Pathogenesis of ANCA-Associated Pulmonary Vasculitis

Abstract

Antineutrophil cytoplasmic antibodies (ANCAs) are autoantibodies specific for antigens located in the cytoplasmic granules of neutrophils and lysosomes of monocytes. ANCAs are associated with a spectrum of necrotizing vasculitis that includes granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis. Pulmonary vasculitis and related extravascular inflammation and fibrosis are frequent components of ANCA vasculitis. In this review, we detail the factors that have been associated with the origin of the ANCA autoimmune response and summarize the most relevant clinical observations, in vitro evidence, and animal studies strongly indicating the pathogenic potential of ANCA. In addition, we describe the putative sequence of pathogenic mechanisms driven by ANCA-induced activation of neutrophils that result in small vessel necrotizing vasculitis and extravascular granulomatous necrotizing inflammation.

Keywords

ANCA - granulomatosis with polyangiitis - microscopic polyangiitis - pulmonary vasculitis

Note

M.A. Alba was supported by Consejo Nacional de Ciencia y Tecnología (CONACyT), Mexico.

• References

• 1 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 (25) 1651-1657
• 2 Jennette JC, Falk RJ, Bacon PA. , et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65 (01) 1-11
• 3 Hoffman GS, Kerr GS, Leavitt RY. , et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992; 116 (06) 488-498
• 4 Anderson G, Coles ET, Crane M. , et al. Wegener's granuloma. A series of 265 British cases seen between 1975 and 1985. A report by a sub-committee of the British Thoracic Society Research Committee. Q J Med 1992; 83 (302) 427-438
• 5 Guillevin L, Durand-Gasselin B, Cevallos R. , et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum 1999; 42 (03) 421-430
• 6 Collins CE, Quismorio Jr FP. Pulmonary involvement in microscopic polyangiitis. Curr Opin Pulm Med 2005; 11 (05) 447-451
• 7 Flores-Suárez LF, Alba MA, Mateos-Toledo H, Ruiz N. Pulmonary involvement in systemic vasculitis. Curr Rheumatol Rep 2017; 19 (09) 56
• 8 Pendergraft III WF, Preston GA, Shah RR. , et al. Autoimmunity is triggered by cPR-3(105-201), a protein complementary to human autoantigen proteinase-3. Nat Med 2004; 10 (01) 72-79
• 9 Yang J, Bautz DJ, Lionaki S. , et al. ANCA patients have T cells responsive to complementary PR-3 antigen. Kidney Int 2008; 74 (09) 1159-1169
• 10 Tadema H, Heeringa P, Kallenberg CG. Bacterial infections in Wegener's granulomatosis: mechanisms potentially involved in autoimmune pathogenesis. Curr Opin Rheumatol 2011; 23 (04) 366-371
• 11 Stegeman CA, Tervaert JW, Sluiter WJ, Manson WL, de Jong PE, Kallenberg CG. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med 1994; 120 (01) 12-17
• 12 Popa ER, Stegeman CA, Abdulahad WH. , et al. Staphylococcal toxic-shock-syndrome-toxin-1 as a risk factor for disease relapse in Wegener's granulomatosis. Rheumatology (Oxford) 2007; 46 (06) 1029-1033
• 13 Zycinska K, Wardyn KA, Zielonka TM, Krupa R, Lukas W. Co-trimoxazole and prevention of relapses of PR3-ANCA positive vasculitis with pulmonary involvement. Eur J Med Res 2009; 14 (Suppl. 04) 265-267
• 14 Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG. ; Dutch Co-Trimoxazole Wegener Study Group. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. N Engl J Med 1996; 335 (01) 16-20
• 15 Bell EK, Chugh SS, Cook WJ. A case of infection-associated antiproteinase-3-negative cytoplasmic antineutrophil cytoplasmic antibody pauci-immune focal necrotizing glomerulonephritis. Nephrol Dial Transplant 2010; 25 (09) 3119-3123
