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Membrane proteinase 3 expression in patients with Wegener's granulomatosis and in human hematopoietic stem cell-derived neutrophils

Item Type:Article
Title:Membrane proteinase 3 expression in patients with Wegener's granulomatosis and in human hematopoietic stem cell-derived neutrophils
Creators Name:Schreiber, A. and Otto, B. and Ju, X. and Zenke, M. and Goebel, U. and Luft, F.C. and Kettritz, R.
Abstract:A large membrane proteinase 3 (mPR3)-positive neutrophil subset (mPR3high) is a risk for Wegener’s granulomatosis (WG). The relationship between mPR3 expression and clinical manifestations was investigated in 81 WG patients and mPR3 expression was studied in CD34+ stem cell–derived human neutrophils. The mPR3high neutrophil percentage correlated with renal function, anemia, and albumin at the time of presentation. The mPR3high neutrophil percentage and renal failure severity correlated directly after 5 yr. For elucidating mechanisms that govern mPR3 expression, studies were conducted to determine whether the genetic information that governs mPR3 expression resides within the neutrophils, even without stimuli possibly related to disease. CD34+ hematopoietic stem cells were differentiated to neutrophils, and their mPR3 expression was determined. A two-step amplification/differentiation protocol was used to differentiate human CD34+ hematopoietic stem cells into neutrophils with G-CSF. The cells progressively expressed the neutrophil surface markers CD66b, CD35, and CD11b. The ferricytochrome C assay demonstrated a strong respiratory burst at day 14 in response to PMA but none at day 0. Intracellular PR3 was detectable from day 4 by Western blotting. An increasing percentage of a mPR3-positive neutrophil subset became detectable by flow cytometry, whereas a second subset remained negative, consistent with a bimodal expression. Finally, human PR3–anti-neutrophil cytoplasmic autoantibodies induced a stronger respiratory burst, compared with human control IgG in stem cell–derived neutrophils. Taken together, these studies underscore the clinical importance of the WG mPR3 phenotype. The surface mPR3 on resting cells is probably genetically determined rather than being dictated by external factors.
Keywords:Antineutrophil Cytoplasmic Antibodies, Hematopoietic Stem Cells, Myeloblastin, Neutrophil Activation, Neutrophils, Renal Insufficiency, Serine Endopeptidases, Wegener Granulomatosis
Source:Journal of the American Society of Nephrology
ISSN:1046-6673
Publisher:American Society of Nephrology (U.S.A.)
Volume:16
Page Range:2216-2224
Date:1 January 2005
Official Publication:https://doi.org/10.1681/ASN.2004070609
PubMed:View item in PubMed

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