Pathogenesis of ANCA-associated vasculitis

Current Rheumatology Reports

Volumn 14, Issue 6, 2012, Pages 481-493

  Cartin Ceba, Rodrigo ^a   Peikert, Tobias ^a   Specks, Ulrich ^a  

^a MAYO CLINIC   (United States)

Author keywords

ANCA; ANCA associated vasculitis; Eosinophilic granulomatosis with polyangiitis; Etiology; Granulomatosis with polyangiitis; Microscopic polyangiitis; Pathogenesis

Indexed keywords

COTRIMOXAZOLE; HYDRALAZINE; NEUTROPHIL CYTOPLASMIC ANTIBODY; PENICILLAMINE; PROPYLTHIOURACIL; RITUXIMAB;

ANCA ASSOCIATED VASCULITIS; B LYMPHOCYTE; CYTOKINE PRODUCTION; ENVIRONMENTAL FACTOR; GENETIC ASSOCIATION; GENETIC PREDISPOSITION; GRANULOMATOSIS WITH POLYANGIITIS; HUMAN; INCIDENCE; INFECTION; INFLAMMATION; MICROSCOPIC POLYANGIITIS; NONHUMAN; PATHOGENESIS; REVIEW; RISK FACTOR; SINGLE NUCLEOTIDE POLYMORPHISM; T LYMPHOCYTE;

ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY-ASSOCIATED VASCULITIS; ANTIBODIES, ANTINEUTROPHIL CYTOPLASMIC; BACTERIAL INFECTIONS; GENETIC PREDISPOSITION TO DISEASE; HUMANS;

EID: 84869212014     PISSN: 15233774     EISSN: 15346307     Source Type: Journal    
DOI: 10.1007/s11926-012-0286-y     Document Type: Review

References (156)

1. Jennette JC, Falk RJ, Andrassy K, Bacon BA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides: the proposal of an international consensus conference. Arthritis Rheum. 1994; 37: 187-92. (Pubitemid 24065492)
2. Hoffman GS, Specks U. Anti-neutrophil cytoplasmic antibodies. Arthritis Rheum. 1998; 41: 1521-37.
3. Keogh KA, Specks U. Churg-Strauss syndrome. clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists. Am J Med. 2003; 115(4): 284-90. (Pubitemid 37088190)
4. Sinico RA, Di Toma L, Maggiore U, Bottero P, Radice A, Tosoni C, et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum. 2005; 52(9): 2926-35. (Pubitemid 41369124)
5. Sable-Fourtassou R, Cohen P, Mahr A, Pagnoux C, Mouthon L, Jayne D, et al. Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med. 2005; 143(9): 632-8. (Pubitemid 41552527)
6. Watts RA, Lane SE, Bentham G, Scott DG. Epidemiology of systemic vasculitis: a ten-year study in the United Kingdom. Arthritis Rheum. 2000; 43(2): 414-9. (Pubitemid 30395752)
7. Watts RA, Gonzalez-GayMA, Lane SE, Garcia-Porrua C, Bentham G, Scott DG. Geoepidemiology of systemic vasculitis: comparison of the incidence in two regions of Europe. Ann Rheum Dis. 2001; 60(2): 170-2. (Pubitemid 32102210)
8. Reinhold-Keller E, Herlyn K, Wagner-Bastmeyer R, Gutfleisch J, Peter HH, Raspe HH, et al. No difference in the incidences of vasculitides between north and south Germany: first results of the German vasculitis register. Rheumatol (Oxford). 2002; 41(5): 540-9. (Pubitemid 34575305)
9. Watts RA, Lane SE, Scott DG, Koldingsnes W, Nossent H, Gonzalez-Gay MA, et al. Epidemiology of vasculitis in Europe. Ann Rheum Dis. 2001; 60(12): 1156-7.
10. Watts RA, Scott DG. Epidemiology of the vasculitides. Semin Respir Crit Care Med. 2004; 25(5): 455-64. (Pubitemid 39518242)
11. Cotch MF, Hoffman GS, Yerg DE, Kaufman GI, Targonski P, Kaslow RA. The epidemiology of Wegener's granulomatosis. Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from population-based data sources. Arthritis Rheum. 1996; 39: 87-92. (Pubitemid 26036382)
12. Watts RA, Scott DG, Jayne DR, Ito-Ihara T, Muso E, Fujimoto S, et al. Renal vasculitis in Japan and the UK-are there differences in epidemiology and clinical phenotype? Nephrol Dial Transplant. 2008; 23(12): 3928-31.
