A Large Subset of Neutrophils Expressing Membrane... : Journal of the American Society of Nephrology (original) (raw)

Immunology and Pathology

A Large Subset of Neutrophils Expressing Membrane Proteinase 3 Is a Risk Factor for Vasculitis and Rheumatoid Arthritis

WITKO-SARSAT, VERONIQUE*; LESAVRE, PHILIPPE*; LOPEZ, SANDRA*; BESSOU, GILLES*; HIEBLOT, CORINNE*; PRUM, BERNARD†; NOËL, LAURE HÉLÈNE*; GUILLEVIN, LOÏC‡; RAVAUD, PHILIPPE§; SERMET-GAUDELUS, ISABELLE∥; TIMSIT, JOSE¶; GRÜNFELD, JEAN-PIERRE*; HALBWACHS-MECARELLI, LISE*

*Institut National de la Santé et de la Recherche Médicale U507 and Department of Nephrology, Necker Hospital, Paris, France.

†Unité de Recherche Associée Centre National de la Recherche Scientifique 1323, Medical Statistics, Université Paris V, Paris, France.

‡Department of Internal Medicine, Avicenne Hospital, Bobigny, France.

§Department of Rheumatology, Ho[Combining Circumflex Accent]pital Cochin, Paris, France.

∥Department of Pediatry, Necker Hospital, Paris, France.

¶Department of Immunology, Necker Hospital, Paris, France.

Correspondence to Dr. Veronique Witko-Sarsat, INSERM U 90, Necker Hospital, 161 rue de Sèvres, 75015 Paris. Phone: 33 144 49 52 32; Fax: 33 145 66 51 33; E-mail: [email protected]

Accepted November 6, 1998

Received March 10, 1998

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.