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

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.

[1]  D A Bloch,et al.  The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. , 2010, Arthritis and rheumatism.

[2]  K. Andrassy,et al.  Pathophysiology of ANCA-associated vasculitis: are ANCA really pathogenic? A note of caution. , 2004, Kidney international.

[3]  T. Colby,et al.  Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo. , 2004, Blood.

[4]  K. Andrassy,et al.  Autoantibodies to neutrophil cytoplasmic antigens (ANCA) do not bind to polymorphonuclear neutrophils in blood. , 2004, Kidney international.

[5]  F. Luft,et al.  Membrane proteinase 3 expression and ANCA-induced neutrophil activation. , 2004, Kidney international.

[6]  H. Rupprecht,et al.  ANCA-associated vasculitis with renal involvement: an outcome analysis. , 2004, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[7]  G. Keller,et al.  The in vitro production and characterization of neutrophils from embryonic stem cells. , 2004, Blood.

[8]  A. Vizjak,et al.  Clinical prognostic factors of renal outcome in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis in elderly patients. , 2003, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[9]  C. Franssen,et al.  Renal survival and prognostic factors in patients with PR3-ANCA associated vasculitis with renal involvement. , 2003, Kidney international.

[10]  P. Heeringa,et al.  Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. , 2002, The Journal of clinical investigation.

[11]  C. Kallenberg,et al.  Neutrophil membrane expression of proteinase 3 (PR3) is related to relapse in PR3-ANCA-associated vasculitis. , 2002, Journal of the American Society of Nephrology : JASN.

[12]  J. Klein,et al.  Phosphatidylinositol 3-kinase controls antineutrophil cytoplasmic antibodies-induced respiratory burst in human neutrophils. , 2002, Journal of the American Society of Nephrology : JASN.

[13]  M. Elghetany.  Surface antigen changes during normal neutrophilic development: a critical review. , 2002, Blood cells, molecules & diseases.

[14]  C. Stegeman,et al.  HIF-1 mediated upregulation of VEGF and VEGF-R in systemic sclerosis (SSc): Imbalance with angiostatic factors suggests VEGF as a novel option for the treatment of ischemia in patients with SSc , 2002, Annals of the rheumatic diseases.

[15]  A. Ben-Smith,et al.  Antineutrophil cytoplasm autoantibodies from patients with systemic vasculitis activate neutrophils through distinct signaling cascades: comparison with conventional Fcgamma receptor ligation. , 2001, Blood.

[16]  C. Savage,et al.  Antineutrophil cytoplasmic antibodies induce reactive oxygen-dependent dysregulation of primed neutrophil apoptosis and clearance by macrophages. , 2000, The American journal of pathology.

[17]  V. Witko-Sarsat,et al.  Presence of proteinase 3 in secretory vesicles: evidence of a novel, highly mobilizable intracellular pool distinct from azurophil granules. , 1999, Blood.

[18]  C. Kallenberg,et al.  In vitro neutrophil activation by antibodies to proteinase 3 and myeloperoxidase from patients with crescentic glomerulonephritis. , 1999, Journal of the American Society of Nephrology : JASN.

[19]  B. Prum,et al.  A large subset of neutrophils expressing membrane proteinase 3 is a risk factor for vasculitis and rheumatoid arthritis. , 1999, Journal of the American Society of Nephrology : JASN.

[20]  R. Falk,et al.  Small-vessel vasculitis. , 1997, The New England journal of medicine.

[21]  R. Kettritz,et al.  Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils. , 1997, Journal of the American Society of Nephrology : JASN.

[22]  S. Rose-John,et al.  A bioactive designer cytokine for human hematopoietic progenitor cell expansion , 1997, Nature Biotechnology.

[23]  W. Seeger,et al.  Neutrophil activation by anti-proteinase 3 antibodies in Wegener's granulomatosis: role of exogenous arachidonic acid and leukotriene B4 generation , 1996, The Journal of experimental medicine.

[24]  G. Crooks,et al.  A functional comparison of CD34 + CD38- cells in cord blood and bone marrow. , 1995, Blood.

[25]  P. Limburg,et al.  Activation of granulocytes by anti‐neutrophil cytoplasmic antibodies (ANCA): a FcγRII‐dependent process , 1994, Clinical and experimental immunology.

[26]  R. Kimberly,et al.  Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa. , 1994, Journal of immunology.

[27]  R J Falk,et al.  Nomenclature of systemic vasculitides. Proposal of an international consensus conference. , 1994, Arthritis and rheumatism.

[28]  J. Pearson,et al.  Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells. , 1992, The American journal of pathology.

[29]  L. To,et al.  Identification and comparison of CD34-positive cells and their subpopulations from normal peripheral blood and bone marrow using multicolor flow cytometry. , 1991, Blood.

[30]  R J Falk,et al.  Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[31]  M. Arnaout,et al.  Wegener9s granulomatosis autoantigen is a novel neutrophil serine proteinase [see comments] , 1989 .

[32]  M. Arnaout,et al.  Wegener's granulomatosis autoantigen is a novel neutrophil serine proteinase. , 1989, Blood.

[33]  C. Hack,et al.  Wegener's granulomatosis autoantibodies identify a novel diisopropylfluorophosphate-binding protein in the lysosomes of normal human neutrophils. , 1989, The Journal of clinical investigation.

[34]  R. Falk,et al.  Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. , 1988, The New England journal of medicine.

[35]  T. H. The,et al.  AUTOANTIBODIES AGAINST NEUTROPHILS AND MONOCYTES: TOOL FOR DIAGNOSIS AND MARKER OF DISEASE ACTIVITY IN WEGENER'S GRANULOMATOSIS , 1985, The Lancet.

[36]  E. Pick,et al.  Rapid microassays for the measurement of superoxide and hydrogen peroxide production by macrophages in culture using an automatic enzyme immunoassay reader. , 1981, Journal of immunological methods.

[37]  A. Busjahn,et al.  Membrane expression of proteinase 3 is genetically determined. , 2003, Journal of the American Society of Nephrology : JASN.