Anti-Neutrophil Cytoplasmic Antibody Pathogenesis in Small-Vessel Vasculitis
2009; Elsevier BV; Volume: 175; Issue: 5 Linguagem: Inglês
10.2353/ajpath.2009.090533
ISSN1525-2191
AutoresJosé A. Gómez‐Puerta, Xavier Bosch,
Tópico(s)Neutrophil, Myeloperoxidase and Oxidative Mechanisms
ResumoVasculitides associated with serum positivity for anti-neutrophil cytoplasmic antibodies (ANCAs) that affect small- to medium-sized vessels are commonly known as ANCA-associated vasculitis (AAV) and include Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Evidence derived from both in vitro studies and recent animal models points to a pathogenic role of ANCAs in AAV. In 2002, the first in vivo breakthrough in the pathogenesis of ANCAs showed that mouse ANCAs against myeloperoxidase (MPO) led to intrinsic pauci-immune renal vasculitis in mice. In 2004, a report using both in vitro and in vivo studies proposed that proteinase 3 (PR3)-directed autoimmunity involved the complementary peptide of PR3 (cPR3), which is encoded by the antisense strand of the PR3 gene. The last breakthrough came in October 2008 with a previously undescribed molecular explanation for the origin and development of injury in pauci-immune renal vasculitis, with potential clinical implications. This report showed that infection by fimbriated bacteria may trigger cross-reactive autoimmunity to a previously characterized ANCA antigen, lysosomal membrane protein-2, which is contained in the same vesicles that harbor MPO and PR3. Infection by fimbriated bacteria resulted in the production of autoantibodies, which activated neutrophils and killed human microvascular endothelium in vitro and caused renal vasculitis in rats. Although the evidence for a pathogenic role of ANCAs, mainly MPO-ANCAs, is striking, various questions remain unanswered. Understanding the key pathogenic mechanisms of AAV may provide a safer, more rational therapeutic approach than the traditional (ie, corticosteroids and immunosuppressants) treatment strategy. Vasculitides associated with serum positivity for anti-neutrophil cytoplasmic antibodies (ANCAs) that affect small- to medium-sized vessels are commonly known as ANCA-associated vasculitis (AAV) and include Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Evidence derived from both in vitro studies and recent animal models points to a pathogenic role of ANCAs in AAV. In 2002, the first in vivo breakthrough in the pathogenesis of ANCAs showed that mouse ANCAs against myeloperoxidase (MPO) led to intrinsic pauci-immune renal vasculitis in mice. In 2004, a report using both in vitro and in vivo studies proposed that proteinase 3 (PR3)-directed autoimmunity involved the complementary peptide of PR3 (cPR3), which is encoded by the antisense strand of the PR3 gene. The last breakthrough came in October 2008 with a previously undescribed molecular explanation for the origin and development of injury in pauci-immune renal vasculitis, with potential clinical implications. This report showed that infection by fimbriated bacteria may trigger cross-reactive autoimmunity to a previously characterized ANCA antigen, lysosomal membrane protein-2, which is contained in the same vesicles that harbor MPO and PR3. Infection by fimbriated bacteria resulted in the production of autoantibodies, which activated neutrophils and killed human microvascular endothelium in vitro and caused renal vasculitis in rats. Although the evidence for a pathogenic role of ANCAs, mainly MPO-ANCAs, is striking, various questions remain unanswered. Understanding the key pathogenic mechanisms of AAV may provide a safer, more rational therapeutic approach than the traditional (ie, corticosteroids and immunosuppressants) treatment strategy. Anti-neutrophil cytoplasmic antibodies (ANCAs) were discovered by chance in 1982 when Davies et al1Davies DJ Moran JE Niall JF Ryan GB Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology?.Br Med J (Clin Res Ed). 1982; 285: 606Crossref PubMed Scopus (814) Google Scholar were studying antinuclear antibodies in serum samples from patients with segmental necrotizing glomerulonephritis. Using indirect immunofluorescence applied to neutrophils, a diffuse cytoplasmic, but not nuclear, staining pattern was observed. In 1985, van der Woude et al2van 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. 