title: A large subset of neutrophils expressing membrane proteinase 3 is a risk factor for vasculitis and rheumatoid arthritis.
abstract: It has been shown previously that proteinase 3 (PR3), a neutrophil intracellular protease that is the main antigen of antineutrophil cytoplasm (ANCA) autoantibodies, is present on the plasma membrane of a subset of freshly isolated neutrophils. This study shows that the size of this subset of membrane PR3-positive (mPR3+) neutrophils is a stable feature of a given individual, most likely genetically controlled. It ranges from 0 to 100% of neutrophils and allows us to define a new polymorphism in the healthy population, with three discrete phenotypes corresponding respectively to less than 20% mPR3 + neutrophils (mPR3low) or to a mean percentage of 47% (mPR3intermediate) and 71.5% (mPR3high) mPR3+ neutrophils. The frequency of the mPR3high phenotype was significantly increased in patients with ANCA-associated vasculitis (85% versus 55% in healthy subjects). The percentage of mPR3+ neutrophils was not affected by disease activity, relapses, or therapy, and did not reflect in vivo cell activation. In addition, mPR3+ phenotypes were normally distributed in cystic fibrosis patients, indicating that infection and/or inflammation per se do not lead to a high percentage of mPR3+ neutrophils. The frequency of the mPR3high phenotype was not related to anti-PR3 autoimmunization, since it was increased in vasculitic patients regardless of the ANCA specificity (anti-PR3, anti-myeloperoxidase, or unknown). Interestingly, the frequency of the mPR3high phenotype was also increased in patients with rheumatoid arthritis. It was normal in type I-diabetes, a T cell-dependent autoimmune disease. It is proposed here that a high proportion of membrane PR3-positive neutrophils could favor the occurrence or the progression of chronic inflammatory diseases.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U507 and Department of Nephrology, Necker Hospital, Paris, France. witko-sarsat@necker.fr
authors.forename: V
authors.initials: V
authors.lastname: Witko-Sarsat
authors.forename: P
authors.initials: P
authors.lastname: Lesavre
authors.forename: S
authors.initials: S
authors.lastname: Lopez
authors.forename: G
authors.initials: G
authors.lastname: Bessou
authors.forename: C
authors.initials: C
authors.lastname: Hieblot
authors.forename: B
authors.initials: B
authors.lastname: Prum
authors.forename: L H
authors.initials: LH
authors.lastname: Noël
authors.forename: L
authors.initials: L
authors.lastname: Guillevin
authors.forename: P
authors.initials: P
authors.lastname: Ravaud
authors.forename: I
authors.initials: I
authors.lastname: Sermet-Gaudelus
authors.forename: J
authors.initials: J
authors.lastname: Timsit
authors.forename: J P
authors.initials: JP
authors.lastname: Grünfeld
authors.forename: L
authors.initials: L
authors.lastname: Halbwachs-Mecarelli
mesh_terms: D000328:Adult; D000368:Aged; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000235:genetics / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D003550:Cystic Fibrosis / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D053146:Myeloblastin; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology; D010375:Pedigree; D010641:Phenotype; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D014657:Vasculitis / Q000235:genetics* / Q000276:immunology
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D012697:Serine Endopeptidases; D053146:Myeloblastin