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Pathogenesis of granulomatosis with polyangiitis and related vasculitides

William F Pendergraft III, MD, PhD
Ronald J Falk, MD
Section Editors
Richard J Glassock, MD, MACP
Gerald B Appel, MD
Deputy Editors
Albert Q Lam, MD
Monica Ramirez Curtis, MD, MPH


Granulomatosis with polyangiitis, which can be abbreviated as GPA, is a complex, immune-mediated disorder in which tissue injury results from the interplay of an initiating inflammatory event and a highly specific immune response. Part of this response is directed against previously shielded epitopes of neutrophil granule proteins, leading to high-titer autoantibodies known as antineutrophil cytoplasmic autoantibodies (ANCA). The production of ANCA is one of the hallmarks of GPA and related forms of vasculitis. ANCA are directed against antigens present within the primary granules of neutrophils and monocytes; these autoantibodies produce tissue damage via interactions with primed neutrophils and endothelial cells.

ANCA are relatively specific for a group of disorders associated with vascular inflammation known as the ANCA-associated vasculitides: GPA, microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss). Importantly, the term "ANCA-associated vasculitis" may be misleading since not all patients with clinical (and even histopathologically proven) diagnoses of GPA, MPA, or EGPA have ANCA.

Approximately 90 percent of patients with GPA have ANCA, although the percentage varies according to disease phenotype (patients with limited GPA are less likely to be ANCA positive). Among patients with MPA or EGPA, the percentages of patients who are ANCA positive are approximately 70 and 50 percent, respectively.

The most commonly identified and evaluated autoantigens in GPA are the following two proteins:

Myeloperoxidase (MPO), which is the target in approximately 10 percent of patients

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Literature review current through: Nov 2017. | This topic last updated: Jan 04, 2017.
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  1. Kallenberg CG, Brouwer E, Weening JJ, Tervaert JW. Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiological potential. Kidney Int 1994; 46:1.
  2. Jennette JC. Pathogenic potential of anti-neutrophil cytoplasmic autoantibodies. Lab Invest 1994; 70:135.
  3. Jennette JC, Falk RJ. Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease. Nat Rev Rheumatol 2014; 10:463.
  4. de Lind van Wijngaarden RA, van Rijn L, Hagen EC, et al. Hypotheses on the etiology of antineutrophil cytoplasmic autoantibody associated vasculitis: the cause is hidden, but the result is known. Clin J Am Soc Nephrol 2008; 3:237.
  5. Stegeman CA, Tervaert JW, Sluiter WJ, et al. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med 1994; 120:12.
  6. Popa ER, Tervaert JW. The relation between Staphylococcus aureus and Wegener's granulomatosis: current knowledge and future directions. Intern Med 2003; 42:771.
  7. 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; 46:1029.
  8. Kain R, Exner M, Brandes R, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med 2008; 14:1088.
  9. Kain R, Matsui K, Exner M, et al. A novel class of autoantigens of anti-neutrophil cytoplasmic antibodies in necrotizing and crescentic glomerulonephritis: the lysosomal membrane glycoprotein h-lamp-2 in neutrophil granulocytes and a related membrane protein in glomerular endothelial cells. J Exp Med 1995; 181:585.
  10. Peschel A, Basu N, Benharkou A, et al. Autoantibodies to hLAMP-2 in ANCA-negative pauci-immune focal necrotizing GN. J Am Soc Nephrol 2014; 25:455.
  11. Bautz DJ, Preston GA, Lionaki S, et al. Antibodies with dual reactivity to plasminogen and complementary PR3 in PR3-ANCA vasculitis. J Am Soc Nephrol 2008; 19:2421.
  12. Berden AE, Nolan SL, Morris HL, et al. Anti-plasminogen antibodies compromise fibrinolysis and associate with renal histology in ANCA-associated vasculitis. J Am Soc Nephrol 2010; 21:2169.
  13. Lyons PA, Rayner TF, Trivedi S, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med 2012; 367:214.
  14. 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; 22:1161.
  15. Jagiello P, Aries P, Arning L, et al. The PTPN22 620W allele is a risk factor for Wegener's granulomatosis. Arthritis Rheum 2005; 52:4039.
  16. Choi HK, Slot MC, Pan G, et al. Evaluation of antineutrophil cytoplasmic antibody seroconversion induced by minocycline, sulfasalazine, or penicillamine. Arthritis Rheum 2000; 43:2488.
  17. Pendergraft WF 3rd, Niles JL. Trojan horses: drug culprits associated with antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. Curr Opin Rheumatol 2014; 26:42.
  18. Pendergraft WF 3rd, Herlitz LC, Thornley-Brown D, et al. Nephrotoxic effects of common and emerging drugs of abuse. Clin J Am Soc Nephrol 2014; 9:1996.
  19. Audrain MA, Sesboüé R, Baranger TA, et al. Analysis of anti-neutrophil cytoplasmic antibodies (ANCA): frequency and specificity in a sample of 191 homozygous (PiZZ) alpha1-antitrypsin-deficient subjects. Nephrol Dial Transplant 2001; 16:39.
  20. Elzouki AN, Segelmark M, Wieslander J, Eriksson S. Strong link between the alpha 1-antitrypsin PiZ allele and Wegener's granulomatosis. J Intern Med 1994; 236:543.
  21. Mahr AD, Edberg JC, Stone JH, et al. Alpha₁-antitrypsin deficiency-related alleles Z and S and the risk of Wegener's granulomatosis. Arthritis Rheum 2010; 62:3760.
  22. Hogan SL, Satterly KK, Dooley MA, et al. Silica exposure in anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and lupus nephritis. J Am Soc Nephrol 2001; 12:134.
  23. Beaudreuil S, Lasfargues G, Lauériere L, et al. Occupational exposure in ANCA-positive patients: a case-control study. Kidney Int 2005; 67:1961.
  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; 12:1129.
  25. Albert D, Clarkin C, Komoroski J, et al. Wegener's granulomatosis: Possible role of environmental agents in its pathogenesis. Arthritis Rheum 2004; 51:656.
  26. Johnson RJ. The mystery of the antineutrophil cytoplasmic antibodies. Am J Kidney Dis 1995; 26:57.
  27. Roth AJ, Ooi JD, Hess JJ, et al. Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis. J Clin Invest 2013; 123:1773.
  28. Pendergraft WF 3rd, 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; 10:72.
  29. Yang J, Bautz DJ, Lionaki S, et al. ANCA patients have T cells responsive to complementary PR-3 antigen. Kidney Int 2008; 74:1159.
  30. Pendergraft WF 3rd, Pressler BM, Jennette JC, et al. Autoantigen complementarity: a new theory implicating complementary proteins as initiators of autoimmune disease. J Mol Med (Berl) 2005; 83:12.
  31. Reynolds J, Preston GA, Pressler BM, et al. Autoimmunity to the alpha 3 chain of type IV collagen in glomerulonephritis is triggered by 'autoantigen complementarity'. J Autoimmun 2015; 59:8.
  32. Lúdvíksson BR, Sneller MC, Chua KS, et al. Active Wegener's granulomatosis is associated with HLA-DR+ CD4+ T cells exhibiting an unbalanced Th1-type T cell cytokine pattern: reversal with IL-10. J Immunol 1998; 160:3602.