• 16 Bonaci-Nikolic B, Andrejevic S, Pavlovic M, Dimcic Z, Ivanovic B, Nikolic M. Prolonged infections associated with antineutrophil cytoplasmic antibodies specific to proteinase 3 and myeloperoxidase: diagnostic and therapeutic challenge. Clin Rheumatol 2010; 29 (08) 893-904
• 17 Dhillon SS, Singh D, Doe N, Qadri AM, Ricciardi S, Schwarz MI. Diffuse alveolar hemorrhage and pulmonary capillaritis due to propylthiouracil. Chest 1999; 116 (05) 1485-1488
• 18 Yermakov VM, Hitti IF, Sutton AL. Necrotizing vasculitis associated with diphenylhydantoin: two fatal cases. Hum Pathol 1983; 14 (02) 182-184
• 19 Yu F, Chen M, Gao Y. , et al. Clinical and pathological features of renal involvement in propylthiouracil-associated ANCA-positive vasculitis. Am J Kidney Dis 2007; 49 (05) 607-614
• 20 Merkel PA. Drug-induced vasculitis. Rheum Dis Clin North Am 2001; 27 (04) 849-862
• 21 Hogan SL, Satterly KK, Dooley MA, Nachman PH, Jennette JC, Falk RJ. ; Glomerular Disease Collaborative Network. Silica exposure in anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and lupus nephritis. J Am Soc Nephrol 2001; 12 (01) 134-142
• 22 Nuyts GD, Van Vlem E, De Vos A. , et al. Wegener granulomatosis is associated to exposure to silicon compounds: a case-control study. Nephrol Dial Transplant 1995; 10 (07) 1162-1165
• 23 Beaudreuil S, Lasfargues G, Lauériere L. , et al. Occupational exposure in ANCA-positive patients: a case-control study. Kidney Int 2005; 67 (05) 1961-1966
• 24 Gómez-Puerta JA, Gedmintas L, Costenbader KH. The association between silica exposure and development of ANCA-associated vasculitis: systematic review and meta-analysis. Autoimmun Rev 2013; 12 (12) 1129-1135
• 25 Albert D, Clarkin C, Komoroski J, Brensinger CM, Berlin JA. Wegener's granulomatosis: possible role of environmental agents in its pathogenesis. Arthritis Rheum 2004; 51 (04) 656-664
• 26 Pai P, Bone JM, Bell GM. Hydrocarbon exposure and glomerulonephritis due to systemic vasculitis. Nephrol Dial Transplant 1998; 13 (05) 1321-1323
• 27 Duna GF, Cotch MF, Galperin C, Hoffman DB, Hoffman GS. Wegener's granulomatosis: role of environmental exposures. Clin Exp Rheumatol 1998; 16 (06) 669-674
• 28 Gatenby PA, Lucas RM, Engelsen O, Ponsonby AL, Clements M. Antineutrophil cytoplasmic antibody-associated vasculitides: could geographic patterns be explained by ambient ultraviolet radiation?. Arthritis Rheum 2009; 61 (10) 1417-1424
• 29 Kemna MJ, Cohen Tervaert JW, Broen K, Timmermans SAMEG, van Paassen P, Damoiseaux JGMC. Seasonal influence on the risk of relapse at a rise of antineutrophil cytoplasmic antibodies in vasculitis patients with renal involvement. J Rheumatol 2017; 44 (04) 473-481
• 30 Lyons PA, Rayner TF, Trivedi S. , et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med 2012; 367 (03) 214-223
• 31 Merkel PA, Xie G, Monach PA. , et al; Vasculitis Clinical Research Consortium. Identification of functional and expression polymorphisms associated with risk for antineutrophil cytoplasmic autoantibody-associated vasculitis. Arthritis Rheumatol 2017; 69 (05) 1054-1066
• 32 Cao Y, Schmitz JL, Yang J. , et al. DRB1*15 allele is a risk factor for PR3-ANCA disease in African Americans. J Am Soc Nephrol 2011; 22 (06) 1161-1167
• 33 Lionaki S, Blyth ER, Hogan SL. , et al. Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis. Arthritis Rheum 2012; 64 (10) 3452-3462
