title: Association between protein tyrosine phosphatase 22 variant R620W in conjunction with the HLA-DRB1 shared epitope and humoral autoimmunity to an immunodominant epitope of cartilage-specific type II collagen in early rheumatoid arthritis.
abstract: OBJECTIVE
  To analyze the genetic impact of allelic variants of the protein tyrosine phosphatase N22 (PTPN22) and HLA-DRB1 alleles on IgG autoantibody formation directed toward an immunodominant conformational epitope (C1(III); amino acid residues 359-369) of type II collagen (CII) in early rheumatoid arthritis (RA).
  
  
  METHODS
  Sera obtained at study inclusion from an inception cohort of RA patients (n = 221; mean symptom duration 6 months) were analyzed for circulating anti-C1(III) IgG autoantibodies. An enzyme-linked immunosorbent assay based on solid-phase-coupled synthetic triple-helical collagen peptides was used to quantify humoral autoimmune responses. HLA-DRB1 genotypes were determined by allele-specific polymerase chain reaction amplification of genomic DNA and sequence-specific hybridization. PTPN22*620W genotyping was performed using an allelic discrimination TaqMan assay.
  
  
  RESULTS
  Anti-C1(III) IgG autoantibody titers were significantly elevated in patients with early RA as compared with those in healthy controls (n = 70). The increased titers were more pronounced in RA patients harboring alleles of the RA-associated HLA-DRB1 shared epitope (SE) consensus sequence than in those lacking the SE. In addition, the PTPN22*620W variant was strongly associated with a vigorous humoral autoimmune response to the cartilage-specific CII determinant C1(III).
  
  
  CONCLUSIONS
  Allelic variants encoding the binding pocket for peptide presentation (SE) to T cells and a functional domain of a negative regulator of T cell receptor signaling (PTPN22*620W), respectively, synergize in early RA to break self tolerance toward C1(III), an evolutionarily conserved cartilage determinant that is also frequently targeted in arthritogenic humoral autoimmunity in mice.
authors.affiliation: Dept. of Internal Medicine III, Friedrich Alexander University of Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany. Harald.Burkhardt@med3.imed.uni-erlangen.de
authors.forename: Harald
authors.initials: H
authors.lastname: Burkhardt
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hüffmeier
authors.forename: Bernd
authors.initials: B
authors.lastname: Spriewald
authors.forename: Beate
authors.initials: B
authors.lastname: Böhm
authors.forename: Rolf
authors.initials: R
authors.lastname: Rau
authors.forename: Stefan
authors.initials: S
authors.lastname: Kallert
authors.forename: Ake
authors.initials: A
authors.lastname: Engström
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.forename: André
authors.initials: A
authors.lastname: Reis
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology*; D002356:Cartilage / Q000276:immunology*; D024043:Collagen Type II / Q000235:genetics* / Q000276:immunology*; D000939:Epitopes / Q000235:genetics* / Q000276:immunology*; D005260:Female; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*
chemical_list: D001323:Autoantibodies; D024043:Collagen Type II; D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases