Pathogenesis of Vascular Inflammation by Anti-Neutrophil Cytoplasmic Antibodies
J. Charles Jennette,
Hong Xiao and
Ronald J. Falk
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Address correspondence to: Dr. J. Charles Jennette, Department of Pathology and Laboratory Medicine, 303 Brinkhous-Bullitt Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525. Phone: 919-966-4676; Fax: 919-966-4542; E-mail: jcj{at}med.unc.edu
The reports of a newborn who developed glomerulonephritis andpulmonary hemorrhage after transplacental transfer of anti-neutrophilcytoplasmic antibody (ANCA) IgG with specificity for myeloperoxidase(MPO) is compelling clinical evidence that ANCA are pathogenic.In vitro studies indicate that ANCA activate cytokine-primedneutrophils and monocytes through both direct Fab'2 bindingand Fc receptor engagement. Neutrophils that have been activatedby ANCA release oxygen radicals, lytic enzymes, and inflammatorycytokines and adhere to and kill endothelial cells. A murinemodel caused by passive administration of mouse anti-mouse MPOIgG provides convincing evidence that ANCA IgG alone in theabsence of antigen-specific T cells can cause necrotizing glomerulonephritisand vasculitis. This pathogenic process is enhanced by synergisticinflammatory factors, probably through priming of neutrophils.Immunization of rats with human MPO induces antibodies thatcross-react with rat MPO and cause glomerulonephritis and vasculitis.These ANCA act in concert with chemokines to cause adherenceof leukocytes to the walls of small vessels with subsequentinjury. To date, animal models of disease that is induced byanti-proteinase 3 are less robust. Clinical and experimentaldata suggest but do not prove that the ANCA autoimmune responseis initiated by an immune response to an antisense peptide ofthe ANCA antigen or its mimic that may be introduced into thebody by an infectious pathogen. This antibody response elicitsanti-idiotypic antibodies that cross-react with ANCA antigens.The pathogenesis of ANCA disease is multifactorial, with geneticand environmental factors influencing onset of the autoimmuneresponse, the mediation of acute injury, and the induction ofthe chronic response to injury.
Anti-neutrophil cytoplasmic antibodies (ANCA) occur in >80%of patients with active, untreated, necrotizing, small-vesselvasculitis that has an absence or paucity of Ig deposited invessel walls (1). The major clinicopathologic expressions ofANCA-associated small-vessel vasculitis are Wegener’sgranulomatosis, microscopic polyangiitis, Churg-Strauss syndrome,and renal-limited vasculitis.
In 1936, Wegener suggested that the disease that now bears hisname was induced by an allergic (i.e., immunologic) reactionto an infection (2). In 1954, Godman and Churg (3) concludedthat Wegener’s granulomatosis, microscopic polyangiitis,and Churg-Strauss syndrome had the same pathogenesis and thatthis most likely involved a "hypersensitivity" (i.e., immunologic)mechanism. In 1978, Fauci et al. (4) contended that "most ofthe vasculitic syndromes are caused by, or closely associatedwith, deposition of immune complexes in blood vessel walls."However, immunohistologic evaluation of vessels from patientswith Wegener’s granulomatosis, microscopic polyangiitis,and renal-limited vasculitis demonstrated an absence or paucityimmunoglobulins (5,6). Therefore, pauci-immune small-vesselvasculitis and glomerulonephritis seemed to have a pathogenesisthat differed from typical immune complex disease.
The first hint of the cause of pauci-immune small-vessel vasculitiswas reported by Davies et al. (7) in 1982, when he observedthat eight patients with pauci-immune segmental necrotizingand crescentic glomerulonephritis had circulating "anti-neutrophilantibodies" that reacted with the cytoplasm of normal neutrophils.These anti-neutrophil antibodies usually disappeared after immunosuppressivetherapy and disease remission and reappeared with disease recurrence.Seven of the eight patients had serologic evidence for RossRiver virus infection, suggesting a possible role for infectionin disease induction.
Davies’s observation was confirmed and extended by twopublications in 1985 (8,9). Fokko van der Woude et al. (9) anda European consortium were the first to emphasize that ANCAwere closely associated with Wegener’s granulomatosisand that the titer correlated with disease activity. Duringthe ensuing 5 yr, the major antigen specificities for myeloperoxidase(MPO-ANCA) and proteinase 3 (PR3-ANCA) were determined (10–14).The possibility that ANCA are not only a serologic marker forpauci-immune small-vessel vasculitis but also the primary pathogenicfactor has been the subject of numerous investigations in thepast 20 yr.
The high prevalence of ANCA in patients with active untreatedpauci-immune small-vessel vasculitis does not prove that ANCAcause the disease, because the same pattern would occur if ANCAwere a secondary epiphenomenon. The correlation between ANCAtiters and disease activity also could be either a cause ora result of the disease. The apparent induction of circulatingANCA by certain drugs, such as propylthiouracil and hydralazine,with subsequent development of pauci-immune necrotizing andcrescentic glomerulonephritis and vasculitis also suggests apathogenic link between ANCA and vasculitis (15); however, onceagain, the induction of the ANCA could be merely a nonpathogenicprocess that occurs concurrent with the primary events thatare causing the vasculitis.
The most compelling clinical evidence that ANCA cause diseaseare the reports of a newborn child who developed glomerulonephritisand pulmonary hemorrhage 48 h after delivery from a mother withactive MPO-ANCA microscopic polyangiitis (16,17). The infant’sblood contained MPO-ANCA IgG. Corticosteroid therapy and plasmaexchange controlled the glomerulonephritis and pulmonary hemorrhageand eliminated the ANCA. A reasonable conclusion is that transplacentaltransfer of MPO-ANCA IgG caused glomerulonephritis and vasculitisin this neonate, but how does ANCA IgG mediate vascular inflammation?
Neutrophil and Monocyte Activation by ANCA In Vitro
Experimental studies from many laboratories have shown thatboth PR3-ANCA and MPO-ANCA IgG activate neutrophils in vitroto release mediators of acute inflammation (18,19). Figure 1illustrates a hypothetical sequence of pathogenic events thatcould result in ANCA-mediated vascular inflammation (20).
Figure 1. Events in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA) small-vessel vasculitis that have been observed in vitro. Beginning in the top left and moving to the right, cytokines or other priming factors induce neutrophils to express more ANCA antigens at the cell surface, where they are available for binding to ANCA, which activates neutrophils by both Fc receptor engagement and direct Fab'2 ligation. Neutrophils that have been activated by ANCA interact with endothelial cells via adhesion molecules and release toxic factors that cause apoptosis and necrosis. Adapted from reference (20) with permission.
Most MPO and PR3 are in the cytoplasm of unstimulated neutrophils;however, there are small amounts of antigen on the surface ofcirculating neutrophils. The proportion of circulating neutrophilsthat has ANCA antigens on the cell surface may be geneticallydetermined, and higher levels seem to be a risk factor for developmentof ANCA vasculitis (21,22). Neutrophils express more ANCA antigensat their surfaces when they are stimulated by a variety of proinflammatoryfactors such as cytokines and microbial products. For example,exposure of neutrophils to low levels of TNF- causes increasedsurface PR3 and MPO (23,24). Incubation of TNF-primed neutrophilswith ANCA IgG causes the release of toxic reactive oxygen speciesand lytic and toxic granule enzymes, including PR3 and MPO (23,24).This neutrophil activation is mediated by both Fc receptor engagement(25,26) and Fab'2 binding (27,28). The precise intracellularsignaling pathways through which ANCA IgG mediates neutrophilactivation are not completely elucidated, but they seem to bedifferent from the pathways that are involved in conventionalimmune complex-mediated activation of neutrophils (29).
Small amounts of immune complexes probably form on the surfaceof cells and exposed tissue matrix in the microenvironment whereANCA-induced inflammation occurs, because MPO and PR3 are cationicproteins that bind well to endothelial cells and matrix (30,31).Therefore, in some respects, this is an immune complex-mediatedprocess; however, it is very different from classical immunecomplex-mediated vasculitis that requires gross accumulationsof immune complexes in vessel walls and typically does not resultin the severe degree of necrotizing injury that is characteristicof ANCA vasculitis. In addition to binding to the surface ofendothelial cells, both PR3 and MPO are internalized into endothelialcells, where they have different pathologic effects (31). Forexample, after internalization, PR3 causes endothelial cellapoptosis, whereas MPO causes generation of intracellular oxidants(31). These differences in MPO and PR3 interaction with endothelialcells could influence the patterns of tissue injury that isinduced when these antigens react with ANCA at the endothelialcell surface. Therefore, the clinicopathologic expression ofdisease, which correlates to a degree with ANCA antigen specificity,might be influenced by ANCA antigen-dependent differential effectson endothelial cells.
Neutrophils that have been activated by ANCA IgG kill culturedendothelial cells (32,33). Close proximity of the activatedneutrophils to endothelial cells is required because the endothelialtoxicity is inhibited by antibodies to 2 integrins (34). Savageand associates (35–37) showed that activation of neutrophilsby ANCA causes integrin- and cytokine receptor-mediated adherenceto cultured endothelial cells and transmigration across theendothelial layer. In addition, activation of neutrophils withANCA causes a conformational change in integrins that enhancesligand binding (37). A role for adhesion molecules in the interactionbetween ANCA-activated neutrophils and vessels also is supportedby the immunohistologic evidence for upregulated adhesion moleculesin glomerular lesions in renal biopsy specimens from patientswith ANCA disease (38).
The target antigens for ANCA are not only in neutrophils butalso in monocytes (9,10), which is an important considerationwhen contemplating the pathogenesis of ANCA disease. Incubationof monocytes with ANCA IgG causes activation with release ofinflammatory mediators such as toxic oxygen metabolites (39),monocyte chemoattractant protein-1 (40), and IL-8 (41). MPOand PR3 are lost as monocytes transform into macrophages (42);therefore, it is unlikely that ANCA IgG can react with maturemacrophages.
Induction of Glomerulonephritis and Vasculitis by Passive Administration of Anti-MPO IgG to Mice
The pathogenicity of ANCA IgG is supported by a mouse modelthat has been developed by Xiao and associates (43–45).This model is induced by the passive transfer of anti-MPO IgG(MPO-ANCA) or anti-MPO lymphocytes into recipient mice. Theanti-MPO IgG or anti-MPO lymphocytes are derived form MPO knockoutmice that have been immunized with mouse MPO. Intravenous injectionof anti-MPO IgG into either immune-competent mice or Rag2–/–mice that have no functioning T or B cells causes pauci-immunecrescentic glomerulonephritis and small-vessel vasculitis thatis remarkably similar to human ANCA disease (43). Within 6 dof the intravenous injection, all mice develop focal segmentalfibrinoid necrosis and crescents in glomeruli, whereas no micethat receive control anti-BSA IgG develop glomerular lesions(Figure 2). Some but not all mice develop systemic vasculitis,including leukocytoclastic angiitis, necrotizing arteritis,pulmonary capillaritis, and necrotizing granulomatous inflammation(Figure 3). Immunofluorescence microscopy reveals only a paucityof Ig and complement in glomeruli. Neutrophils are concentratedat sites of segmental necrotizing injury, and macrophages areconcentrated in crescents (44). T lymphocytes are rare in acuteglomerular lesions.
Figure 2. Glomeruli from a Rag2–/– mouse 6 d after intravenous injection of anti-myeloperoxidase (anti-MPO) IgG showing no histologic lesion (a), segmental fibrinoid necrosis (arrow; b), segmental fibrinoid necrosis with a small cellular crescents (arrow; c), large circumferential crescent (arrows; d), fibrin in a crescent by immunofluorescence microscopy (e), and a paucity of segmental IgG by immunofluorescence microscopy (f). Reprinted from reference (42) with permission.
Figure 3. Vasculitic lesion from a wild-type mouse 6 d after intravenous injection of anti-MPO IgG, including pulmonary alveolar capillaritis with septal infiltration of neutrophils (a) and necrotizing arteritis with leukocytoclasia in the dermis of the ear (b). Adapted from reference (42) with permission.
The severity, histologic appearance, and tissue distributionof disease that is induced by anti-MPO IgG is no different inimmune-deficient Rag2–/– mice compared with wild-typemice. Rag2–/– mice have a genetic defect that preventsthe recombination events that are required for the productionof functioning Ig molecules and T cell antigen receptors. Theinduction of disease in Rag2–/– mice demonstratesthat antigen-specific T cells are not required to induce theacute injury. However, this does not address whether antigen-specificT cells are involved in the immunogenesis of human ANCA diseaseor in the progression or modulation of injury. For example,because the ANCA immune response is predominantly IgG, T lymphocytesmust be involved in the immunogenesis of this response to facilitateisotype switching.
NIMP-R14 rat mAb that selectively depletes mouse neutrophilswas used to investigate the importance of neutrophils in thepathogenesis of anti-MPO glomerulonephritis (44). Depletionof neutrophils completely blocks the induction of glomerulonephritisby injection of anti-MPO IgG, which indicates a pivotal rolefor neutrophils in this model. These blocking studies do notrule out a contributory role by monocytes, but any activationof monocytes was not adequate to cause identifiable disease.
Although all mice that received an adequate dose of anti-MPOIgG develop focal necrotizing glomerulonephritis, only approximately15% of glomeruli have lesions (43). As reviewed earlier, invitro experiments indicate that ANCA are more effective at activatingneutrophils that have been primed by inflammatory stimuli. Therefore,a synergistic proinflammatory stimulus should exacerbate anti-MPO-induceddisease. This was tested by treating mice with bacterial LPS(45). The LPS caused increased circulating levels of TNF- anda dose-dependent increase in the severity of glomerulonephritis.Administration of antibodies to TNF- prevented the LPS effect.These experiments support the hypothesis that neutrophil primingfacilitates the induction of glomerulonephritis by ANCA. Differencesin the onset and severity of ANCA disease in humans is influencedby infectious (46) and noninfectious (47,48) environmental influencesthat augment the responsivity of neutrophils to ANCA.
In summary, this mouse model of ANCA disease strongly supportsa primary pathogenic role of ANCA IgG. The experimental animaldata also suggest that the induction of disease is facilitatedand modified by synergistic proinflammatory events. This modelalso shows that glomerulonephritis and small-vessel vasculitisthat is remarkably similar to human ANCA disease can be inducedby anti-MPO IgG in the absence of antigen-specific T lymphocytes.
Induction of Glomerulonephritis and Vasculitis by Transfer of Anti-MPO Lymphocytes to Mice
Severe necrotizing and crescentic glomerulonephritis and systemicvasculitis can be induced by the passive transfer of splenocytesfrom MPO–/– mice that have been immunized with murineMPO (43). Splenocytes consist of B lymphocytes, T lymphocytes,and other cells. Lymphocyte transfer requires that the recipientmice be immune deficient (e.g., Rag2–/– mice) becauseautoreactive anti-MPO lymphocytes will be eliminated in immune-competentmice. Glomerulonephritis that is caused by injection of anti-MPOin the absence of any synergistic inflammatory stimulus typicallycauses necrosis and crescents in <25% of glomeruli, whereasintravenous injection of anti-MPO splenocytes causes necrosisand crescents in approximately 80% of glomeruli even thoughthe circulating titer of anti-MPO antibodies is similar (43).However, this lymphocyte transfer model is complicated by thefact that the transfer of immune-competent lymphocytes intothe immune-deficient Rag2–/– recipients resultsin immune complex deposits in glomeruli. The immune complexdeposits are no different after transfer of normal control splenocytesor anti-MPO lymphocytes and therefore are not caused by theanti-MPO immune response. Mice that receive control splenocytesdevelop no necrosis or crescents even though they have the glomerularimmune deposits. This background of glomerular immune complexesmay be responsible for the more severe disease after anti-MPOsplenocyte transfer compared with anti-MPO IgG transfer becauseof a priming effect on neutrophils in glomeruli. Alternatively,the splenocyte transfer could be more pathogenic because ofthe additive effect of anti-MPO T lymphocytes.
To test the importance of anti-MPO T lymphocytes, we transferredsplenocyte preparations with different numbers of anti-MPO Tcells into Rag2–/– mice (49). Unfractionated splenocytescontained approximately 25% T cells and 65% B cells. Two differentpreparations that were enriched for T cells were injected, onewith approximately 80% T cells and 10% B cells and the otherwith >99% T cells. Injection of the unfractionated splenocytescaused crescents and necrosis in approximately 80% of glomeruli,whereas the preparation with 80% T cells caused necrosis andcrescents in only 5% of glomeruli and the >99% pure T cellpreparation caused no crescents or necrosis. These data do notsupport a pathogenic role for anti-MPO T cells in the inductionof acute injury in this experimental model. The lymphocyte transferexperiments add further support to the importance of a synergisticinflammatory stimulus in augmenting ANCA-induced inflammation(in this instance, background immune complex deposition) anddo not support a role for antigen-specific T cells in the inductionof acute injury.
Induction of Glomerulonephritis and Vasculitis by Active Immunization of Rats with Human MPO
Little et al. (50) caused focal segmental pauci-immune glomerulonephritisand focal pulmonary capillaritis in rats by immunization withhuman MPO, which induced anti-MPO antibodies that cross-reactwith human and rat MPO. Intravital microscopy of mesentericvessels was used to observe directly the interaction of leukocyteswith the walls of small vessels. Application of CXCL-1 chemokineto the mesentery of rats with circulating anti-MPO resultedin increased firm adherence and transmigration of leukocytes.This same effect was observed in unimmunized rats after injectionof IgG from rats that had been immunized with human MPO. Bothinduction of circulating anti-MPO by active immunization andpassive transfer caused focal hemorrhage in the mesenteric microvasculatureat sites of chemokine application. This rat model demonstratesthat, in the presence of synergistic factors (e.g., chemokines),anti-MPO IgG (MPO-ANCA) activates leukocytes and induced themto adhere to and injure small vessels in vivo.
Enhancement of Dermal Inflammation in Mice by Injection of Anti-PR3
Pfister et al. (51) knocked out the genes for PR3 and elastasein mice. Immunization of these mice with recombinant murinePR3 resulted in circulating anti-PR3 antibodies that reactedwith the cytoplasm of mouse neutrophils; however, the mice didnot develop glomerulonephritis or vasculitis. Intravenous injectionof anti-PR3 into mice, even into mice that had been primed withLPS, produced only equivocal "incipient" glomerulonephritisand pulmonary capillaritis. However, intravenous injection ofanti-PR3 enhanced dermal inflammation at sites of TNF- injection.Pfister et al. (51) concluded that this observation supportedthe pathogenic potential of anti-PR3. Nevertheless, the injurythat is induced by anti-PR3 in this model is not as convincingas the injury in the anti-MPO models. This suggests that anti-MPOand anti-PR3 antibodies have different mechanisms of actionin animal models, which is in line with the clinically and pathologicallydifferent expression of disease in humans with MPO-ANCA versusPR3-ANCA.
The clinical and experimental data that have been reviewed stronglysupport a primary pathogenic role for ANCA but do not explainwhy ANCA develop. Pendergraft et al. (52) reported intriguingobservations that suggest but do not yet prove a role for peptidesthat are mimics of the antisense complementary peptides of theautoantigen in the immunogenesis of the antibody response tothe sense peptides of the autoantigen. Some but not all patientswith PR3-ANCA glomerulonephritis and small-vessel vasculitishave antibodies that react with a peptide translated from themiddle portion of the antisense DNA strand of PR3 (complementaryPR3). Although not yet demonstrated experimentally, it is possiblethat patients who do not react with the middle portion of complementaryPR3 do react with the N-terminal or C-terminal portions of complementaryPR3. In patients with anticomplementary antibodies, these anticomplementaryantibodies bound to anti-PR3 antibodies, indicating that theanticomplementary PR3 and anti-PR3 antibodies form an idiotypicand anti-idiotypic pair. Furthermore, mice that are immunizedwith complementary PR3 peptide produce not only antibodies toantisense PR3 peptide but also antibodies to sense PR3 peptide.These observations are the basis for the hypothesis that anti-PR3autoantibodies (PR3-ANCA) are generated by an immune responsethat initially is mounted against a peptide that is antisenseor complementary to the autoantigen. This could be an endogenouslyderived antisense peptide or an exogenously derived mimic ofthe true antisense peptide, such as a complementary peptidemimic introduced by an infectious pathogen. The antibody responseto the complementary peptide or its mimic induces anti-idiotypicantibodies that cross-react with the sense peptides of the autoantigenand thus function as autoantibodies.
Chronic nasal infection with Staphylococcus aureus is associatedwith Wegener’s granulomatosis and is a risk factor forrelapses (46). Of interest with respect to the complementarypeptide hypothesis, Staphylococcus aureus contains a proteinwith an amino acid sequence that mimics the antisense sequenceof PR3. Two other infections that are know to be associatedwith PR3-ANCA disease also are caused by pathogens with peptidethat mimic the complementary peptide of PR3: Ross River virusand Entamoeba histolytica (52).
The theory of autoantigen complementarity is far from provedas the primary cause for ANCA disease; however, the preliminaryevidence warrants further study of this possibility. Additionalsupport for this theory derives from a variety of other autoimmunediseases that have autoantigen epitopes that have complementarysequences that are mimicked by infectious pathogens that areincriminated in susceptibility to these diseases (53).
The induction of ANCA small-vessel vasculitis and glomerulonephritisis a multifactorial process that is influenced by genetic susceptibilityand environmental factors that can influence not only the initialonset of disease but also the evolution of disease over time(Figure 4). Genetically determined factors include differencesin the expression of ANCA antigens by neutrophils, defects inantiproteinase alleles, and polymorphisms in genes that produceproteins that are involved in adaptive or innate immune responses,such as adhesion molecules, chemokine receptors, and lymphocyteimmune regulatory molecules (54). Environmental factors suchas infections (e.g., Staphylococcus), drugs (e.g., propylthiouracil),and phlogogenic irritants (e.g., silica) seem to be adjuvantsif not primary stimuli for the ANCA autoimmune response. Experimentaldata provide strong evidence that neutrophils are the principaleffector cells that are responsible for mediating ANCA-inducedacute necrotizing vascular inflammation. However, all destructiveacute inflammatory injury engenders a response by the innateimmune system that is orchestrated by macrophages and T cellsand often results in sclerosis or fibrosis. This response toacute injury may be extremely important in the clinical manifestationsand ultimate outcome of a disease process. Little currentlyis known about this late phase in the pathogenesis of ANCA disease.
Figure 4. Pathogenic events during the evolution of ANCA disease. Loss of tolerance is required for the production of pathogenic amounts of ANCA. ANCA activate neutrophils and monocytes, resulting in acute inflammation and necrosis, which elicits a response that is orchestrated by macrophages and T cells. Multiple genetic and environmental factors modulate each pathogenic step from onset to outcome.
In the 20 years since the discovery of ANCA, there have beentremendous advances in the knowledge of the pathophysiologyof ANCA-associated small-vessel vasculitis and glomerulonephritis.In the coming 20 years, this knowledge should be valuable inguiding the development of more effective treatment strategiesand possibly even preventive measures.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
Godman GC, Churg J: Wegener’s granulomatosis. Pathology and review of the literature.
Arch Pathol 58
: 533
–553, 1954[Medline]
Fauci AS, Haynes BF, Katz P: The spectrum of vasculitis. Clinical, pathologic, immunologic, and therapeutic considerations.
Ann Intern Med 89
: 660
–676, 1978[Medline]
Stilmant MM, Bolton WK, Sturgill BC, Schmitt GW, Couser WG: Crescentic glomerulonephritis without immune deposits: Clinicopathologic features.
Kidney Int 15
: 184
–196, 1979[Medline]
Ronco P, Verroust P, Mifnon F, Kourilsky O, Vanhille P, Meyrier A, Mery JP, Morel-Maroger L: Immunopathological studies of polyarteritis nodosa and Wegener’s granulomatosis: A report of 43 patients with 51 renal biopsies.
Q J Med 52
: 212
–223, 1983
Davies DJ, Moran JE, Niall JF, Ryan GB: Segmental necrotising glomerulonephritis with antineutrophil antibody: Possible arbovirus aetiology?
BMJ 285
: 606
, 1982[Medline]
Hall SL, Miller LC, Duggan E, Mauer SM, Beatty EC, Hellerstein S: Wegener granulomatosis in pediatric patients.
J Pediatr 106
: 739
–744, 1985[CrossRef][Medline]
van der Woude FJ, Rasmussen N, Lobatto S, Wiik A, Permin H, van Es LA, van der Giessen M, van der Hem GK, The TH: Autoantibodies against neutrophils and monocytes: Tool for diagnosis and marker of disease activity in Wegener’s granulomatosis.
Lancet 1
: 425
–429, 1985[Medline]
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 318
: 1651
–1657, 1988[Abstract]
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 84
: 1577
–1587, 1989[Medline]
Niles JL, McCluskey T, Ahmad MF, Amin Arnaout MA: Wegener’s granulomatosis autoantigen is a novel neutrophil serine proteinase.
Blood 74
: 1888
–1893, 1989[Abstract/Free Full Text]
Ludemann J, Utecht B, Gross WL: Anti-neutrophil cytoplasm antibodies in Wegener’s granulomatosis recognize an elastinolytic enzyme.
J Exp Med 171
: 357
–362, 1990[Abstract/Free Full Text]
Jennette JC, Hoidal JH, Falk RJ: Specificity of anti-neutrophil cytoplasmic autoantibodies for proteinase 3.
Blood 75
: 2263
–2264, 1990[Free Full Text]
Morita S, Ueda Y, Eguchi K: Anti-thyroid drug-induced ANCA-associated vasculitis: A case report and review of the literature.
Endocrine J 47
: 467
–470, 2000
Bansal PJ, Tobin MC: Neonatal microscopic polyangiitis secondary to transfer of maternal myeloperoxidase-antineutrophil cytoplasmic antibody resulting in neonatal pulmonary hemorrhage and renal involvement.
Ann Allergy Asthma Immunol 93
: 398
–401, 2004[Medline]
Schlieben DJ, Korbet SM, Kimura RE, Schwartz MM, Lewis EJ: Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs.
Am J Kidney Dis 45
: 758
–761, 2005[CrossRef]
Williams JM, Kamesh L, Savage CO: Translating basic science into patient therapy for ANCA-associated small vessel vasculitis.
Clin Sci 108
: 101
–112, 2005[Medline]
Jennette JC, Falk RJ: Pathogenesis of the vascular and glomerular damage in ANCA-positive vasculitis.
Nephrol Dial Transplant 13 [Suppl 1]
: 16
–20, 1998
Schreiber A, Busjahn A, Luft FC, Kettritz R: Membrane expression of proteinase 3 is genetically determined.
J Am Soc Nephrol 14
: 68
–75, 2003[Abstract/Free Full Text]
Schreiber A, Luft FC, Kettritz R: Membrane proteinase 3 expression and ANCA-induced neutrophil activation.
Kidney Int 65
: 2172
–2183, 2004[CrossRef][Medline]
Falk RJ, Terrell R, Charles LA, Jennette JC: Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals.
Proc Natl Acad Sci U S A 87
: 4115
–4119, 1990[Abstract/Free Full Text]
Charles LA, Caldas MLR, Falk RJ, Terrell RS, Jennette JC: Antibodies against granule proteins activate neutrophils in vitro.
J Leukoc Biol 50
: 539
–546, 1991[Abstract]
Porges AJ, Redecha PB, Kimberly WT, Csernok E, Gross WL, Kimberly RP: Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa.
J Immunol 153
: 1271
–1280, 1994[Abstract]
Mulder AH, Heeringa P, Brouwer E, Limburg PC, Kallenberg CG: Activation of granulocytes by anti-neutrophil cytoplasmic antibodies (ANCA): A Fc gamma RII-dependent process.
Clin Exp Immunol 98
: 270
–278, 1994[Medline]
Kettritz R, Jennette JC, Falk RJ: Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils.
J Am Soc Nephrol 8
: 386
–394, 1997[Abstract]
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 14
: 661
–669, 2003[Abstract/Free Full Text]
Ben-Smith A, Dove SK, Martin A, Wakelam MJ, Savage CO: Antineutrophil cytoplasm autoantibodies from patients with systemic vasculitis activate neutrophils through distinct signaling cascades: Comparison with conventional Fc gamma receptor ligation.
Blood 98
: 1448
–1455, 2001[Abstract/Free Full Text]
Savage CO, Gaskin G, Pusey CD, Pearson JD: Myeloperoxidase binds to vascular endothelial cells, is recognized by ANCA and can enhance complement dependent cytotoxicity.
Adv Exp Med Biol 336
: 121
–123, 1993[Medline]
Yang JJ, Preston GA, Pendergraft WF, Segelmark M, Heeringa P, Hogan SL, Jennette JC, Falk RJ: Internalization of proteinase 3 is concomitant with endothelial cell apoptosis and internalization of myeloperoxidase with generation of intracellular oxidants.
Am J Pathol 158
: 581
–592, 2001[Abstract/Free Full Text]
Ewert BH, Jennette JC, Falk RJ: Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells.
Kidney Int 41
: 375
–383, 1992[Medline]
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 141
: 335
–342, 1992[Abstract]
Radford DJ, Savage CO, Nash GB: Treatment of rolling neutrophils with antineutrophil cytoplasmic antibodies causes conversion to firm integrin-mediated adhesion.
Arthritis Rheum 43
: 1337
–1345, 2000[CrossRef][Medline]
Radford DJ, Luu NT, Hewins P, Nash GB, Savage CO: Antineutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelial cells.
Arthritis Rheum 44
: 2851
–2861, 2001[CrossRef][Medline]
Calderwood JW, Williams JM, Morgan MD, Nash GB, Savage CO: ANCA induces beta2 integrin and CXC chemokine-dependent neutrophil-endothelial cell interactions that mimic those of highly cytokine-activated endothelium.
J Leukoc Biol 77
: 33
–43, 2005[Abstract/Free Full Text]
Moon KC, Park SY, Kim HW, Hong HK, Lee HS: Expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in human crescentic glomerulonephritis.
Histopathology 41
: 158
–165, 2002[CrossRef][Medline]
Weidner S, Neupert W, Goppelt-Struebe M, Rupprecht HD: Antineutrophil cytoplasmic antibodies induce human monocytes to produce oxygen radicals in vitro.
Arthritis Rheum 44
: 1698
–1706, 2001[CrossRef][Medline]
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 126
: 495
–502, 1995[Medline]
Charles LA, Falk RJ, Jennette JC: Reactivity of anti-neutrophil cytoplasmic autoantibodies with mononuclear phagocytes.
J Leukoc Biol 51
: 65
–68, 1992[Abstract]
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 110
: 955
–963, 2002[CrossRef][Medline]
Xiao H, Heeringa P, Liu Z, Huugen D, Hu P, Maeda N, Falk RJ, Jennette JC: The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies.
Am J Pathol 167
: 39
–45, 2005[Abstract/Free Full Text]
Huugen D, Xiao H, van Esch A, Falk RJ, Peutz-Kootstra CJ, Buurman WA, Tervaert JW, Jennette JC, Heeringa P: Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: Role of tumor necrosis factor-alpha.
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Jennette JC, Xiao H, Heeringa P, Hu P, Liu Z, Falk RJ: Adoptive transfer of T lymphocytes alone from MPO knockout mice immunized with MPO can not induce necrotizing and crescentic glomerulonephritis.
Kidney Blood Press Res 26
: 254
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Little MA, Smyth CL, Yadav R, Ambrose L, Cook HT, Nourshargh S, Pusey CD: Anti-neutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo.
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Pfister H, Ollert M, Frohlich LF, Quintanilla-Martinez L, Colby TV, Specks U, Jenne DE: Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo.
Blood 104
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Nat Med 10
: 72
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J Mol Med 83
: 12
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Borgmann S, Haubitz M: Genetic impact of pathogenesis and prognosis of ANCA-associated vasculitides.
Clin Exp Rheumatol 22[Suppl 36]
: S79
–S86, 2004
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causes increased surface PR3 and MPO (23,24). Incubation of TNF-primed neutrophils with ANCA IgG causes the release of toxic reactive oxygen species and lytic and toxic granule enzymes, including PR3 and MPO (23,24). This neutrophil activation is mediated by both Fc receptor engagement (25,26) and Fab'2 binding (27,28). The precise intracellular signaling pathways through which ANCA IgG mediates neutrophil activation are not completely elucidated, but they seem to be different from the pathways that are involved in conventional immune complex-mediated activation of neutrophils (29). 
2 integrins (34). Savage and associates (35–37) showed that activation of neutrophils by ANCA causes integrin- and cytokine receptor-mediated adherence to cultured endothelial cells and transmigration across the endothelial layer. In addition, activation of neutrophils with ANCA causes a conformational change in 
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