• 34 Alba MA, Flores-Suárez LF, Henderson AG. , et al. Interstital lung disease in ANCA vasculitis. Autoimmun Rev 2017; 16 (07) 722-729
• 35 Geffriaud-Ricouard C, Noël LH, Chauveau D, Houhou S, Grünfeld JP, Lesavre P. Clinical spectrum associated with ANCA of defined antigen specificities in 98 selected patients. Clin Nephrol 1993; 39 (03) 125-136
• 36 Shin MS, Young KR, Ho KJ. Wegener's granulomatosis upper respiratory tract and pulmonary radiographic manifestations in 30 cases with pathogenetic consideration. Clin Imaging 1998; 22 (02) 99-104
• 37 Néel A, Espitia-Thibault A, Arrigoni PP. , et al. Bronchiectasis is highly prevalent in anti-MPO ANCA-associated vasculitis and is associated with a distinct disease presentation. Semin Arthritis Rheum 2018; 48 (01) 70-76
• 38 Alberici F, Martorana D, Vaglio A. Genetic aspects of anti-neutrophil cytoplasmic antibody-associated vasculitis. Nephrol Dial Transplant 2015; 30 (Suppl. 01) i37-i45
• 39 Knight A, Sandin S, Askling J. Risks and relative risks of Wegener's granulomatosis among close relatives of patients with the disease. Arthritis Rheum 2008; 58 (01) 302-307
• 40 Ciavatta DJ, Yang J, Preston GA. , et al. Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis. J Clin Invest 2010; 120 (09) 3209-3219
• 41 Abdgawad M, Gunnarsson L, Bengtsson AA. , et al. Elevated neutrophil membrane expression of proteinase 3 is dependent upon CD177 expression. Clin Exp Immunol 2010; 161 (01) 89-97
• 42 Morgan MD, Day CJ, Piper KP. , et al. Patients with Wegener's granulomatosis demonstrate a relative deficiency and functional impairment of T-regulatory cells. Immunology 2010; 130 (01) 64-73
• 43 Rimbert M, Hamidou M, Braudeau C. , et al. Decreased numbers of blood dendritic cells and defective function of regulatory T cells in antineutrophil cytoplasmic antibody-associated vasculitis. PLoS One 2011; 6 (04) e18734
• 44 Free ME, Bunch DO, McGregor JA. , et al. Patients with antineutrophil cytoplasmic antibody-associated vasculitis have defective Treg cell function exacerbated by the presence of a suppression-resistant effector cell population. Arthritis Rheum 2013; 65 (07) 1922-1933
• 45 Lamprecht P, Erdmann A, Mueller A. , et al. Heterogeneity of CD4 and CD8+ memory T cells in localized and generalized Wegener's granulomatosis. Arthritis Res Ther 2003; 5 (01) R25-R31
• 46 Komocsi A, Lamprecht P, Csernok E. , et al. Peripheral blood and granuloma CD4(+)CD28(-) T cells are a major source of interferon-gamma and tumor necrosis factor-alpha in Wegener's granulomatosis. Am J Pathol 2002; 160 (05) 1717-1724
• 47 Nogueira E, Hamour S, Sawant D. , et al. Serum IL-17 and IL-23 levels and autoantigen-specific Th17 cells are elevated in patients with ANCA-associated vasculitis. Nephrol Dial Transplant 2010; 25 (07) 2209-2217
• 48 Abdulahad WH, Lepse N, Stegeman CA. , et al. Increased frequency of circulating IL-21 producing Th-cells in patients with granulomatosis with polyangiitis (GPA). Arthritis Res Ther 2013; 15 (03) R70
• 49 Gutfleisch J, Baumert E, Wolff-Vorbeck G, Schlesier M, Strutz HJ, Peter HH. Increased expression of CD25 and adhesion molecules on peripheral blood lymphocytes of patients with Wegener's granulomatosis (WG) and ANCA positive vasculitides. Adv Exp Med Biol 1993; 336: 397-404
• 50 Popa ER, Stegeman CA, Bos NA, Kallenberg CG, Tervaert JW. Differential B- and T-cell activation in Wegener's granulomatosis. J Allergy Clin Immunol 1999; 103 (5 Pt 1): 885-894
• 51 Abdulahad WH, van der Geld YM, Stegeman CA, Kallenberg CG. Persistent expansion of CD4+ effector memory T cells in Wegener's granulomatosis. Kidney Int 2006; 70 (05) 938-947
• 52 Abdulahad WH, Kallenberg CG, Limburg PC, Stegeman CA. Urinary CD4+ effector memory T cells reflect renal disease activity in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2009; 60 (09) 2830-2838
• 53 Moosig F, Csernok E, Wang G, Gross WL. Costimulatory molecules in Wegener's granulomatosis (WG): lack of expression of CD28 and preferential up-regulation of its ligands B7-1 (CD80) and B7-2 (CD86) on T cells. Clin Exp Immunol 1998; 114 (01) 113-118
• 54 Abdulahad WH, Stegeman CA, Limburg PC, Kallenberg CG. Skewed distribution of Th17 lymphocytes in patients with Wegener's granulomatosis in remission. Arthritis Rheum 2008; 58 (07) 2196-2205
• 55 Lamprecht P, Csernok E, Gross WL. Effector memory T cells as driving force of granuloma formation and autoimmunity in Wegener's granulomatosis. J Intern Med 2006; 260 (03) 187-191
• 56 Bunch DO, McGregor JG, Khandoobhai NB. , et al. Decreased CD5⁺ B cells in active ANCA vasculitis and relapse after rituximab. Clin J Am Soc Nephrol 2013; 8 (03) 382-391
• 57 Lepse N, Abdulahad WH, Rutgers A, Kallenberg CG, Stegeman CA, Heeringa P. Altered B cell balance, but unaffected B cell capacity to limit monocyte activation in anti-neutrophil cytoplasmic antibody-associated vasculitis in remission. Rheumatology (Oxford) 2014; 53 (09) 1683-1692
• 58 Culton DA, Nicholas MW, Bunch DO. , et al. Similar CD19 dysregulation in two autoantibody-associated autoimmune diseases suggests a shared mechanism of B-cell tolerance loss. J Clin Immunol 2007; 27 (01) 53-68
• 59 Schneeweis C, Rafalowicz M, Feist E. , et al. Increased levels of BLyS and sVCAM-1 in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitides (AAV). Clin Exp Rheumatol 2010; 28 (01) (Suppl. 57) 62-66
• 60 Cornec D, Berti A, Hummel A, Peikert T, Pers JO, Specks U. Identification and phenotyping of circulating autoreactive proteinase 3-specific B cells in patients with PR3-ANCA associated vasculitis and healthy controls. J Autoimmun 2017; 84: 122-131
• 61 Roth AJ, Ooi JD, Hess JJ. , et al. Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis. J Clin Invest 2013; 123 (04) 1773-1783
• 62 Jennette JC, Falk RJ. Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease. Nat Rev Rheumatol 2014; 10 (08) 463-473
• 63 Silva F, Specks U, Sethi S, Irazabal MV, Fervenza FC. Successful pregnancy and delivery of a healthy newborn despite transplacental transfer of antimyeloperoxidase antibodies from a mother with microscopic polyangiitis. Am J Kidney Dis 2009; 54 (03) 542-545
• 64 Eisenberger U, Fakhouri F, Vanhille P. , et al. ANCA-negative pauci-immune renal vasculitis: histology and outcome. Nephrol Dial Transplant 2005; 20 (07) 1392-1399
• 65 Xiao H, Hu P, Falk RJ, Jennette JC. Overview of the pathogenesis of ANCA-associated vasculitis. Kidney Dis (Basel) 2016; 1 (04) 205-215
• 66 Schreiber A, Busjahn A, Luft FC, Kettritz R. Membrane expression of proteinase 3 is genetically determined. J Am Soc Nephrol 2003; 14 (01) 68-75
• 67 Fussner LA, Hummel AM, Schroeder DR. , et al; Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research Group. Factors determining the clinical utility of serial measurements of antineutrophil cytoplasmic antibodies targeting proteinase 3. Arthritis Rheumatol 2016; 68 (07) 1700-1710
• 68 Jayne DR, Gaskin G, Rasmussen N. , et al; European Vasculitis Study Group. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 2007; 18 (07) 2180-2188
• 69 Jones RB, Tervaert JW, Hauser T. , et al; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010; 363 (03) 211-220
• 70 Stone JH, Merkel PA, Spiera R. , et al; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010; 363 (03) 221-232
• 71 Miloslavsky EM, Specks U, Merkel PA. , et al; Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research Group. Rituximab for the treatment of relapses in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol 2014; 66 (11) 3151-3159
• 72 Charles P, Terrier B, Perrodeau É. , et al; French Vasculitis Study Group. Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). Ann Rheum Dis 2018; 77 (08) 1143-1149
• 73 Han WK, Choi HK, Roth RM, McCluskey RT, Niles JL. Serial ANCA titers: useful tool for prevention of relapses in ANCA-associated vasculitis. Kidney Int 2003; 63 (03) 1079-1085
• 74 Kallenberg CG, Brouwer E, Weening JJ, Tervaert JW. Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiological potential. Kidney Int 1994; 46 (01) 1-15
• 75 Falk RJ, Jennette JC. ANCA disease: where is this field heading?. J Am Soc Nephrol 2010; 21 (05) 745-752
• 76 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 2004; 93 (04) 398-401
• 77 Williams JM, Kamesh L, Savage CO. Translating basic science into patient therapy for ANCA-associated small vessel vasculitis. Clin Sci (Lond) 2005; 108 (02) 101-112
• 78 Rarok AA, Limburg PC, Kallenberg CG. Neutrophil-activating potential of antineutrophil cytoplasm autoantibodies. J Leukoc Biol 2003; 74 (01) 3-15
• 79 Jennette JC, Falk RJ. Pathogenesis of the vascular and glomerular damage in ANCA-positive vasculitis. Nephrol Dial Transplant 1998; 13 (Suppl. 01) 16-20
• 80 Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A 1990; 87 (11) 4115-4119
• 81 Charles LA, Caldas ML, Falk RJ, Terrell RS, Jennette JC. Antibodies against granule proteins activate neutrophils in vitro. J Leukoc Biol 1991; 50 (06) 539-546
• 82 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 1993; 336: 121-123
• 83 Schreiber A, Xiao H, Jennette JC, Schneider W, Luft FC, Kettritz R. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J Am Soc Nephrol 2009; 20 (02) 289-298
• 84 Falk RJ, Hogan S, Carey TS, Jennette JC. ; The Glomerular Disease Collaborative Network. Clinical course of anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and systemic vasculitis. Ann Intern Med 1990; 113 (09) 656-663
• 85 Huugen D, Xiao H, van Esch A. , et al. Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-alpha. Am J Pathol 2005; 167 (01) 47-58
• 86 Radford DJ, Savage CO, Nash GB. Treatment of rolling neutrophils with antineutrophil cytoplasmic antibodies causes conversion to firm integrin-mediated adhesion. Arthritis Rheum 2000; 43 (06) 1337-1345
• 87 Ewert BH, Jennette JC, Falk RJ. Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells. Kidney Int 1992; 41 (02) 375-383
• 88 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 (02) 335-342
• 89 Vargunam M, Adu D, Taylor CM. , et al. Endothelium myeloperoxidase-antimyeloperoxidase interaction in vasculitis. Nephrol Dial Transplant 1992; 7 (11) 1077-1081
• 90 Gupta AK, Joshi MB, Philippova M. , et al. Activated endothelial cells induce neutrophil extracellular traps and are susceptible to NETosis-mediated cell death. FEBS Lett 2010; 584 (14) 3193-3197
• 91 Kessenbrock K, Krumbholz M, Schönermarck U. , et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 2009; 15 (06) 623-625
• 92 Nolan SL, Kalia N, Nash GB, Kamel D, Heeringa P, Savage CO. Mechanisms of ANCA-mediated leukocyte-endothelial cell interactions in vivo. J Am Soc Nephrol 2008; 19 (05) 973-984
• 93 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 1994; 153 (03) 1271-1280
• 94 Kettritz R, Jennette JC, Falk RJ. Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils. J Am Soc Nephrol 1997; 8 (03) 386-394
• 95 Guilpain P, Chéreau C, Goulvestre C. , et al. The oxidation induced by antimyeloperoxidase antibodies triggers fibrosis in microscopic polyangiitis. Eur Respir J 2011; 37 (06) 1503-1513
• 96 Guilpain P, Servettaz A, Goulvestre C. , et al. Pathogenic effects of antimyeloperoxidase antibodies in patients with microscopic polyangiitis. Arthritis Rheum 2007; 56 (07) 2455-2463
• 97 Xiao H, Heeringa P, Hu P. , et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002; 110 (07) 955-963
• 98 Xiao 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 (01) 52-64
• 99 Xiao H, Heeringa P, Liu Z. , et al. The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies. Am J Pathol 2005; 167 (01) 39-45
• 100 Schreiber A, Xiao H, Falk RJ, Jennette JC. Bone marrow-derived cells are sufficient and necessary targets to mediate glomerulonephritis and vasculitis induced by anti-myeloperoxidase antibodies. J Am Soc Nephrol 2006; 17 (12) 3355-3364
• 101 Xiao H, Ciavatta D, Aylor DL. , et al. Genetically determined severity of anti-myeloperoxidase glomerulonephritis. Am J Pathol 2013; 182 (04) 1219-1226
• 102 Xing GQ, Chen M, Liu G. , et al. Complement activation is involved in renal damage in human antineutrophil cytoplasmic autoantibody associated pauci-immune vasculitis. J Clin Immunol 2009; 29 (03) 282-291
• 103 Gou SJ, Yuan J, Wang C, Zhao MH, Chen M. Alternative complement pathway activation products in urine and kidneys of patients with ANCA-associated GN. Clin J Am Soc Nephrol 2013; 8 (11) 1884-1891
• 104 Yuan J, Gou SJ, Huang J, Hao J, Chen M, Zhao MH. C5a and its receptors in human anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Arthritis Res Ther 2012; 14 (03) R140
• 105 Jayne DRW, Bruchfeld AN, Harper L. , et al; CLEAR Study Group. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol 2017; 28 (09) 2756-2767
• 106 Little MA, Smyth L, Salama AD. , et al. Experimental autoimmune vasculitis: an animal model of anti-neutrophil cytoplasmic autoantibody-associated systemic vasculitis. Am J Pathol 2009; 174 (04) 1212-1220
• 107 Little MA, Bhangal G, Smyth CL. , et al. Therapeutic effect of anti-TNF-alpha antibodies in an experimental model of anti-neutrophil cytoplasm antibody-associated systemic vasculitis. J Am Soc Nephrol 2006; 17 (01) 160-169
• 108 Ruth AJ, Kitching AR, Kwan RY. , et al. Anti-neutrophil cytoplasmic antibodies and effector CD4+ cells play nonredundant roles in anti-myeloperoxidase crescentic glomerulonephritis. J Am Soc Nephrol 2006; 17 (07) 1940-1949
• 109 Salama AD, Little MA. Animal models of antineutrophil cytoplasm antibody-associated vasculitis. Curr Opin Rheumatol 2012; 24 (01) 1-7
• 110 Little MA, Al-Ani B, Ren S. , et al. Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system. PLoS One 2012; 7 (01) e28626
• 111 Tomer Y, Gilburd B, Blank M. , et al. Characterization of biologically active antineutrophil cytoplasmic antibodies induced in mice. Pathogenetic role in experimental vasculitis. Arthritis Rheum 1995; 38 (10) 1375-1381
• 112 Hattar K, Oppermann S, Ankele C. , et al. c-ANCA-induced neutrophil-mediated lung injury: a model of acute Wegener's granulomatosis. Eur Respir J 2010; 36 (01) 187-195
• 113 Charles Jennette J, Falk RJ. L1. Pathogenesis of ANCA-associated vasculitis: observations, theories and speculations. Presse Med 2013; 42 (4 Pt 2): 493-498
