title: The autoimmune-associated genetic variant PTPN22 R620W enhances neutrophil activation and function in patients with rheumatoid arthritis and healthy individuals.
abstract: OBJECTIVE
  A genetic variant of the leukocyte phosphatase PTPN22 (R620W) is strongly associated with autoimmune diseases including rheumatoid arthritis (RA). Functional studies on the variant have focussed on lymphocytes, but it is most highly expressed in neutrophils. We have investigated the effects of the variant on neutrophil function in health and in patients with RA.
  
  
  METHODS
  Healthy individuals and patients with RA were genotyped for PTPN22 (R620W) and neutrophils isolated from peripheral blood. Neutrophil adhesion and migration across inflamed endothelium were measured. Calcium (Ca(2+)) release and reactive oxygen species (ROS) production in response to fMLP stimulation were also assessed.
  
  
  RESULTS
  Expression of R620W enhanced neutrophil migration through cytokine activated endothelium (non-R620W=24%, R620W=45% migrating cells, p<0.001). Following fMLP stimulation, neutrophils that were heterozygous and homozygous for R620W released significantly more Ca(2+) when compared to non-R620W neutrophils, in healthy individuals and patients with RA. fMLP stimulation, after TNF-α priming, provoked more ROS from neutrophils heterozygous for R620W in patients with RA (non-R620W vs R620W=∼1.75-fold increase) and healthy individuals (non-R620W vs R620W=fourfold increase) and this increase was statistically significant in healthy individuals (p<0.001) but not in patients with RA (p<0.25).
  
  
  CONCLUSIONS
  Expression of PTPN22 (R620W) enhanced neutrophil effector functions in health and RA, with migration, Ca(2+) release and production of ROS increased. Neutrophils are found in large numbers in the RA joint, and this hyperactivity of R620W cells may directly contribute to the joint damage, as well as to the initiation and perpetuation of the chronic immune-mediated inflammatory processes driving the disease.
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, School of Immunity and Infection, University of Birmingham, Birmingham, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bayley
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, School of Immunity and Infection, University of Birmingham, Birmingham, UK.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Kite
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, School of Immunity and Infection, University of Birmingham, Birmingham, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: McGettrick
authors.affiliation: Department of Rheumatology, Dudley Group of Hospitals NHS Trust, Russell's Hall Hospital, Dudley, West Midlands, UK.
authors.forename: Jacqueline P
authors.initials: JP
authors.lastname: Smith
authors.affiliation: Department of Rheumatology, Dudley Group of Hospitals NHS Trust, Russell's Hall Hospital, Dudley, West Midlands, UK.
authors.forename: George D
authors.initials: GD
authors.lastname: Kitas
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, School of Immunity and Infection, University of Birmingham, Birmingham, UK.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, School of Immunity and Infection, University of Birmingham, Birmingham, UK.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Young
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D055815:Young Adult
chemical_list: D017382:Reactive Oxygen Species; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22
keywords: Autoimmune Diseases; Gene Polymorphism; Rheumatoid Arthritis