1985; 1: 425-429Abstract PubMed Scopus (1395) Google Scholar found that cytoplasmic ANCAs occurred mainly in patients with Wegener's granulomatosis (WG), and interest in ANCAs skyrocketed. In 1988,3Falk 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: 1651-1657Crossref PubMed Scopus (1227) Google Scholar a distinct perinuclear pattern in serum samples from patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis was reported. Enzyme-linked immunosorbent assay showed that myeloperoxidase (MPO) was the chief antigenic target of perinuclear ANCAs. Two years later, proteinase 3 (PR3) was recognized as the major autoantigen accounting for the cytoplasmic ANCA pattern of WG.4Jenne DE Tschopp J Ludemann J Utecht B Gross WL Wegener's autoantigen decoded.Nature. 1990; 346: 520Crossref PubMed Scopus (206) Google Scholar, 5Jennette JC Hoidal JR Falk RJ Specificity of anti-neutrophil cytoplasmic autoantibodies for proteinase 3.Blood. 1990; 75: 2263-2264Crossref PubMed Google ScholarThe vasculitides are often serious and sometimes fatal diseases that require prompt recognition and treatment. Symptomatic involvement of affected organs may occur in isolation or in combination with multiple organ involvement. Vasculitic syndromes are normally categorized by the type and predominant size of the blood vessels most commonly affected (Table 1).6Seo P Stone JH The antineutrophil cytoplasmic antibody-associated vasculitides.Am J Med. 2004; 117: 39-50Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 7Jennette JC Falk RJ Small-vessel vasculitis.N Engl J Med. 1997; 337: 1512-1523Crossref PubMed Scopus (1176) Google Scholar The distribution of affected organs may suggest a particular vasculitic disorder, but there is significant overlap.Table 1Classification of VasculitisLarge-vessel vasculitisMedium-sized vessel vasculitisSmall-vessel vasculitisTakayasu arteritisPolyarteritis nodosaANCA-related vasculitis Churg-Strauss syndromeGiant cell arteritisKawasaki disease Wegener's granulomatosisIsolated central nervous system vasculitis Microscopic polyangiitis Drug-induced ANCA-associated vasculitisHenoch-Schönlein purpuraEssential cryoglobulinemic vasculitisHypersensitivity vasculitisHypersensitivity vasculitisVasculitis due to connective tissue disordersVasculitis due to viral infectionParaneoplastic small-vessel vasculitisModified from Jennette and Falk.7Jennette JC Falk RJ Small-vessel vasculitis.N Engl J Med. 1997; 337: 1512-1523Crossref PubMed Scopus (1176) Google Scholar Open table in a new tab ANCA-associated small-vessel vasculitis should be suspected in any patient presenting with multisystemic disease not caused by infectious or malignant processes (eg, renal failure, skin rashes, pulmonary infiltrates, or neurological manifestations such as peripheral neuropathy). Constitutional symptoms are also common.6Seo P Stone JH The antineutrophil cytoplasmic antibody-associated vasculitides.Am J Med. 2004; 117: 39-50Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 7Jennette JC Falk RJ Small-vessel vasculitis.N Engl J Med. 1997; 337: 1512-1523Crossref PubMed Scopus (1176) Google Scholar, 8Mansi IA Opran A Rosner F ANCA-associated small-vessel vasculitis.Am Fam Physician. 2002; 65: 1615-1620PubMed Google Scholar Renal involvement in vasculitis may progress to renal failure and renal biopsy commonly reveals glomerulonephritis. Although renal-limited vasculitis is closely associated with ANCAs, WG, microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS) are systemic forms of ANCA-associated vasculitis (AAV) with common extrarenal involvement.Vasculitides associated with serum positivity for ANCAs that affect small to medium-sized vessels are commonly known as AAV. Focal necrosis, crescentic formation, and the absence or paucity of immunoglobulin deposits characterize glomerulonephritis in patients with AAV. Lung involvement ranges from fleeting focal infiltrates or interstitial disease to massive pulmonary hemorrhagic alveolar capillaritis, the most life-threatening manifestation of small-vessel vasculitis.7Jennette JC Falk RJ Small-vessel vasculitis.N Engl J Med. 1997; 337: 1512-1523Crossref PubMed Scopus (1176) Google Scholar ANCAs directed to proteinase 3 (PR3-ANCAs) are detected mainly in WG, whereas anti-myeloperoxidase antibodies (MPO-ANCAs) are predominantly found in MPA and CSS.Vasculitis ClassificationClassification criteria for most of the major forms of vasculitis were established by the American College of Rheumatology in 19909Hunder GG Arend WP Bloch DA Calabrese LH Fauci AS Fries JF Leavitt RY Lie JT Lightfoot Jr, RW Masi AT et al.The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction.Arthritis Rheum. 1990; 33: 1065-1067Crossref PubMed Scopus (612) Google Scholar and were based on prospective data from patients with vasculitis; they do not include all characteristics of a particular disorder, only those that help distinguish it from other vasculitides. The criteria were revisited in 1994 at the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis, at which the concept of MPA was firmly established.WG predominantly affects the upper and lower respiratory tracts and the kidneys, in which it may lead to rapidly progressive glomerulonephritis as a result of necrotizing and crescentic glomerulonephritis. In the lungs, WG can cause life-threatening diffuse alveolar hemorrhage as a result of (pauci-immune) alveolar necrotizing capillaritis.10Bosch X Guilabert A Font J Antineutrophil cytoplasmic antibodies.Lancet. 2006; 368: 404-418Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar Localized forms of WG are usually limited to the eyes, ears, nose, and lungs. Histologically, WG is characterized by granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small- to medium-sized vessels (eg, capillaries, venules, arterioles, and arteries).8Mansi IA Opran A Rosner F ANCA-associated small-vessel vasculitis.Am Fam Physician. 2002; 65: 1615-1620PubMed Google ScholarCSS is characterized by asthma, hypereosinophilia, and transient pulmonary infiltrates. Rapidly progressive glomerulonephritis and pulmonary hemorrhage are less common than in MPA and WG. The typical histopathological features of CSS include eosinophil-rich, granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small- to medium-sized vessels and associated with asthma and eosinophilia.8Mansi IA Opran A Rosner F ANCA-associated small-vessel vasculitis.Am Fam Physician. 2002; 65: 1615-1620PubMed Google Scholar, 10Bosch X Guilabert A Font J Antineutrophil cytoplasmic antibodies.Lancet. 2006; 368: 404-418Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar The natural history of CSS is characterized by three clinical stages: a prodromic phase consisting of severe asthma (99% of patients11Keogh KA Specks U Churg-Strauss syndrome.Semin Respir Crit Care Med. 2006; 27: 148-157Crossref PubMed Scopus (81) Google Scholar), followed by eosinophil infiltration into tissues (eg, pulmonary infiltrates), and, last, MPO-ANCA-associated systemic vasculitis affecting mainly the skin, kidneys, and peripheral nerves in addition to asthma and peripheral eosinophilia (3 to 4 years after onset).12Pagnoux C Guilpain P Guillevin L Churg-Strauss syndrome.Curr Opin Rheumatol. 2007; 19: 25-32Crossref PubMed Scopus (195) Google Scholar There may be granulomatous disease in the third stage.13Hellmich B Csernok E Gross WL Proinflammatory cytokines and autoimmunity in Churg-Strauss syndrome.Ann NY Acad Sci. 2005; 1051: 121-131Crossref PubMed Scopus (90) Google Scholar However, the three stages do not have to follow each other. Studies of ANCA prevalence and disease patterns show two general subsets of patients depending on ANCA positivity: one with ANCAs and a predominance of histology-proven necrotizing small-vessel vasculitis and another without ANCAs and with a higher incidence of eosinophil infiltration of the lung, heart, and gastrointestinal tract.14Kallenberg CG Antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis.Curr Opin Rheumatol. 2007; 19: 17-24Crossref PubMed Scopus (65) Google Scholar A recent study linked HLA-DRB4 with CSS and an increased risk of vasculitic manifestations.15Vaglio A Martorana D Maggiore U Grasselli C Zanetti A Pesci A Garini G Manganelli P Bottero P Tumiati B Sinico RA Savi M Buzio C Neri TM HLA-DRB4 as a genetic risk factor for Churg-Strauss syndrome.Arthritis Rheum. 2007; 56: 3159-3166Crossref PubMed Scopus (147) Google ScholarMPA is characterized by pauci-immune necrotizing small-vessel vasculitis without granuloma formation, with or without involvement of medium-sized arteries. The clinical spectrum is similar to WG, although ear, nose, throat, and lung involvement is less common10Bosch X Guilabert A Font J Antineutrophil cytoplasmic antibodies.Lancet. 2006; 368: 404-418Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar and renal involvement may be the only manifestation. About half the patients with MPA develop necrotizing alveolar capillaritis-induced pulmonary hemorrhage. MPA is the most common cause of pulmonary-renal syndrome (Figure 1). Histologically, MPA is characterized by necrotizing vasculitis with few or no immune deposits affecting small vessels (capillaries, venules, and arterioles). There may be necrotizing arteritis involving small- and medium-sized arteries.8Mansi IA Opran A Rosner F ANCA-associated small-vessel vasculitis.Am Fam Physician. 