• 114 Xiao H, Morrison T, Heise M, Falk R, Jennette J. MPO-ANCA IgG and influenza: a viral infection acts in concert to induce severe hemorrhagic pulmonary capillaritis. Clin Exp Rheumatol 2007; 25: S-91
• 115 Hu P, Xiao X, Alba MA, Falk R, Jennette C. Anti-MPO antibodies cause granulomatosis in mice: an animal model of GPA. Rheumatology 2017; 56: iii29-iii31
• 116 Schönermarck U, Csernok E, Gross WL. Pathogenesis of anti-neutrophil cytoplasmic antibody-associated vasculitis: challenges and solutions 2014. Nephrol Dial Transplant 2015; 30 (Suppl. 01) i46-i52
• 117 Chen SF, Wang FM, Li ZY, Yu F, Chen M, Zhao MH. Myeloperoxidase influences the complement regulatory activity of complement factor H. Rheumatology (Oxford) 2018
• 118 Wang H, Wang C, Zhao MH, Chen M. Neutrophil extracellular traps can activate alternative complement pathways. Clin Exp Immunol 2015; 181 (03) 518-527
• 119 Ralston DR, Marsh CB, Lowe MP, Wewers MD. Antineutrophil cytoplasmic antibodies induce monocyte IL-8 release. Role of surface proteinase-3, alpha1-antitrypsin, and Fcgamma receptors. J Clin Invest 1997; 100 (06) 1416-1424
• 120 Jennette JC, Falk RJ. ANCAs are also antimonocyte cytoplasmic autoantibodies. Clin J Am Soc Nephrol 2015; 10 (01) 4-6
• 121 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 (05) 495-502
• 122 Millet A, Martin KR, Bonnefoy F. , et al. Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis. J Clin Invest 2015; 125 (11) 4107-4121
• 123 Travis WD, Hoffman GS, Leavitt RY, Pass HI, Fauci AS. Surgical pathology of the lung in Wegener's granulomatosis. Review of 87 open lung biopsies from 67 patients. Am J Surg Pathol 1991; 15 (04) 315-333
• 124 Gaudin PB, Askin FB, Falk RJ, Jennette JC. The pathologic spectrum of pulmonary lesions in patients with anti-neutrophil cytoplasmic autoantibodies specific for anti-proteinase 3 and anti-myeloperoxidase. Am J Clin Pathol 1995; 104 (01) 7-16
• 125 Jennette JC, Falk RJ, Hu P, Xiao H. Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Annu Rev Pathol 2013; 8: 139-160
• 126 Mueller A, Holl-Ulrich K, Lamprecht P, Gross WL. Germinal centre-like structures in Wegener's granuloma: the morphological basis for autoimmunity?. Rheumatology (Oxford) 2008; 47 (08) 1111-1113
• 127 Lamprecht P, Gross WL. Current knowledge on cellular interactions in the WG-granuloma. Clin Exp Rheumatol 2007; 25 (01) (Suppl. 44) S49-S51
• 128 Voswinkel J, Müller A, Lamprecht P. Is PR3-ANCA formation initiated in Wegener's granulomatosis lesions? Granulomas as potential lymphoid tissue maintaining autoantibody production. Ann N Y Acad Sci 2005; 1051: 12-19
• 129 Birnbaum J, Danoff S, Askin FB, Stone JH. Microscopic polyangiitis presenting as a “pulmonary-muscle” syndrome: is subclinical alveolar hemorrhage the mechanism of pulmonary fibrosis?. Arthritis Rheum 2007; 56 (06) 2065-2071
• 130 Schnabel A, Reuter M, Csernok E, Richter C, Gross WL. Subclinical alveolar bleeding in pulmonary vasculitides: correlation with indices of disease activity. Eur Respir J 1999; 14 (01) 118-124
• 131 Pineton de Chambrun M, Nunes H, Brochériou I, Hertig A. Idiopathic lung fibrosis and anti myeloperoxidase glomerulonephritis: the tree that hides the forest. BMC Pulm Med 2015; 15: 130
• 132 Franks TJ, Koss MN. Pulmonary capillaritis. Curr Opin Pulm Med 2000; 6 (05) 430-435
• 133 Heeringa P, Schreiber A, Falk RJ, Jennette JC. Pathogenesis of pulmonary vasculitis. Semin Respir Crit Care Med 2004; 25 (05) 465-474