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

Publisher Website
Google Scholar
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 (C1III; 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–C1III 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–C1III 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 C1III. 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 C1III, an evolutionarily conserved cartilage determinant that is also frequently targeted in arthritogenic humoral autoimmunity in mice.

This publication has 16 references indexed in Scilit: