• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of amjpatholAmerican Journal of Pathology For AuthorsAmerican Journal of Pathology SubscribeAmerican Journal of Pathology SearchAmerican Journal of Pathology Current IssueAmerican Journal of Pathology About the JournalAmerican Journal of Pathology
Am J Pathol. Jul 2005; 167(1): 39–45.
PMCID: PMC1603451

The Role of Neutrophils in the Induction of Glomerulonephritis by Anti-Myeloperoxidase Antibodies


In humans, circulating anti-neutrophil cytoplasm autoantibodies (ANCAs) with specificity for myeloperoxidase (MPO) are strongly associated with the development of pauci-immune necrotizing and crescentic glomerulonephritis (NCGN). In mice, we have demonstrated that intravenous injection of mouse antibodies specific for mouse MPO induces NCGN that closely mimics the human disease. We now report that the development of NCGN in this experimental model is accompanied by glomerular accumulation of neutrophils and macrophages. Neutrophil infiltration was most conspicuous at sites of glomerular necrosis and crescent formation, with macrophages also most numerous in crescents. Lymphocytes, however, were sparse in acute lesions. Importantly, mice that were depleted of circulating neutrophils with NIMP-R14 rat monoclonal antibodies were completely protected from anti-MPO IgG-induced NCGN. These findings provide direct evidence that neutrophils play a major role in the pathogenesis of anti-MPO-induced NCGN in this animal model and implicate neutrophils in the induction of human ANCA disease. This raises the possibility that therapeutic strategies to reduce circulating neutrophils could be beneficial to patients with ANCA-induced NCGN.

Anti-neutrophil cytoplasm autoantibodies (ANCAs) are specific for constituents of the primary granules of neutrophils and the peroxidase-positive lysosomes of monocytes.1 The two major antigen specificities are for myeloperoxidase (MPO-ANCA) and proteinase 3 (PR3-ANCA).1–3 ANCAs are found in 80 to 90% of patients with necrotizing and crescentic glomerulonephritis (NCGN) that is characterized immunohistologically by the absence or paucity of immunoglobulin in vessel walls (ie, pauci-immune NCGN).1,4,5 ANCA NCGN is the most common form of aggressive glomerulonephritis and often is accompanied by a pauci-immune systemic necrotizing small vessel vasculitis, such as microscopic polyangiitis or Wegener’s granulomatosis.4–6

Numerous observations suggest that neutrophils are important effector cells in the pathogenesis of human ANCA NCGN. In renal biopsies from patients with ANCA NCGN, activated neutrophils are present in affected glomeruli and in the renal interstitium.7 The number of activated intraglomerular neutrophils correlates with the severity of renal injury as reflected in serum creatinine levels.7 In vitro, ANCAs can activate cytokine-primed neutrophils, causing an oxidative burst, degranulation, release of inflammatory cytokines, and damage to endothelial cells.8,9 Recently, our laboratory developed an experimental animal model of NCGN that involves the adoptive transfer of mouse anti-MPO lymphocytes into immune-deficient mice or the passive infusion of mouse anti-MPO IgG into either immune-deficient or immune-competent mice.10 The resulting NCGN has remarkable pathological similarity to human ANCA glomerulonephritis.

In the current study, we investigated the hypothesis that neutrophils are key effector cells in the pathogenesis of MPO-ANCA-mediated NCGN in this experimental model. The results show that anti-MPO-induced NCGN is associated with the accumulation of neutrophils and macrophages at sites of glomerular injury, and that neutrophil-depleted mice are protected from induction of NCGN by anti-MPO IgG. Taken together, these results indicate that neutrophils play a major role in anti-MPO-induced NCGN in this model.

Materials and Methods


Breeding pairs of C57BL/6J (B6) mice were purchased from Jackson Laboratories (Bar Harbor, ME) and maintained by the University of North Carolina Division of Laboratory Animal Medicine. Mice lacking MPO (MPO−/− mice) were the sixth-generation progeny of a backcross into B6 mice originally generated by Aratani and colleagues.11 MPO−/− mice (8 to 10 weeks old) were used for immunization and as donors of anti-MPO antibodies. Wild-type (WT) B6 mice (9 to 10 weeks old) were used as recipients for passive transfer experiments. The University of North Carolina Institutional Animal Care and Use Committee approved all animal experiments.

Preparation of Pathogenic Mouse Anti-Murine MPO IgG and Control Mouse Anti-Bovine Serum Albumin (BSA) IgG

The purification of mouse MPO and the immunization of MPO−/− mice were performed as previously described.10 Briefly, mouse MPO was purified from WEHI-3 cells by Dounce homogenization, Concanavalin A affinity chromatography, ion exchange, and gel filtration chromatography. MPO−/− mice were immunized intraperitoneally with 10 μg of purified murine MPO or BSA in complete Freund’s adjuvant. Development of antibodies was monitored by anti-MPO enzyme-linked immunosorbent assay. The presence of circulating anti-MPO antibodies was confirmed in selected animals by indirect immunofluorescence microscopy assay on murine neutrophils as described.10 The IgG fraction was isolated from the serum of MPO−/− mice immunized with murine MPO by 50% ammonium sulfate precipitation and protein G affinity chromatography as previously described.10 The IgG fractions were concentrated, sterilized by ultrafiltration, and the protein concentrations were determined by Coomassie protein assay reagent kit (Pierce, Rockford, IL). The purity of the isolated antibodies was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

Induction of Anti-MPO Disease

Two different regimens were used to produce anti-MPO-induced glomerulonephritis. Studies of the effects of neutrophil depletion on induction of glomerulonephritis used one intravenous injection of 50 μg/g body weight of anti-MPO IgG in phosphate-buffered saline (PBS) on day 0 with sacrifice on day 6. Control mice received the same dose of anti-BSA or no IgG. For more detailed evaluation of glomerular infiltration by neutrophils, a more severe expression of disease was induced by a double dose of anti-MPO IgG. The first intravenous 50 μg/g body weight dose of anti-MPO IgG was administered on day 0, the second dose was administered on day 3, and the mice were sacrificed on day 6. The control group of B6 mice for this study received the same amount of anti-BSA IgG on days 0 and 3. Induction of circulating anti-MPO was monitored in all mice by anti-MPO enzyme-linked immunosorbent assay.10

Laboratory and Pathological Evaluation of Disease Induction

Five days after injection of anti-MPO and 1 day before sacrifice, mice were placed in metabolic cages for 12 hours to collect urine for analysis. Urine was tested by dipstick for hematuria, proteinuria, and leukocyturia (Roche Diagnostics Corp., Indianapolis, IN). A reference range was established from the urine analysis of 305 normal B6 mice, which had hematuria 0.1 ± 0.4, proteinuria 1.0 ± 0.1, and leukocyturia 0.0 ± 0.1. Thus, using the mean plus 2 SDs for the reference range, abnormal hematuria was set at >0.9, proteinuria >1.2, and leukocyturia >0.2. Mice were euthanized on day 6 with methoxyflurane. At the time of postmortem examination, samples of kidney were fixed in 10% formalin and processed for light microscopy, or snap-frozen and processed for immunofluorescence microscopy. For light microscopy, specimens were stained with hematoxylin and eosin, periodic acid-Schiff, and Masson trichrome stains. For immunofluorescence microscopy to detect glomerular localization of immune determinants, frozen sections were stained with fluoresceinated antibodies specific for mouse IgG, IgM, IgA, C3, and MPO (ICN/Cappel, Aurora, OH). For detection of leukocytes in frozen tissue, sections were stained with rat antibodies to neutrophils (anti-Gr-1, clone RB6-8C5; BD Pharmingen, Franklin Lakes, NJ), monocytes/macrophages (anti-F4/80 clone A3-1, Research Diagnostics, Flanders, NJ; and anti-CD68, clone FA11, Serotec, Raleigh, NC), and lymphocytes (anti-CD3, clone KT3; Beckman Coulter, Fullerton, CA). Rat antibody binding was detected using peroxidase-labeled secondary rabbit anti-rat IgG and tertiary goat anti-rabbit IgG antibodies (DAKO, Carpinteria, CA). Staining was generated with 3-amino-9-ethylcarbazole and hydrogen peroxide. Sections were counterstained with hematoxylin. Leukocyte localization was expressed as the average leukocytes per cross-section of glomeruli based on evaluating an average of 48 glomeruli per specimen (range, 30 to 80 glomeruli). For more detailed evaluation of neutrophil infiltration in the mice that received two doses of anti-MPO, immunostaining for neutrophils was performed on 5-μm paraffin sections of kidney using a biotin-labeled rat monoclonal anti-mouse neutrophil antibody NIMP-R14 (Cedarlane Laboratories Ltd., Ontario, Canada) with detection achieved with peroxidase-conjugated streptavidin (BioGenex, San Ramon, CA) and a DAKO Liquid DAB+ substrate-chromogen system (DAKO, Carpinteria, CA). A kidney from each of six mice that received two doses of anti-MPO was evaluated at two levels of section at least 50 μm apart for a total of 12 levels. Similarly, one kidney from six mice that received two doses of anti-BSA was evaluated at two levels of section for a total of 12 levels. Neutrophil accumulation was quantified by direct counting of stained cells in glomeruli at each of the levels of section. Results were expressed as the number of glomeruli with positive staining for neutrophils, the average number of neutrophils per positive glomerular cross-section, and the average number of neutrophils per all glomerular cross-sections.

In Vivo Kinetics of Circulating Neutrophils after Injected Anti-Neutrophil Antibodies

To evaluate the kinetics of neutrophil depletion, B6 mice (n = 7) were injected intraperitoneally with 1 mg of the monoclonal rat anti-murine neutrophil antibody, NIMP-R14, in 0.5 ml of PBS. NIMP-R14 selectively depletes mouse neutrophils in vivo.12–14 The control groups (n = 6) received rat IgG (1 mg of IgG in 0.5 ml of PBS). Neutrophil depletion was assessed before injection and on day 1, 2, 3, 4, 5, and 6 after antibody injection by direct cell counting of peripheral blood smears stained with Diff-Quik Giemsa Stain Set (Dade Behring Inc., Newark, DE).

Effect of Neutrophil Depletion on the Induction of Glomerulonephritis by Anti-MPO IgG

B6 mice (n = 6) were injected intraperitoneally with 1 mg of NIMP-R14 monoclonal antibody in 0.5 ml of PBS. The control groups (n = 6) received the same amount of control rat IgG. Both experimental and control mice received 50 μg/g body weight of anti-mouse MPO IgG by intravenous injection 16 hours after receiving the anti-neutrophil antibodies. The effect of NIMP-R14 on peripheral blood leukocytes was determined by differential cell counting of neutrophils, monocytes, and lymphocytes in Diff-Quik Giemsa-stained peripheral blood smears. Introduction of circulating anti-MPO was monitored by anti-MPO enzyme-linked immunosorbent assay. The mice were sacrificed on day 6 and kidney tissue processed for light and immunofluorescence microscopy.

Statistical Analysis

Ranked analysis of variance and Kruskal-Wallis tests were used to evaluate differences across groups, with differences between specific groups evaluated within the ranked analysis of variance test.


Depletion of Circulating Neutrophils after Injection of NIMP-R14 Monoclonal Antibodies

Within 1 day after a single injection of 1 mg of NIMP-R14 monoclonal antibody in 0.5 ml of PBS into B6 mice (n = 7), the number of circulating neutrophils was dramatically reduced from 14% of white blood cells to 1%, and remained at this low level for up to 5 days. Thereafter, neutrophils gradually returned toward normal (Figure 1). Control mice (n = 6) injected with the same volume of control IgG exhibited normal levels of circulating neutrophils.

Figure 1
Neutrophil depletion by NIMP-R14. B6 mice were injected either with 1 mg of NIMP-R14 rat anti-murine neutrophil monoclonal antibody (n = 7) (open circles) or control rat IgG (n = 6) (filled diamonds). Circulating neutrophils were quantified ...