13. O'Donnell JL, Stevanovic VR, Frampton C, Stamp LK, Chapman PT. Wegener's granulomatosis in New Zealand: evidence for a latitude-dependent incidence gradient. Intern Med J. 2007; 37 (4): 242-6. (Pubitemid 46457498)
14. Mahr A, Guillevin L, Poissonnet M, Ayme S. Prevalences of polyarteritis nodosa, microscopic polyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in 2000: a capture-recapture estimate. Arthritis Rheum. 2004; 51(1): 92-9. (Pubitemid 38222288)
15. Moins-Teisserenc HT, Gadola SD, Cella M, Dunbar PR, Exley A, Blake N, et al. Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class-I molecules. Lancet [Res Support, Non-US Gov't]. 1999; 354(9190): 1598-603. (Pubitemid 29515952)
16. Villa-Forte A, de la Salle H, Fricker D, Hentges F, Zimmer J. HLA class I deficiency syndrome mimicking Wegener's granulomatosis. Arthritis Rheuma [Case Rep Res Support, Non-US Gov't]. 2008; 58(8): 2579-82.
17. Moins-Teisserenc HT, Gadola SD, Cella M, Dunbar PR, Exley A, Blake N, et al. Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class-I molecules. Lancet. 1999; 354(9190): 1598-603. (Pubitemid 29515952)
18. 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(1): 302-7.
19. Rottem M, Cotch MF, Fauci AS, Hoffman GS. Familial vasculitis: report of 2 families. J Rheumatol. 1994; 21(3): 561-3. (Pubitemid 24102847)
20. Manganelli P, Giacosa R, Fietta P, Zanetti A, Neri TM. Familial vasculitides: Churg-Strauss syndrome and Wegener's granulomatosis in 2 first-degree relatives. J Rheumatol. 2003; 30(3): 618-21. (Pubitemid 36301958)
21. Willcocks LC, Lyons PA, Rees AJ, Smith KG. The contribution of genetic variation and infection to the pathogenesis of ANCAassociated systemic vasculitis. Arthritis Res Ther. 2010; 12 (1): 202.
22. Shiina T, Inoko H, Kulski JK. An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens [Review]. 2004; 64(6): 631-49. (Pubitemid 39628044)
23. Yang R, Cui Z, Zhao J, Zhao MH. The role of HLA-DRB1 alleles on susceptibility of Chinese patients with anti-GBM disease. Clin Immunol [Res Support, Non-US Gov't]. 2009; 133(2): 245-50.
24. Gencik M, Borgmann S, Zahn R, Albert E, Sitter T, Epplen JT, et al. Immunogenetic risk factors for anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis. Clin Exp Immunol. 1999; 117(2): 412-7. (Pubitemid 29343618)
25. Heckmann M, Holle JU, Arning L, Knaup S, Hellmich B, Nothnagel M, et al. The Wegener's granulomatosis quantitative trait locus on chromosome 6p21.3 as characterised by tagSNP genotyping. Ann Rheum Dis. 2008; 67(7): 972-9. (Pubitemid 351956660)
26. Tsuchiya N, Kobayashi S, Hashimoto H, Ozaki S, Tokunaga K. Association of HLA-DRB1*0901-DQB1*0303 haplotype with microscopic polyangiitis in Japanese. Genes Immun [Comp Study Res Support, Non-US Gov't]. 2006; 7(1): 81-4.
27. Tsuchiya N, Kobayashi S, Kawasaki A, Kyogoku C, Arimura Y, Yoshida M, et al. Genetic background of Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis: association of HLA-DRB1*0901 with microscopic polyangiitis. J Rheumatol. 2003; 30(7): 1534-40. (Pubitemid 36835452)
28. Vaglio A, Martorana D, Maggiore U, Grasselli C, Zanetti A, Pesci A, et al. HLA-DRB4 as a genetic risk factor for Churg-Strauss syndrome. Arthritis Rheum. 2007; 56(9): 3159-66. (Pubitemid 47502764)
29. Wieczorek S, Hellmich B, Gross WL, Epplen JT. Associations of Churg-Strauss syndrome with the HLA-DRB1 locus, and relationship to the genetics of antineutrophil cytoplasmic antibodyassociated vasculitides: comment on the article by Vaglio et al. Arthritis Rheum. 2008; 58(1): 329-30.
30. Arning L, Holle JU, Harper L, Millar DS, Gross WL, Epplen JT, et al. Are there specific genetic risk factors for the different forms of ANCA-associated vasculitis? Ann Rheum Dis. 2011; 70(4): 707-8.
31. Cao Y, Schmitz JL, Yang J, Hogan SL, Bunch D, Hu Y, et al. DRB1*15 allele is a risk factor for PR3-ANCA disease in African Americans. J Am Soc Nephrol. 2011; 22(6): 1161-7.
32. Jagiello P, Aries P, Arning L, Wagenleiter SE, Csernok E, Hellmich B, et al. The PTPN22 620W allele is a risk factor for Wegener's granulomatosis. Arthritis Rheum. 2005; 52(12): 4039-43. (Pubitemid 41798244)
33. Carr EJ, Niederer HA, Williams J, Harper L, Watts RA, Lyons PA, et al. Confirmation of the genetic association of CTLA4 and PTPN22 with ANCA-associated vasculitis. BMC Med Genet. 2009; 10: 121.
34. Gregersen PK, Lee HS, Batliwalla F, Begovich AB. PTPN22: setting thresholds for autoimmunity. Semin Immunol. 2006; 18 (4): 214-23. (Pubitemid 43903284)
35. Bluestone JA. Is CTLA-4 a master switch for peripheral T cell tolerance? J Immunol. 1997; 158(5): 1989-93.
36. Steiner K, Moosig F, Csernok E, Selleng K, Gross WL, Fleischer B, et al. Increased expression of CTLA-4 (CD152) by T and B lymphocytes in Wegener's granulomatosis. Clin Exp Immunol. 2001; 126(1): 143-50. (Pubitemid 32989504)
37. Gough SC,Walker LS, Sansom DM. CTLA4 gene polymorphism and autoimmunity. Immunol Rev. 2005; 204: 102-15. (Pubitemid 40460496)
38. Wang XB, Zhao X, Giscombe R, Lefvert AK. A CTLA-4 gene polymorphism at position -318 in the promoter region affects the expression of protein. Genes Immun. 2002; 3(4): 233-4. (Pubitemid 38961137)
39. Lee YH, Choi SJ, Ji JD, Song GG. CTLA-4 and TNF-alpha promoter-308 A/G polymorphisms and ANCA-associated vasculitis susceptibility: a meta-analysis. Mol Biol Rep. 2012; 39(1): 319-26.
40. Gencik M, Meller S, Borgmann S, Fricke H. Proteinase 3 gene polymorphisms and Wegener's granulomatosis. Kidney Int. 2000; 58(6): 2473-7.
41. Halbwachs-Mecarelli L, Bessou G, Lesavre P, Lopez S, Witko- Sarsat V. Bimodal distribution of proteinase 3 (PR3) surface expression reflects a constitutive heterogeneity in the polymorphonuclear neutrophil pool. FEBS. 1995; 374: 29-33.
42. Schreiber A, Busjahn A, Luft FC, Kettritz R. Membrane expression of proteinase 3 is genetically determined. J Am Soc Nephrol. 2003; 14(1): 68-75. (Pubitemid 36026298)
43. von Vietinghoff S, Busjahn A, Schonemann C, Massenkeil G, Otto B, Luft FC, et al. Major histocompatibility complex HLA region largely explains the genetic variance exercised on neutrophil membrane proteinase 3 expression. J Am Soc Nephrol. 2006; 17(11): 3185-91. (Pubitemid 44707779)
44. Witko-Sarsat V, Lesavre P, Lopez S, Bessou G, Hieblot C, Prum B, et al. A large subset of neutrophils expressing membrane proteinase 3 is a risk factor for vasculitis and rheumatoid arthritis. J Am Soc Nephrol. 1999; 10(6): 1224-33. (Pubitemid 29246987)
45. 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(9): 2232-8. (Pubitemid 34925233)
46. Mahr AD, Edberg JC, Stone JH, Hoffman GS, St Clair EW, Specks U, et al. Alpha 1-antitrypsin deficiency-related alleles Z and S and the risk for Wegener's granulomatosis. Arthritis Rheum. 8 Sep 2010
47. Morris H, Morgan MD, Wood AM, Smith SW, Ekeowa UI, Herrmann K, et al. ANCA-associated vasculitis is linked to carriage of the Z allele of alpha antitrypsin and its polymers. Ann Rheum Dis. 2011; 70(10): 1851-6.
48. Segelmark M, Elzouki AN, Wieslander J, Eriksson S. The PiZ gene of alpha 1-antitrypsin as a determinant of outcome in PR3- ANCA-positive vasculitis. Kidney Int. 1995; 48(3): 844-50.
49. Stankiewicz P, Lupski Jr. Structural variation in the human genome and its role in disease. Annu Rev Med. 2010; 61: 437-55.
50. Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, et al. Genetically Distinct Subsets within ANCA-Associated Vasculitis. N Engl J Med [Res Support, Non-US Gov't]. 2012; 367 (3): 214-23. First AAV GWAS that confirmed that the pathogenesis of AAV has a genetic component with genetic distinctions between GPA and MPA that are associated with ANCA specificity where the response against the autoantigen PR3 is a central feature of PR3 AAV patients.
51. Hogan SL, Cooper GS, Savitz DA, Nylander-French LA, Parks CG, Chin H, et al. Association of silica exposure with antineutrophil cytoplasmic autoantibody small-vessel vasculitis: a population-based, case-control study. Clin J Am Soc Nephrol. 2007; 2(2): 290-9.
52. Franchi L, Eigenbrod T, Nunez G. Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol [Res Support, NIH, Extramural Research Support, Non-US Gov't]. 2009; 183(2): 792-6.
53. Short AK, Lockwood CM. Antigen specificity in hydralazine associated ANCA positive systemic vasculitis. Q J Med. 1995; 88: 775-83.
54. Choi HK, Merkel PA, Walker AM, Niles JL. Drug-associated antineutrophil cytoplasmic antibody-positive vasculitis: prevalence among patients with high titers of antimyeloperoxidase antibodies. Arthritis Rheum. 2000; 43(2): 405-13. (Pubitemid 30395751)
55. Carrington CB, Liebow A. Limited forms of angiitis and granulomatosis of Wegener's type. Am J Med. 1966; 41(4): 497-527.
56. Fahey J. E L, J C, GC G. Wegener's Granulomatosis. Am J Med. 1954; 17: 168-79.
57. Walton E. Giant-cell granuloma of the respiratory tract (Wegener's granulomatosis). Br Med J. 1958; 2: 497-527.
58. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21years. Ann Intern Med. 1983; 98(1): 76-85. (Pubitemid 13217969)
59. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients.[see comment]. Ann Intern Med. 1992; 116(6): 488-98.
60. Pinching AJ, Rees AJ, Pussell BA, Lockwood CM, Mitchison RS, Peters DK. Relapses in Wegener's granulomatosis: the role of infection. Br Med J. 1980; 281(6244): 836-8. (Pubitemid 10059945)
61. Raynauld JP, Bloch DA, Fries JF. Seasonal variation in the onset of Wegener's granulomatosis, polyarteritis nodosa and giant cell arteritis. J Rheumatol. 1993; 20(9): 1524-6. (Pubitemid 24027325)
62. Choi HK, Lamprecht P, Niles JL, Gross WL, Merkel PA. Subacute bacterial endocarditis with positive cytoplasmic antineutrophil cytoplasmic antibodies and anti-proteinase 3 antibodies. Arthritis Rheum. 2000; 43(1): 226-31. (Pubitemid 30368232)
63. Capizzi SA, Specks U. Does infection play a role in the pathogenesis of pulmonary vasculitis? Semin Respir Infect. 2003; 18 (1): 17-22. (Pubitemid 36373412)
64. Albert LJ, Inman RD. Molecular mimicry and autoimmunity. N Engl J Med. 1999; 341(27): 2068-74. (Pubitemid 30035957)
65. Craft J, Fatenejad S. Self antigens and epitope spreading in systemic autoimmunity. Arthritis Rheum. 1997; 40: 1374-82. (Pubitemid 27430946)
66. Vanderlugt CJ, Miller SD. Epitope spreading. Curr Opin Immunol. 1996; 8: 831-6. (Pubitemid 27007649)
67. Kain R, Exner M, Brandes R, Ziebermayr R, Cunningham D, Alderson CA, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med. 2008; 14(10): 1088-96.
68. Kain R, Tadema H, McKinney EF, Benharkou A, Brandes R, Peschel A, et al. High Prevalence of Autoantibodies to hLAMP-2 in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis. J Am Soc Nephrol. 2012; 23(3): 556-66.
69. Roth AJ, Brown MC, Smith RN, Badhwar AK, Parente O, Chung HC, et al. Anti-LAMP-2 Antibodies Are Not Prevalent in Patients With Antineutrophil Cytoplasmic Autoantibody Glomerulonephritis. J Am Soc Nephrol. 2012; 23(3): 545-55.
70. Pendergraft 3rd WF, Preston GA, Shah RR, Tropsha A, Carter Jr CW, Jennette JC, et al. Autoimmunity is triggered by cPR-3(105- 201), a protein complementary to human autoantigen proteinase-3. Nat Med. 2004; 10(1): 72-9. (Pubitemid 38524701)
71. Shoenfeld Y. Idiotypic induction of autoimmunity: a new aspect of the idiotypic network. FASEB J. 1994; 8(15): 1296-301.
72. Astern JM. Myeloperoxidase in vascular disease and autoimmunity. Chapel Hill: University of North Carolina; 2007.
73. Tadema H, Kallenberg CG, Stegeman CA, Heeringa P. Reactivity against complementary proteinase-3 is not increased in patients with PR3-ANCA-associated vasculitis. PLoS One. 2011; 6(3): e17972.
74. Bautz DJ, Preston GA, Lionaki S, Hewins P, Wolberg AS, Yang JJ, et al. Antibodies with Dual Reactivity to Plasminogen and Complementary PR3 in PR3-ANCA Vasculitis. J Am Soc Nephrol. 13 Aug 2008
75. Merkel PA, Lo GH, Holbrook JT, Tibbs AK, Allen NB, Davis Jr JC, et al. High incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener's Clinical Occurrence of Thrombosis (WeCLOT) Study. Ann Intern Med. 2005; 142(8): 620-6. (Pubitemid 40529958)
76. Stegeman CA. Cohen Tervaert JW, Sluiter WJ, Manson WL, de Jong PE, Kallenberg CGM. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med. 1994; 120: 12-7. (Pubitemid 24011495)
77. Stegeman CA, Cohen Tervaert JW, de Jong PE, Kallenberg CG. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. N Engl J Med. 1996; 335(1): 16-20. (Pubitemid 26230808)
78. Zycinska K, Wardyn KA, Zielonka TM, Krupa R, Lukas W. Cotrimoxazole and prevention of relapses of PR3-ANCA positive vasculitis with pulmonary involvement. Eur J Med Res. 2009; 14 Suppl 4: 265-7.
79. Proft T, Fraser JD. Bacterial superantigens. Clin Exp Immunol. 2003; 133(3): 299-306. (Pubitemid 37051503)
80. Zouali M. Exploitation of host signaling pathways by B cell superantigens-potential strategies for developing targeted therapies in systemic autoimmunity. Ann N Y Acad Sci. 2007; 1095: 342-54. (Pubitemid 47092466)
81. Popa ER, Stegeman CA, Abdulahad WH, van der Meer B, Arends J, Manson WM, et al. Staphylococcal toxic-shocksyndrome- toxin-1 as a risk factor for disease relapse in Wegener's granulomatosis. Rheumatol (Oxford). 2007; 46(6): 1029-33. (Pubitemid 47062516)
82. Popa ER, Stegeman CA, Bos NA, Kallenberg CG, Tervaert JW. Staphylococcal superantigens and T cell expansions in Wegener's granulomatosis. Clin Exp Immunol. 2003; 132(3): 496-504. (Pubitemid 36713957)
83. Li H, Nooh MM, Kotb M, Re F. Commercial peptidoglycan preparations are contaminated with superantigen-like activity that stimulates IL-17 production. J Leukoc Biol. 2008; 83(2): 409-18. (Pubitemid 351225622)
84. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007; 8(6): 639-46. (Pubitemid 46785128)
85. Gerosa F, Baldani-Guerra B, Lyakh LA, Batoni G, Esin S, Winkler-Pickett RT, et al. Differential regulation of interleukin 12 and interleukin 23 production in human dendritic cells. J Exp Med. 2008; 205(6): 1447-61. (Pubitemid 351831499)
86. Fouser LA, Wright JF, Dunussi-Joannopoulos K, Collins M. Th17 cytokines and their emerging roles in inflammation and autoimmunity. Immunol Rev. 2008; 226: 87-102.
87. Oukka M. Th17 cells in immunity and autoimmunity. Ann Rheum Dis. 2008; 67(Suppl 3: iii): 26-9.
88. Nogueira E, Hamour S, Sawant D, Henderson S, Mansfield N, Chavele KM, 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 (7): 2209-17. T cells producing IL-17 (Th17) have been implicated in the pathogenesis of several autoimmune diseases and this study identified that serum IL-17 levels and autoantigen-specific Th17 cells were elevated in patients with active AAVas compared to healthy individuals.
89. 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 (7): 2196-205. (Pubitemid 351988114)
90. Voswinkel J, Mueller A, Kraemer JA, Lamprecht P, Herlyn K, Holl-Ulrich K, et al. B lymphocyte maturation in Wegener's granulomatosis: a comparative analysis of VH genes from endonasal lesions. Ann Rheum Dis. 2006; 65(7): 859-64.
91. Hurtado PR, Jeffs L, Nitschke J, Patel M, Sarvestani G, Cassidy J, et al. CpG oligodeoxynucleotide stimulates production of antineutrophil cytoplasmic antibodies in ANCA associated vasculitis. BMC Immunol. 2008; 9: 34.
92. Tadema H, Abdulahad WH, Lepse N, Stegeman CA, Kallenberg CG, Heeringa P. Bacterial DNA motifs trigger ANCA production in ANCA-associated vasculitis in remission. Rheumatol (Oxford). 2011; 50(4): 689-96. This in vitro study showed that bacterial DNA motifs (CpG) trigger the production of ANCA by B lymphocytes in patients with AAV in remission.
93. Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol. 2007; 5(8): 577-82. (Pubitemid 47074113)
94. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007; 176(2): 231-41. (Pubitemid 46143263)
95. Kessenbrock K, Krumbholz M, Schonermarck U, Back W, Gross WL, Werb Z, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med. 2009; 15(6): 623-5. Neutrophil extracellular traps (NETs) are released by ANCA-stimulated neutrophils in the absence of microbial infection and contain proteinase-3 and myeloperoxidase. Deposition of NETs in inflamed tissue suggest that NET formation triggers vasculitis.
96. Pilsczek FH, Salina D, Poon KK, Fahey C, Yipp BG, Sibley CD, et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol. 2010; 185(12): 7413-25. Neutrophils responded uniquely to Staphylococcus aureus via a novel process of NET formation that did not require neutrophil lysis. S. aureus strongly induce NETs and S. aureus infections are linked to relapses of AAV.
97. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgMand Toll-like receptors. Nature. 2002; 416(6881): 603-7. (Pubitemid 34406754)
98. Tadema H, Abdulahad WH, Stegeman CA, Kallenberg CG, Heeringa P. Increased expression of Toll-like receptors by monocytes and natural killer cells in ANCA-associated vasculitis. PLoS One. 2011; 6(9): e24315. Toll-like receptors (TLRs) sense pathogen associated patterns and bacterial infections are known to be associated with AAV. In patients with AAV, monocytes and NK cells were shown to have an increased TLR expression probably resulting from increased activation, which could play a role in disease reactivation.
99. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCAassociated vasculitis. N Engl J Med. 2010; 363(3): 221-32.
100. Odendahl M, Mei H, Hoyer BF, Jacobi AM, Hansen A, Muehlinghaus G, et al. Generation of migratory antigenspecific plasma blasts and mobilization of resident plasma cells in a secondary immune response. Blood. 2005; 105(4): 1614-21. (Pubitemid 40223682)
101. Huang H, Benoist C, Mathis D. Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis. Proc Natl Acad Sci U S A. 2010; 107(10): 4658-63.
102. 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): 885-94. (Pubitemid 29297593)
103. Krumbholz M, Specks U, Wick M, Kalled SL, Jenne D, Meinl E. BAFF is elevated in serum of patients with Wegener's granulomatosis. J Autoimmun. 2005; 25(4): 298-302. (Pubitemid 41642976)
104. Schneeweis C, Rafalowicz M, Feist E, Buttgereit F, Rudolph PE, Burmester GR, et al. Increased levels of BLyS and sVCAM-1 in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitides (AAV). Clin Exp Rheumatol. 2010; 28(1 Suppl 57): 62-6. Levels of endothelial cell activation (sVCAM-1) were elevated in patients with AAV as compared to healthy controls.
105. Bader L, Koldingsnes W, Nossent J. B-lymphocyte activating factor levels are increased in patients with Wegener's granulomatosis and inversely correlated with ANCA titer. Clin Rheumatol. 2010; 29(9): 1031-5.
