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Increased membrane expression of proteinase 3 during neutrophil adhesion in the presence of anti proteinase 3 antibodies.

Abstract
We investigated membrane proteinase 3 (mPR3) expression during TNF-alpha-induced adhesion of neutrophils in the presence of anti-PR3 antibodies, a situation occurring during anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis. Three increasing levels of mPR3 expression were observed on the mPR3(+) neutrophil subset after stepwise cell activation. TNF-alpha activation without adhesion, TNF-alpha-induced adhesion, and adhesion in the presence of anti-PR3 mAb or human anti-PR3 ANCA resulted, respectively, in a two-, seven-, and 24-fold increase of mPR3 levels. In plasma, anti-PR3 antibodies poorly recognized suspended neutrophils, whereas they bound to mPR3 on adherent cells. mPR3 upregulation was also triggered by IL-8, formyl-methionyl-leucyl-phenylalanine (fMLP), and neutrophil adhesion to activated human umbilical vein endothelial cells. It involved beta2 integrins and Fcgamma receptor, because it was prevented by anti-CD18 antibodies and was not observed with anti-PR3 F(ab')(2). Furthermore, it was specific to anti-PR3 mAb, and no mPR3 upregulation was observed with anti-myeloperoxidase or anti-HLA-ABC mAb. Newly expressed mPR3 molecules, after TNF-induced adhesion, were mobilized from secretory vesicles (CD35(+)) and secondary granules (CD11b(+)). The adhesion- and antibody-dependent upregulations of mPR3 expression occurred with little azurophilic granule degranulation, no sign of apoptosis, and no further CD177 upregulation. In conclusion, this study describes an amplifying loop in polymorphonuclear neutrophil activation process, whereby ANCA are involved in the membrane expression of their own antigen during cell adhesion. This could explain the restriction of ANCA-associated vasculitis to small vessels, the main site of neutrophil adhesion.
AuthorsSoumeya Brachemi, Agnès Mambole, Fadi Fakhouri, Luc Mouthon, Loïc Guillevin, Philippe Lesavre, Lise Halbwachs-Mecarelli
JournalJournal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 18 Issue 8 Pg. 2330-9 (Aug 2007) ISSN: 1046-6673 [Print] United States
PMID17634439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Antineutrophil Cytoplasmic
  • CD18 Antigens
  • Interleukin-8
  • Tumor Necrosis Factor-alpha
  • N-Formylmethionine Leucyl-Phenylalanine
  • Peroxidase
  • Myeloblastin
Topics
  • Antibodies, Antineutrophil Cytoplasmic (blood, immunology)
  • Antibody Specificity
  • CD18 Antigens (metabolism)
  • Cell Adhesion (drug effects, immunology)
  • Cell Membrane (enzymology, immunology)
  • Endothelium, Vascular (cytology, immunology)
  • Humans
  • Interleukin-8 (metabolism)
  • Myeloblastin (immunology, metabolism)
  • N-Formylmethionine Leucyl-Phenylalanine (pharmacology)
  • Neutrophils (cytology, enzymology, immunology)
  • Peroxidase (immunology, metabolism)
  • Tumor Necrosis Factor-alpha (metabolism)
  • Umbilical Veins (cytology)
  • Up-Regulation (immunology)
  • Vasculitis (immunology, metabolism)

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