2002; 65: 1615-1620PubMed Google ScholarCurrently, immunosuppressants combined with glucocorticoids are the mainstay of AAV treatment, including renal-limited vasculitis. Although dramatically improving survival, 25% of patients have severe treatment-related adverse events and the 5-year relapse rate is 50% such that AAV becomes a chronic, relapsing disorder with accumulative, irreversible organ damage. Repeated disease episodes then lead to intensification of toxic immunosuppressants. Understanding the key pathogenic mechanisms of AAV may provide a safer, more rational therapeutic approach.Pathogenesis: Animal ModelsA pathogenic role for ANCAs has always been suspected because of their association with small-vessel vasculitis. Numerous animal models reinforce the theoretical pathogenicity of ANCAs (Table 2).14Kallenberg CG Antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis.Curr Opin Rheumatol. 2007; 19: 17-24Crossref PubMed Scopus (65) Google Scholar, 16Little MA Smyth CL Yadav R Ambrose L Cook HT Nourshargh S Pusey CD Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo.Blood. 2005; 106: 2050-2058Crossref PubMed Scopus (238) Google Scholar, 17Xiao 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: 955-963Crossref PubMed Scopus (987) Google Scholar, 18Pfister 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. 2004; 104: 1411-1418Crossref PubMed Scopus (218) Google Scholar, 19Huugen 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-α.Am J Pathol. 2005; 167: 47-58Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 20Xiao 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. 2005; 167: 39-45Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar, 21Xiao H Schreiber A Heeringa P Falk RJ Jennette JC Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies.Am J Pathol. 2007; 170: 52-64Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar, 22Ruth AJ Kitching AR Kwan RY Odobasic D Ooi JD Timoshanko JR Hickey MJ Holdsworth SR Anti-neutrophil cytoplasmic antibodies and effector CD4+ cells play nonredundant roles in anti-myeloperoxidase crescentic glomerulonephritis.J Am Soc Nephrol. 2006; 17: 1940-1949Crossref PubMed Scopus (125) Google Scholar, 23Huugen D van Esch A Xiao H Peutz-Kootstra CJ Buurman WA Tervaert JW Jennette JC Heeringa P Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice.Kidney Int. 2007; 71: 646-654Crossref PubMed Scopus (192) Google Scholar, 24Kessenbrock K Krumbholz M Schonermarck U Back W Gross WL Werb Z Grone HJ Brinkmann V Jenne DE Netting neutrophils in autoimmune small-vessel vasculitis.Nat Med. 2009; 15: 623-625Crossref PubMed Scopus (1115) Google Scholar For example, Xiao et al17Xiao 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: 955-963Crossref PubMed Scopus (987) Google Scholar immunized MPO-knockout mice with murine MPO. When MPO-immunized splenocytes were transferred to mice lacking B-functioning and T-functioning lymphocytes (Rag2−/−), MPO-ANCAs developed in a dose-dependent manner. Mice receiving the largest amount of MPO-immunized splenocytes developed severe necrotizing and crescentic glomerulonephritis and systemic vasculitis, including pulmonary capillaritis. However, all mice receiving the highest splenocyte dose developed nonsevere immune complex-mediated glomerulonephritis. In addition, the researchers injected MPO-ANCAs into Rag2−/− and wild-type mice to trigger anti-idiotype antibodies, which react with the original autoantigen. Both strains presented focal necrotizing and crescentic glomerulonephritis without immune complexes. The authors concluded that MPO-ANCAs intrinsically produced pauci-immune necrotizing and crescentic glomerulonephritis. However, because renal lesions in Rag2−/− mice receiving MPO-ANCAs were not as widespread as those seen in Rag2−/− mice given MPO-immunized splenocytes, other factors (eg, T lymphocytes and low-level immune complex deposition) might enhance the inflammatory process.Table 2Animal Models of ANCA-Associated VasculitisAuthor and referenceHypothesis testedExperimental modelMain resultsLittle et al16Little MA Smyth CL Yadav R Ambrose L Cook HT Nourshargh S Pusey CD Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo.Blood. 2005; 106: 2050-2058Crossref PubMed Scopus (238) Google ScholarMPO-ANCAs are able to promote leukocyte-endothelium interactions in vivoWistar-Kyoto rats were immunized with human MPO and developed human anti-MPO that cross-reacted with murine MPORats immunized with human MPO developed NCGN and capillaritisLeukocyte adherence and transmigration with microvasculature focal hemorrhage was observed (by intravital microscopy) in both immunized and nonimmunized rats in places where CXCL-1 was appliedIgG from immunized rats was passively transferred to nonimmunized ratsCXCL-1 was applied to the mesenterium of ratsXiao et al17Xiao 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: 955-963Crossref PubMed Scopus (987) Google ScholarMPO-ANCAs are pathogenicPassive administration of anti-MPO IgG (derived from the immunization of MPO knockout mice with murine MPO) to mice without functioning T or B lymphocytes (Rag2−/−) and to wild-type B6 miceRag 2−/− mice developed focal NCGN without immune deposits with approximately 15% of glomeruli suffering damagePfister et al18Pfister 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. 2004; 104: 1411-1418Crossref PubMed Scopus (218) Google ScholarPR3-ANCAs are pathogenicPassive transfer of PR3-ANCA-containing IgG (obtained from immunization of mice lacking PR3 and elastase with mouse PR3) to wild-type mice in the presence of LPSNo development of human AAV featuresHuugen et al19Huugen 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-α.Am J Pathol. 2005; 167: 47-58Abstract Full Text Full Text PDF PubMed Scopus (206) Google ScholarA proinflammatory stimulus of infectious origin would aggravate MPO-ANCA-dependent damageWild-type B6 mice were transferred with IgG MPO-ANCAs and also treated with bacterial LPSDose-dependant increase of the glomerular damageXiao et al20Xiao 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. 2005; 167: 39-45Abstract Full Text Full Text PDF PubMed Scopus (267) Google ScholarNeutrophils are key-effector cells in the pathogenesis of MPO-ANCA-induced NCGNIgG MPO-ANCAs were transferred to wild-type B6 miceNeutrophil depletion prevented MPO-ANCA IgG-related NCGNNeutrophils were depleted using NIMP-R14 rat monoclonal antibodiesXiao et al21Xiao H Schreiber A Heeringa P Falk RJ Jennette JC Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies.Am J Pathol. 2007; 170: 52-64Abstract Full Text Full Text PDF PubMed Scopus (406) Google ScholarComplement plays a role in AAV pathogenesisWild-type B6 mice were administered IgG MPO-ANCAs and Rag2−/− mice received anti-MPO splenocytesComplement depletion totally blocked NCGN in all miceIgG MPO-ANCAs caused disease in wild-type B6 and C4 mice but not in C5−/− and factor B−/− mice, suggesting involvement of the alternative complement pathwayComplement was depleted using cobra venom factorC5, C4, and factor B knockout mice were also administered IgG MPO-ANCAsRuth22Ruth AJ Kitching AR Kwan RY Odobasic D Ooi JD Timoshanko JR Hickey MJ Holdsworth SR Anti-neutrophil cytoplasmic antibodies and effector CD4+ cells play nonredundant roles in anti-myeloperoxidase crescentic glomerulonephritis.J Am Soc Nephrol. 2006; 17: 1940-1949Crossref PubMed Scopus (125) Google ScholarBoth anti MPO-CD4+ T lymphocytes (cellular response) and MPO-ANCAs play a role in NCGNWild-type B6, MPO−/−, and μMT−/− (mice lacking mature B cells) were immunized with human MPO and developed both humoral (except μMT−/− mice) and cellular autoimmunity to mice MPOImmunized wild-type B6 mice presented accumulation of neutrophils, CD4+ cells, macrophages, and crescent formation after injection of anti-GBM antibodiesSheep anti-mouse GMB antibodies were used to induce neutrophil recruitment to the glomeruliAdministration of anti-CD4 antibodies to immunized wild-type mice prevented crescent formation and recruitment of macrophages and leukocytes but not neutrophilsAnti-CD4+ monoclonal antibodies were employed to neutralize CD4+ T cellsHuugen et al23Huugen D van Esch A Xiao H Peutz-Kootstra CJ Buurman WA Tervaert JW Jennette JC Heeringa P Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice.Kidney Int. 2007; 71: 646-654Crossref PubMed Scopus (192) Google ScholarInhibition of C5 neutralizes MPO-ANCA-related damageWild-type B6 mice were injected with IgG MPO-ANCAs, LPS, and antimurine C5 monoclonal antibody BB5.1Anti-C5 pretreatment prevented NCGN induced by Ig MPO-ANCAs and LPSAnti-C5 treatment strongly attenuated NCGN induced by Ig MPO-ANCAs and LPSKessenbrock et al24Kessenbrock K Krumbholz M Schonermarck U Back W Gross WL Werb Z Grone HJ Brinkmann V Jenne DE Netting neutrophils in autoimmune small-vessel vasculitis.Nat