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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

Burkhardt, H ; Huffmeier, U ; Spriewald, B ; Bohm, B ; Rau, R ; Kallert, S ; Engstrom, A ; Holmdahl, Rikard LU and Reis, A (2006) In Arthritis and Rheumatism 54(1). p.82-89
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 11 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 Immoral autoimmune responses. HLA-DRB1 genotypes were determined by allele-specific polymerase chain reaction... (More)
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 11 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 Immoral 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 Immoral 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. (Less)
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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Arthritis and Rheumatism
volume
54
issue
1
pages
82 - 89
publisher
John Wiley and Sons Inc.
external identifiers
  • pmid:16385499
  • wos:000234605200012
  • scopus:31044442026
ISSN
1529-0131
DOI
10.1002/art.21498
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Medical Inflammation Research (013212019)
id
e221687f-8dea-41c7-a1ec-151022c8dbd1 (old id 421460)
date added to LUP
2016-04-01 11:55:33
date last changed
2020-01-12 08:52:32
@article{e221687f-8dea-41c7-a1ec-151022c8dbd1,
  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 11 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 Immoral 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 Immoral 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.},
  author       = {Burkhardt, H and Huffmeier, U and Spriewald, B and Bohm, B and Rau, R and Kallert, S and Engstrom, A and Holmdahl, Rikard and Reis, A},
  issn         = {1529-0131},
  language     = {eng},
  number       = {1},
  pages        = {82--89},
  publisher    = {John Wiley and Sons Inc.},
  series       = {Arthritis and Rheumatism},
  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},
  url          = {http://dx.doi.org/10.1002/art.21498},
  doi          = {10.1002/art.21498},
  volume       = {54},
  year         = {2006},
}