Prevention of Anti-MPO IgG-Induced NCGN by Neutrophil Depletion

To directly determine whether neutrophils are required for MPO-ANCA-mediated NCGN, B6 mice (n = 6) were pretreated with a single intraperitoneal injection of neutrophil-specific NIMP-R14 monoclonal antibody (1 mg of IgG in 0.5 ml of PBS) before injection of anti-MPO IgG. A differential leukocyte count of Giemsa-stained blood smears 16 hours after the injection of NIMP-R14 antibody revealed 1.1 ± 0.4% neutrophils, 1.1 ± 0.4% monocytes, and 97.8 ± 0.6% lymphocytes. In contrast, control mice had 14.0 ± 4.4% neutrophils, 1.4 ± 0.7% monocytes, and 84.6 ± 4.3% lymphocytes. The difference between the two groups was statistically different for neutrophils (P < 0.0001) and lymphocytes (P < 0.0001) but not for monocytes (P > 0.2).

Sixteen hours after injection of either anti-neutrophil (NIMP-R14) or control IgG, mice received an intravenous injection of anti-MPO IgG. After 5 days, mice injected with anti-MPO IgG without neutrophil depletion developed urine abnormalities consistent with glomerulonephritis, ie, 2.5 ± 0.5 hematuria, 1.9 ± 0.55 proteinuria, and 0.8 ± 0.8 leukocyturia. In contrast, mice that were depleted of circulating neutrophils by pretreatment with NIMP-R14 anti-neutrophil antibodies had urine analysis results that were within the reference ranges, ie, 0.2 ± 0.4 hematuria, 1.0 ± 0 proteinuria, and 0 ± 0 leukocyturia. Levels of circulating anti-MPO IgG in the neutrophil-depleted mice were similar to those found in the control mice (2.02 + 0.12 in neutrophil-depleted mice with no NCGN versus 1.78 + 0.72 in anti-MPO mice with NCGN (P = 0.25).

All mice that were pretreated with normal rat IgG before receiving anti-MPO rather than with NIMP-R14 developed focal glomerular necrosis (mean, 5.8 ± 1.1% of glomeruli with necrosis) and glomerular crescents (mean, 11.5 ± 2.8% of glomeruli with crescents) whereas none of the mice that were pretreated with NIMP-R14 developed glomerular necrosis or crescents (Figure 2 and Table 1). Glomeruli that did not have necrosis or crescents appeared normal by light microscopy with no hypercellularity and no increase in matrix material.

Figure 2
Neutrophil depletion prevents anti-MPO antibody-induced necrotizing and crescentic glomerulonephritis. B6 mice were pretreated with the neutrophil-depleting antibody NIMP-R14 (n = 6) or control rat IgG (n = 6). Sixteen hours later, the ...
Table 1
Pathologic Findings in Mice that Received One Injection of Anti-MPO IgG, Anti-MPO IgG after Depletion of Neutrophils, Anti-BSA IgG, or No Injection of IgG

Glomerular immunoglobulin and complement deposition in mice that received anti-MPO alone was absent or sparse and similar to that in mice that received anti-MPO along with neutrophil depletion; and also was similar to glomerular immunoglobulin and complement localization in mice that received anti-BSA IgG or healthy control mice that received no immunoglobulin (Table 1). Glomerular leukocyte phenotyping demonstrated that mice that received anti-MPO without neutrophil depletion had statistically significant increased glomerular infiltration by neutrophils and monocytes/macrophages but not lymphocytes when compared to control mice that received no immunoglobulin injections (Table 1). Neutrophils were most numerous in glomeruli with inflammation and necrosis, and macrophages tended to cluster within crescents (Figure 3). Mice that had neutrophil depletion before receiving anti-MPO IgG and mice that received anti-BSA IgG had no significant increase in neutrophils, monocytes/macrophages, or lymphocytes when compared to control mice (Table 1).

Figure 3
Glomerular leukocytes 6 days after injection of a single dose of anti-MPO IgG. The panels show infiltration of an inflamed glomerulus by neutrophils that are scattered throughout the tuft (top left marked with anti-Gr-1), macrophages that are concentrated ...

Glomerular Influx of Neutrophils after Induction of Glomerulonephritis with Two Doses of Anti-MPO IgG

To induce more robust glomerular injury, two doses of anti-MPO were given at day 0 and day 3. These mice developed hematuria (2.6+), proteinuria (2.8+), leukocyturia (1.4+), and elevated blood urea nitrogen (45.2 mg/dl) in contrast to the mice that received two doses of anti-BSA IgG and had no significant elevation in hematuria (0+), proteinuria (0.9+), leukocyturia (0+), or blood urea nitrogen (25.5 mg/dl). The blood urea nitrogen in mice that received anti-MPO was significantly elevated over the blood urea nitrogen in the control mice (P < 0.04). By light microscopy, all mice that received anti-MPO IgG had glomerular necrosis (average 17.8 ± 7.8% of glomeruli involved in each mouse) and crescents (average 12.0 ± 6.1% of glomeruli involved) whereas mice that received anti-BSA IgG had no renal histological abnormalities. Thus, these mice with two doses of anti-MPO at days 0 and 3 had more severe glomerular injury with a greater degree of necrotizing injury than mice that received only one dose of anti-MPO IgG at day 0. However, even in the mice that received two doses of anti-MPO, most glomeruli had no abnormalities by light microscopy. This is similar to acute focal human ANCA NCGN in which glomeruli that do not have necrosis or crescents often appear histologically normal.

Immunohistological staining of paraffin sections with NIMP-R14 for neutrophils demonstrated that induction of glomerulonephritis by anti-MPO IgG was accompanied by glomerular influx of neutrophils (Table 2 and Figure 4). Although increased neutrophils occurred in some glomeruli that had not yet developed histological lesions, neutrophils were concentrated at sites of segmental necrotizing glomerular injury, and occasionally were identified in Bowman’s space in glomeruli with necrosis or crescents, and in a few afferent arterioles (Figure 4). Positively staining fragments of neutrophils were present in some necrotic areas (Figure 4d).

Figure 4
Glomerular neutrophil accumulation in B6 mice that received two doses of anti-MPO IgG on day 0 and day 3 followed by sacrifice on day 6. Mice that received anti-BSA IgG had only rare neutrophils in a few glomeruli (not shown). Immunoenzyme microscopy ...
Table 2
Pathologic Findings in Mice that Received Two Injections of Anti-MPO IgG or Anti-BSA IgG


In this mouse model of ANCA NCGN, neutrophils and macrophages are present at the sites of acute glomerular injury, and neutrophil depletion completely protects mice from induction of NCGN by anti-MPO IgG even in the presence of levels of circulating anti-MPO IgG that cause NCGN in 100% of mice with normal levels of neutrophils. These observations support the concept that neutrophils are the key effector cells in anti-MPO antibody-induced NCGN.

Numerous in vitro studies have documented the ability of human ANCA IgG (ie, both anti-MPO and anti-PR3 IgG) to activate neutrophils with the resultant release of toxic oxygen metabolites, lytic and toxic proteases, nitric oxide, and inflammatory cytokines.15–19 This activation involves increased display of ANCA antigens at the surface of neutrophils facilitating both the attachment of the antigen-binding portion of the autoantibodies as well as the engagement of Fc receptors on the surface of neutrophils.20–22 Neutrophils that have been activated by ANCA IgG adhere to and kill endothelial cells in vivo23–25 and are induced to migrate through endothelial monolayers.26 If these events that have been observed repeatedly in vitro are reproduced in vivo by ANCA IgG-induced stimulation on neutrophils, this would provide a clear pathogenic mechanism for the mediation of acute inflammatory vascular injury, including glomerulonephritis and vasculitis, by activation of neutrophils by ANCA IgG.8

The experiments reported here provide evidence for an important role for neutrophils in this experimental model, but they do not rule out the participation of monocytes in disease induction. Monocytes express both MPO and PR3 and can be activated by ANCA IgG to release many of the same mediators that are released by neutrophils after activation by ANCA.27–30 Under the conditions tested in the current model, any activation of monocytes that may be occurring is not sufficient to produce detectable injury in the absence of neutrophils. However, the immunophenotyping of leukocytes demonstrated the clear participation of macrophages in the necrotizing and especially the crescentic lesions. One possibility is that the initial induction of acute necrotizing injury is primarily mediated by neutrophils, whereas the macrophage infiltration is a component of the innate inflammatory response to the injury and plays a major role in the initiation of crescent formation. The leukocyte phenotyping revealed only a few lymphocytes at the sites of acute injury. This lack of substantial participation of lymphocytes in the acute injury is consistent with the observation that this model of glomerulonephritis can be induced by injecting anti-MPO IgG into immune-deficient mice that lack functional T cells.10

In summary, our results demonstrate that neutrophils are crucial in the induction of NCGN by anti-MPO antibodies in this experimental model. This supports the possibility that neutrophils are similarly important in human ANCA NCGN. If this is the case, therapeutic strategies that target ANCA-induced neutrophil recruitment and activation could be beneficial in the treatment of ANCA diseases.


Address reprint requests to J. Charles Jennette, Department of Pathology and Laboratory Medicine, 303 Brinkhous-Bullitt Building, University of North Carolina, Chapel Hill, NC 27599-7525. .ude.cnu.dem@jcj :liam-E

Supported by the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases grant PO1 DK58335) and the Dutch Kidney Foundation (grant PC115 to P.H. and D.H.).


  • Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med. 1988;318:1651–1657. [PubMed]
  • Goldschmeding R, van der Schoot CE, ten Bokkel Huinink D, Hack CE, van den Ende ME, Kallenberg CG, von dem Borne AE. Wegener’s granulomatosis autoantibodies identify a novel diisopropylfluorophosphate-binding protein in the lysosomes of normal human neutrophils. J Clin Invest. 1989;84:1577–1587. [PMC free article] [PubMed]
  • Jennette JC, Hoidal JR, Falk RJ. Specificity of anti-neutrophil cytoplasmic autoantibodies for proteinase 3. Blood. 1990;75:2263–2264. [PubMed]
  • Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med. 1997;337:1512–1523. [PubMed]
  • Savige J, Davies D, Falk RJ, Jennette JC, Wiik A. Antineutrophil cytoplasmic antibodies (ANCA) and associated diseases. Kidney Int. 2000;57:846–862. [PubMed]
  • Jennette JC. Rapidly progressive and crescentic glomerulonephritis. Kidney Int. 2003;63:1164–1172. [PubMed]
  • Brouwer E, Huitema MG, Mulder AH, Heeringa P, van Goor H, Tervaert JW, Weening JJ, Kallenberg CG. Neutrophil activation in vitro and in vivo in Wegener’s granulomatosis. Kidney Int. 1994;45:1120–1131. [PubMed]
  • Jennette JC, Falk RJ. Pathogenesis of the vascular and glomerular damage in ANCA-positive vasculitis. Nephrol Dial Transplant. 1998;13(Suppl 1):16–20. [PubMed]
  • Rarok AA, Limburg PC, Kallenberg CG. Neutrophil-activating potential of antineutrophil cytoplasm autoantibodies. J Leukoc Biol. 2003;74:3–15. [PubMed]
  • Xiao H, Heeringa P, Hu P, Liu Z, Zhao M, Aratani Y, Maeda N, Falk RJ, Jennette JC. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest. 2002;110:955–963. [PMC free article] [PubMed]
  • Aratani Y, Koyama H, Nyui S, Suzuki K, Kura F, Maeda N. Severe impairment in early host defense against Candida albicans in mice deficient in myeloperoxidase. Infect Immun. 1999;67:1828–1836. [PMC free article] [PubMed]
  • Lopez AF, Strath M, Sanderson CJ. Differentiation antigens on mouse eosinophils and neutrophils identified by monoclonal antibodies. Br J Haematol. 1984;57:489–494. [PubMed]
  • de Vries B, Kohl J, Leclercq WK, Wolfs TG, van Bijnen AA, Heeringa P, Buurman WA. Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils. J Immunol. 2003;170:3883–3889. [PubMed]
  • Tacchini-Cottier F, Zweifel C, Belkaid Y, Mukankundiye C, Vasei M, Launois P, Milon G, Louis JA. An immunomodulatory function for neutrophils during the induction of a CD4+ Th2 response in BALB/c mice infected with Leishmania major. J Immunol. 2000;165:2628–2636. [PubMed]
  • Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Nat Acad Sci USA. 1990;87:4115–4119. [PMC free article] [PubMed]
  • Charles LA, Caldas MLR, Falk RJ, Terrell RS, Jennette JC. Antibodies against granule proteins activate neutrophils in vitro. J Leukoc Biol. 1991;50:539–546. [PubMed]
  • Brooks CJ, King WJ, Radford DJ, Adu D, McGrath M, Savage CO. IL-1 beta production by human polymorphonuclear leucocytes stimulated by anti-neutrophil cytoplasmic autoantibodies: relevance to systemic vasculitis. Clin Exp Immunol. 1996;106:273–279. [PMC free article] [PubMed]
  • Cockwell P, Brooks CJ, Adu D, Savage COS. Interleukin-8: a pathogenetic role in antineutrophil cytoplasmic autoantibody-associated glomerulonephritis. Kidney Int. 1999;55:852–863. [PubMed]
  • Tse WY, Williams J, Pall A, Wilkes M, Savage COS, Adu D. Antineutrophil cytoplasm antibody-induced neutrophil nitric oxide production is nitric oxide synthase independent. Kidney Int. 2001;59:593–600. [PubMed]
  • Kettritz R, Jennette JC, Falk RJ. Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils. J Am Soc Nephrol. 1997;8:386–394. [PubMed]
  • Ben-Smith A, Dove SK, Martin A, Wakelam MJO, Savage COS. Autoantibodies from patients with systemic vasculitis activate primed neutrophils via Fc gamma receptor dependent pathways. Blood. 2001;98:1448–1455. [PubMed]
  • Williams JM, Ben-Smith A, Hewins P, Dove SK, Hughes P, McEwan R, Wakelam MJ, Savage CO. Activation of the G(i) heterotrimeric G protein by ANCA IgG F(ab′)2 fragments is necessary but not sufficient to stimulate the recruitment of those downstream mediators used by intact ANCA IgG. J Am Soc Nephrol. 2003;14:661–669. [PubMed]
  • Ewert BH, Jennette JC, Falk RJ. Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells. Kidney Int. 1992;41:375–383. [PubMed]
  • Savage CO, Pottinger BE, Gaskin G, Pusey CD, Pearson JD. Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells. Am J Pathol. 1992;141:335–342. [PMC free article] [PubMed]
  • Radford DJ, Savage COS, Nash GB. Treatment of rolling neutrophils with anti-neutrophil cytoplasm autoantibodies causes conversion to firm integrin-mediated adhesion. Arthritis Rheum. 2000;43:1337–1344. [PubMed]
  • Radford DJ, Nash GB, Savage COS. Anti-neutrophil cytoplasm antibodies (ANCA) potentiate the adhesion and migration of flowing neutrophils on endothelial cells treated with tumour necrosis factor-a. Arthritis Rheum. 2001;44:2851–2861. [PubMed]
  • Charles LA, Falk RJ, Jennette JC. Reactivity of antineutrophil cytoplasmic autoantibodies with mononuclear phagocytes. J Leukoc Biol. 1992;51:65–68. [PubMed]
  • Casselman BL, Kilgore KS, Miller BF, Warren JS. Antibodies to neutrophil cytoplasmic antigens induce monocyte chemoattractant protein-1 secretion from human monocytes. J Lab Clin Med. 1995;126:495–502. [PubMed]
  • Ralston DR, Marsh CB, Lowe MP, Wewers MD. Antineutrophil cytoplasmic antibodies induce monocyte IL-8 release. Role of surface proteinase-3, alpha1-antitrypsin, and Fc gamma receptors. J Clin Invest. 1997;100:1416–1424. [PMC free article] [PubMed]
  • Hattar K, Bickenbach A, Csernok E, Rosseau S, Grandel U, Seeger W, Grimminger F, Sibelius U. Wegener’s granulomatosis: antiproteinase 3 antibodies induce monocyte cytokine and prostanoid release—role of autocrine cell activation. J Leukoc Biol. 2002;71:996–1004. [PubMed]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...