Med. 2009; 15: 623-625Crossref PubMed Scopus (1115) Google ScholarANCA-mediated activation induces NETs formationPrimed neutrophils with TNF-α and incubated them with purified IgG from individuals with small-vessel vasculitisNET formation in neutrophils incubated with ANCA-IgGInduction of NETs with PR3 mouse monoclonal antibodyKain et al25Kain R Exner M Brandes R Ziebermayr R Cunningham D Alderson CA Davidovits A Raab I Jahn R Ashour O Spitzauer S Sunder-Plassmann G Fukuda M Klemm P Rees AJ Kerjaschki D Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis.Nat Med. 2008; 14: 1088-1096Crossref PubMed Scopus (352) Google ScholarCharacterized autoantibodies to LAMP-2 and showed that they are a new ANCA subtype in almost all individualsImmunized rats with rabbit immunoglobulin against human LAMP-2, which cross-reacts with rat LAMP-2All rats developed severe renal injury 22% of glomeruli exhibited focal capillary necrosis after 24 hours, which was present in 21% of glomeruli developed crescentsInjected 15 Wistar-Kyoto rats i.v. with human LAMP-2 rabbit IgG that cross-reacts LAMP-2 with ratNCGN, necrotizing and crescentic glomerulonephritis; LPS, lipopolysaccharide; GMB, glomerular basement membrane; NET, neutrophil extracellular trap. Open table in a new tab Although ANCA-associated vasculitides do not, by definition, have immune complexes, immune deposits were shown by electron microscopy in 50% of renal biopsy specimens from patients with ANCA-positive necrotizing and crescentic glomerulonephritis, necrotizing arteritis, or both.26Bacon PA The spectrum of Wegener's granulomatosis and disease relapse.N Engl J Med. 2005; 352: 330-332Crossref PubMed Scopus (102) Google Scholar The addition of bacterial lipopolysaccharide increased the number of glomeruli affected and augmented tumor necrosis factor-α (TNF-α) levels.19Huugen 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-α.Am J Pathol. 2005; 167: 47-58Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar This result seems to confirm in vitro hypotheses underlining the importance of synergistic TNF-α priming for effective neutrophil activation and suggests how infection might exacerbate the effects of ANCAs. The role of Toll-like receptors in neutrophil priming also deserves investigation. Subsequent experiments in mice have demonstrated an essential role for both neutrophils20Xiao 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. 2005; 167: 39-45Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar and the alternative complement pathway in AAV.21Xiao H Schreiber A Heeringa P Falk RJ Jennette JC Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies.Am J Pathol. 2007; 170: 52-64Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar, 23Huugen D van Esch A Xiao H Peutz-Kootstra CJ Buurman WA Tervaert JW Jennette JC Heeringa P Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice.Kidney Int. 2007; 71: 646-654Crossref PubMed Scopus (192) Google ScholarIn 2005, Little et al16Little MA Smyth CL Yadav R Ambrose L Cook HT Nourshargh S Pusey CD Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo.Blood. 2005; 106: 2050-2058Crossref PubMed Scopus (238) Google Scholar developed a Wistar-Kyoto rat model in which focal necrotizing glomerulonephritis (FNGN) and pulmonary capillaritis were induced after immunization with purified human MPO, and the effects of MPO-ANCAs on the induction of leukocyte-endothelium interactions were explored using intravital microscopy of mesenteric venules. Administration of the chemokine CXCL-1 (a rat homolog of interleukin-8) in the mesenterium of both immunized and naïve rats, which received purified IgG from sera of MPO-immunized rats, led to increased leukocyte adherence and transmigration, with microvasculature focal hemorrhage at chemokine application sites. This experiment not only reinforced the pathogenic effect of ANCAs but also confirmed in vitro flow models showing that ANCAs in collaboration with a synergistic proinflammatory stimulus promote neutrophil adhesion to the endothelium in vivo. In contrast to accumulated evidence from MPO-ANCA animal models, there is no convincing in vivo evidence of PR3-ANCA pathogenicity.Recently, Kain et al25Kain R Exner M Brandes R Ziebermayr R Cunningham D Alderson CA Davidovits A Raab I Jahn R Ashour O Spitzauer S Sunder-Plassmann G Fukuda M Klemm P Rees AJ Kerjaschki D Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis.Nat Med. 2008; 14: 1088-1096Crossref Pu
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