106. Mellbye OJ, Mollnes TE, Steen LS. IgG subclass distribution and complement activation ability of autoantibodies to neutrophil cytoplasmic antigens (ANCA). Clin Immunol Immunopathol. 1994; 70(1): 32-9. (Pubitemid 24034686)
107. Cohen Tervaert JW, Mulder L, Stegeman C, Elema J, Huitema M, The H, et al. Occurrence of autoantibodies to human leucocyte elastase in Wegener's granulomatosis and other inflammatory disorders. Ann Rheum Dis. 1993; 52: 115-20. (Pubitemid 23065670)
108. Caux C, Dezutter-Dambuyant C, Schmitt D, Bandhereau J. GMCSF and TNF-a cooperate in the generation of dendritic Langerhans cells. Nature. 1992; 360(6401): 258-61.
109. 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(5): 938-47. (Pubitemid 44285972)
110. Abdulahad WH, Stegeman CA, van der Geld YM, Doornbos-van der Meer B, Meer B, Limburg PC, et al. Functional defect of circulating regulatory CD4+ T cells in patients with Wegener's granulomatosis in remission. Arthritis Rheum. 2007; 56(6): 2080-91. (Pubitemid 47110408)
111. Morgan MD, Day CJ, Piper KP, Khan N, Harper L, Moss PA, et al. Patients with Wegener's granulomatosis demonstrate a relative deficiency and functional impairment of T-regulatory cells. Immunology. 2010; 130(1): 64-73. Immune balance is important in controlling autoimmune diseases and in this study the percentage of regulatory T cells (Foxp3 positive cells) were found to be decreased in patients with GPA as compared to healthy controls. In addition, the percentage of regulatory T cells was found to be inversely related to the rate of disease relapse.
112. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nature Immunol Res Support, NIH, Extramural Res Support, Non-US Gov't Rev. 2007; 8(4): 345-50. (Pubitemid 46745409)
113. Abdulahad WH, Stegeman CA, Kallenberg CG. Review article: The role of CD4(+) T cells in ANCA-associated systemic vasculitis. Nephrol (Carlton). 2009; 14(1): 26-32.
114. Ordonez L, Bernard I, L'Faqihi-Olive FE, Tervaert JW, Damoiseaux J, Saoudi A. CD45RC isoform expression identifies functionally distinct Tcell subsets differentially distributed between healthy individuals and AAV patients. PloS one [Res Support, Non-US Gov't]. 2009; 4(4): e5287.
115. Altmann F, Staudacher E,Wilson IB, Marz L. Insect cells as hosts for the expression of recombinant glycoproteins. Glycoconj J. 1999; 16(2): 109-23. (Pubitemid 29472137)
116. Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, ZhangM, et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol. 1998; 160(7): 3513-21. (Pubitemid 28164746)
117. 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 USA. 1990; 87: 4115-9. (Pubitemid 20217992)
118. Csernok E, Ernst M, Schmitt W, Bainton DF, Gross WL. Activated neutrophils express proteinase 3 on their plasma membrane in vitro and in vivo. Clin Exp Immunol. 1994; 95(2): 244-50. (Pubitemid 24207134)
119. Franssen CF, Huitema MG, Muller Kobold AC, Oost-Kort WW, Limburg PC, Tiebosch A, et al. In vitro neutrophil activation by antibodies to proteinase 3 and myeloperoxidase from patients with crescentic glomerulonephritis. J Am Soc Nephrol. 1999; 10 (7): 1506-15. (Pubitemid 29297525)
120. Kettritz R, Jennette JC, Falk RJ. Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils. J Am Soc Nephrol. 1997; 8: 386-94. (Pubitemid 127454174)
121. Weidner S, Neupert W, Goppelt-Struebe M, Rupprecht HD. Antineutrophil cytoplasmic antibodies induce human monocytes to produce oxygen radicals in vitro. Arthritis Rheum. 2001; 44 (7): 1698-706. (Pubitemid 32642233)
122. 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 (3): 796-808. (Pubitemid 38294811)
123. van der Veen BS, Chen M, Muller R, van Timmeren MM, Petersen AH, Lee PA, et al. Effects of p38 mitogen-activated protein kinase inhibition on anti-neutrophil cytoplasmic autoantibody pathogenicity in vitro and in vivo. Ann Rheum Dis. 9 Nov 2010
124. Radford DJ, Lord JM, Savage CO. The activation of the neutrophil respiratory burst by anti-neutrophil cytoplasm autoantibody (ANCA) from patients with systemic vasculitis requires tyrosine kinases and protein kinase C activation. Clin Exp Immunol. 1999; 118(1): 171-9. (Pubitemid 29479799)
125. Mayet WJ, Schwarting A, Orth T, Duchmann R, Buschenfelde KH Mz. Antibodies to proteinase 3 mediate expression of vascular cell adhesion molecule-1 (VCAM-1). Clin Exp Immunol. 1996; 103(2): 259-67. (Pubitemid 26046591)
126. De Bandt M, Meyer O, Hakim J, Pasquier C. Antibodies to proteinase-3 mediate expression of intercellular adhesion molecule-1 (ICAM-1, CD 54). Br J Rheumatol. 1997; 36(8): 839-46.
