276:immunology; D015809:HLA-DR7 Antigen / Q000276:immunology; D006801:Humans; D007114:Immunization; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D011989:Receptors, Thyrotropin / Q000276:immunology*
chemical_list: D000939:Epitopes; D006680:HLA Antigens; D006684:HLA-DR Antigens; D015803:HLA-DR3 Antigen; D015809:HLA-DR7 Antigen; D011989:Receptors, Thyrotropin; D001224:Aspartic Acid; D018698:Glutamic Acid
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