  33. Muller Kobold AC, Kallenberg CG, Tervaert JW. Monocyte activation in patients with Wegener's granulomatosis. Ann Rheum Dis 1999; 58:237.
  34. Marinaki S, Kälsch AI, Grimminger P, et al. Persistent T-cell activation and clinical correlations in patients with ANCA-associated systemic vasculitis. Nephrol Dial Transplant 2006; 21:1825.
  35. 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; 70:938.
  36. Moins-Teisserenc HT, Gadola SD, Cella M, et al. Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class-I molecules. Lancet 1999; 354:1598.
  37. Masutani K, Tokumoto M, Nakashima H, et al. Strong polarization toward Th1 immune response in ANCA-associated glomerulonephritis. Clin Nephrol 2003; 59:395.
  38. Ewert BH, Jennette JC, Falk RJ. Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells. Kidney Int 1992; 41:375.
  39. Zhou Y, Huang D, Paris PL, et al. An analysis of CTLA-4 and proinflammatory cytokine genes in Wegener's granulomatosis. Arthritis Rheum 2004; 50:2645.
  40. Schreiber A, Otto B, Ju X, et al. Membrane proteinase 3 expression in patients with Wegener's granulomatosis and in human hematopoietic stem cell-derived neutrophils. J Am Soc Nephrol 2005; 16:2216.
  41. Yang JJ, Pendergraft WF, Alcorta DA, et al. Circumvention of normal constraints on granule protein gene expression in peripheral blood neutrophils and monocytes of patients with antineutrophil cytoplasmic autoantibody-associated glomerulonephritis. J Am Soc Nephrol 2004; 15:2103.
  42. 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; 120:3209.
  43. Van Rossum AP, van der Geld YM, Limburg PC, Kallenberg CG. Human anti-neutrophil cytoplasm autoantibodies to proteinase 3 (PR3-ANCA) bind to neutrophils. Kidney Int 2005; 68:537.
  44. Kettritz R, Jennette JC, Falk RJ. Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils. J Am Soc Nephrol 1997; 8:386.
  45. Mulder AH, Heeringa P, Brouwer E, et al. Activation of granulocytes by anti-neutrophil cytoplasmic antibodies (ANCA): a Fc gamma RII-dependent process. Clin Exp Immunol 1994; 98:270.
  46. Porges AJ, Redecha PB, Kimberly WT, et al. Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa. J Immunol 1994; 153:1271.
  47. Hewins P, Williams JM, Wakelam MJ, Savage CO. Activation of Syk in neutrophils by antineutrophil cytoplasm antibodies occurs via Fcgamma receptors and CD18. J Am Soc Nephrol 2004; 15:796.
  48. Little MA, Smyth CL, Yadav R, et al. Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo. Blood 2005; 106:2050.
  49. 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; 87:4115.
  50. Brouwer E, Huitema MG, Mulder AH, et al. Neutrophil activation in vitro and in vivo in Wegener's granulomatosis. Kidney Int 1994; 45:1120.
  51. Cockwell P, Brooks CJ, Adu D, Savage CO. Interleukin-8: A pathogenetic role in antineutrophil cytoplasmic autoantibody-associated glomerulonephritis. Kidney Int 1999; 55:852.
  52. Kettritz R, Choi M, Butt W, et al. Phosphatidylinositol 3-kinase controls antineutrophil cytoplasmic antibodies-induced respiratory burst in human neutrophils. J Am Soc Nephrol 2002; 13:1740.
  53. Schreiber A, Luft FC, Kettritz R. Membrane proteinase 3 expression and ANCA-induced neutrophil activation. Kidney Int 2004; 65:2172.
  54. Pendergraft WF 3rd, Rudolph EH, Falk RJ, et al. Proteinase 3 sidesteps caspases and cleaves p21(Waf1/Cip1/Sdi1) to induce endothelial cell apoptosis. Kidney Int 2004; 65:75.
  55. Rarok AA, Stegeman CA, Limburg PC, Kallenberg CG. Neutrophil membrane expression of proteinase 3 (PR3) is related to relapse in PR3-ANCA-associated vasculitis. J Am Soc Nephrol 2002; 13:2232.
  56. Williams JM, Savage CO. Characterization of the regulation and functional consequences of p21ras activation in neutrophils by antineutrophil cytoplasm antibodies. J Am Soc Nephrol 2005; 16:90.
  57. Alcorta DA, Barnes DA, Dooley MA, et al. Leukocyte gene expression signatures in antineutrophil cytoplasmic autoantibody and lupus glomerulonephritis. Kidney Int 2007; 72:853.
  58. Arimura Y, Minoshima S, Kamiya Y, et al. Serum myeloperoxidase and serum cytokines in anti-myeloperoxidase antibody-associated glomerulonephritis. Clin Nephrol 1993; 40:256.
  59. Nowack R, Schwalbe K, Flores-Suárez LF, et al. Upregulation of CD14 and CD18 on monocytes In vitro by antineutrophil cytoplasmic autoantibodies. J Am Soc Nephrol 2000; 11:1639.
  60. Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. Dutch Co-Trimoxazole Wegener Study Group. N Engl J Med 1996; 335:16.
  61. Tse WY, Nash GB, Hewins P, et al. ANCA-induced neutrophil F-actin polymerization: implications for microvascular inflammation. Kidney Int 2005; 67:130.
  62. Papayannopoulos V, Zychlinsky A. NETs: a new strategy for using old weapons. Trends Immunol 2009; 30:513.
  63. Kessenbrock K, Krumbholz M, Schönermarck U, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 2009; 15:623.
  64. Berger SP, Seelen MA, Hiemstra PS, et al. Proteinase 3, the major autoantigen of Wegener's granulomatosis, enhances IL-8 production by endothelial cells in vitro. J Am Soc Nephrol 1996; 7:694.
