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

Arthritis Rheum. 2006 Jan;54(1):82-9. doi: 10.1002/art.21498.


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).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology*
  • Autoantibodies / biosynthesis
  • Autoantibodies / immunology*
  • Cartilage / immunology*
  • Collagen Type II / genetics*
  • Collagen Type II / immunology*
  • Epitopes / genetics*
  • Epitopes / immunology*
  • Female
  • HLA-DR Antigens / genetics*
  • HLA-DR Antigens / immunology*
  • HLA-DRB1 Chains
  • Humans
  • Immunodominant Epitopes / genetics
  • Immunodominant Epitopes / immunology
  • Immunoglobulin G / biosynthesis
  • Immunoglobulin G / immunology*
  • Male
  • Middle Aged
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22
  • Protein Tyrosine Phosphatases / genetics*


  • Autoantibodies
  • Collagen Type II
  • Epitopes
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • Immunodominant Epitopes
  • Immunoglobulin G
  • PTPN22 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22
  • Protein Tyrosine Phosphatases