  65. Mayet WJ, Meyer zum Büschenfelde KH. Antibodies to proteinase 3 increase adhesion of neutrophils to human endothelial cells. Clin Exp Immunol 1993; 94:440.
  66. Mayet WJ, Schwarting A, Orth T, et al. Antibodies to proteinase 3 mediate expression of vascular cell adhesion molecule-1 (VCAM-1). Clin Exp Immunol 1996; 103:259.
  67. Rastaldi MP, Ferrario F, Tunesi S, et al. Intraglomerular and interstitial leukocyte infiltration, adhesion molecules, and interleukin-1 alpha expression in 15 cases of antineutrophil cytoplasmic autoantibody-associated renal vasculitis. Am J Kidney Dis 1996; 27:48.
  68. Arrizabalaga P, Solé M, Iglesias C, et al. Renal expression of ICAM-1 and VCAM-1 in ANCA-associated glomerulonephritis--are there differences among serologic subgroups? Clin Nephrol 2006; 65:79.
  69. Mayet WJ, Csernok E, Szymkowiak C, et al. Human endothelial cells express proteinase 3, the target antigen of anticytoplasmic antibodies in Wegener's granulomatosis. Blood 1993; 82:1221.
  70. King WJ, Adu D, Daha MR, et al. Endothelial cells and renal epithelial cells do not express the Wegener's autoantigen, proteinase 3. Clin Exp Immunol 1995; 102:98.
  71. De Bandt M, Meyer O, Dacosta L, et al. Anti-proteinase-3 (PR3) antibodies (C-ANCA) recognize various targets on the human umbilical vein endothelial cell (HUVEC) membrane. Clin Exp Immunol 1999; 115:362.
  72. Pendergraft WF, Alcorta DA, Segelmark M, et al. ANCA antigens, proteinase 3 and myeloperoxidase, are not expressed in endothelial cells. Kidney Int 2000; 57:1981.
  73. Tervaert JW. Proteinase 3: A cofactor for the binding of antineutrophil cytoplasm antibodies (ANCA) to endothelial cells? Kidney Int 2000; 57:2171.
  74. Holmén C, Christensson M, Pettersson E, et al. Wegener's granulomatosis is associated with organ-specific antiendothelial cell antibodies. Kidney Int 2004; 66:1049.
  75. Kurosawa S, Esmon CT, Stearns-Kurosawa DJ. The soluble endothelial protein C receptor binds to activated neutrophils: involvement of proteinase-3 and CD11b/CD18. J Immunol 2000; 165:4697.
  76. Noronha IL, Krüger C, Andrassy K, et al. In situ production of TNF-alpha, IL-1 beta and IL-2R in ANCA-positive glomerulonephritis. Kidney Int 1993; 43:682.
  77. Jamin C, Dugué C, Alard JE, et al. Induction of endothelial cell apoptosis by the binding of anti-endothelial cell antibodies to Hsp60 in vasculitis-associated systemic autoimmune diseases. Arthritis Rheum 2005; 52:4028.
  78. Pallan L, Savage CO, Harper L. ANCA-associated vasculitis: from bench research to novel treatments. Nat Rev Nephrol 2009; 5:278.
  79. Cupps TR, Edgar LC, Fauci AS. Suppression of human B lymphocyte function by cyclophosphamide. J Immunol 1982; 128:2453.
  80. Popa ER, Stegeman CA, Bos NA, et al. Differential B- and T-cell activation in Wegener's granulomatosis. J Allergy Clin Immunol 1999; 103:885.
  81. Kallenberg CG, Heeringa P. Complement system activation in ANCA vasculitis: A translational success story? Mol Immunol 2015; 68:53.
  82. Xiao H, Dairaghi DJ, Powers JP, et al. C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol 2014; 25:225.
  83. Gou SJ, Yuan J, Chen M, et al. Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Kidney Int 2013; 83:129.
  84. Gou SJ, Yuan J, Wang C, et al. Alternative complement pathway activation products in urine and kidneys of patients with ANCA-associated GN. Clin J Am Soc Nephrol 2013; 8:1884.
  85. Mrowka C, Csernok E, Gross WL, et al. Distribution of the granulocyte serine proteinases proteinase 3 and elastase in human glomerulonephritis. Am J Kidney Dis 1995; 25:253.
  86. Sommarin Y, Rasmussen N, Wieslander J. Characterization of monoclonal antibodies to proteinase-3 and application in the study of epitopes for classical anti-neutrophil cytoplasm antibodies. Exp Nephrol 1995; 3:249.
  87. Mulder AH, Stegeman CA, Kallenberg CG. Activation of granulocytes by anti-neutrophil cytoplasmic antibodies (ANCA) in Wegener's granulomatosis: a predominant role for the IgG3 subclass of ANCA. Clin Exp Immunol 1995; 101:227.
  88. Holland M, Hewins P, Goodall M, et al. Anti-neutrophil cytoplasm antibody IgG subclasses in Wegener's granulomatosis: a possible pathogenic role for the IgG4 subclass. Clin Exp Immunol 2004; 138:183.
  89. Tse WY, Abadeh S, Jefferis R, et al. Neutrophil FcgammaRIIIb allelic polymorphism in anti-neutrophil cytoplasmic antibody (ANCA)-positive systemic vasculitis. Clin Exp Immunol 2000; 119:574.
  90. Kocher M, Edberg JC, Fleit HB, Kimberly RP. Antineutrophil cytoplasmic antibodies preferentially engage Fc gammaRIIIb on human neutrophils. J Immunol 1998; 161:6909.
  91. Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002; 110:955.
  92. Ooi JD, Gan PY, Chen T, et al. FcγRIIB regulates T-cell autoreactivity, ANCA production, and neutrophil activation to suppress anti-myeloperoxidase glomerulonephritis. Kidney Int 2014; 86:1140.
  93. Schlieben DJ, Korbet SM, Kimura RE, et al. Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs. Am J Kidney Dis 2005; 45:758.