127. Muller Kobold AC, van Wijk RT, Franssen CF, Molema G, Kallenberg CG, Tervaert JW. In vitro up-regulation of Eselectin and induction of interleukin-6 in endothelial cells by autoantibodies in Wegener's granulomatosis and microscopic polyangiitis. Clin Exp Rheumatol. 1999; 17(4): 433-40. (Pubitemid 29343627)
128. 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(6): 1337-45. (Pubitemid 30416318)
129. Taekema-Roelvink ME, Kooten C, Kooij SV, Heemskerk E, Daha MR. Proteinase 3 enhances endothelial monocyte chemoattractant protein-1 production and induces increased adhesion of neutrophils to endothelial cells by upregulating intercellular cell adhesion molecule-1. J Am Soc Nephrol. 2001; 12(5): 932-40. (Pubitemid 32378333)
130. 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(5): 495-502. (Pubitemid 3017721)
131. Berger SP, Seelen MAJ, Hiemstra PS, Gerritsma JSJ, Heemskerk E, van der Woude FJ, 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: 694-701. (Pubitemid 27466002)
132. Brooks CJ, King WJ, Radford DJ, Adu D, McGrath M, Savage COS. IL-1b production by human polymorphonuclear leucocytes stimulated by anti-neutrophil cytoplasmic autoantibodies: relevance to systemic vasculitis. Clin Exp Immunol. 1996; 106: 273-9. (Pubitemid 26359893)
133. 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(6): 1416-24. (Pubitemid 27425766)
134. Zhou Z, Dionne A, Richard C, Menard HA. On the origin of surface proteinase 3 of nonmyeloid cells: evidence favoring an exogenous source. Clin Immunol. 2000; 97(2): 171-81.
135. Yang JJ, Preston GA, Pendergraft WF, Segelmark M, Heeringa P, Hogan SL, et al. Internalization of proteinase 3 is concomitant with endothelial cell apoptosis and internalization of myeloperoxidase with generation of intracellular oxidants. Am J Pathol. 2001; 158(2): 581-92. (Pubitemid 32158619)
136. Brons RH, de Jong MC, de Boer NK, Stegeman CA, Kallenberg CG, Cohen Tervaert JW. Detection of immune deposits in skin lesions of patients with Wegener's granulomatosis. Ann Rheum Dis. 2001; 60(12): 1097-102. (Pubitemid 33096073)
137. Haas M, Eustace JA. Immune complex deposits in ANCAassociated crescentic glomerulonephritis: a study of 126 cases. Kidney Int. 2004; 65(6): 2145-52. (Pubitemid 38670000)
138. Harper L, Cockwell P, Adu D, Savage CO. Neutrophil priming and apoptosis in anti-neutrophil cytoplasmic autoantibodyassociated vasculitis. Kidney Int. 2001; 59(5): 1729-38. (Pubitemid 32336787)
139. Harper L, Ren Y, Savill J, Adu D, Savage CO. Antineutrophil cytoplasmic antibodies induce reactive oxygen-dependent dysregulation of primed neutrophil apoptosis and clearance by macrophages. Am J Pathol. 2000; 157(1): 211-20. (Pubitemid 30641738)
140. Xiao H, Heeringa P, Hu P, Liu Z, Zhao M, Aratani Y, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest. 2002; 110(7): 955-63.
141. Little MA, Smyth CL, Yadav R, Ambrose L, Cook HT, Nourshargh S, et al. Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo. Blood. 2005; 106(6): 2050-8. (Pubitemid 41291719)
142. Pfister H, Ollert M, Frohlich LF, Quintanilla-Martinez L, Colby TV, Specks U, et al. Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo. Blood. 2004; 104(5): 1411-8. (Pubitemid 39166519)
143. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of multifocal motor neuropathy. Report of a joint task
144. Haas M, Jafri J, Bartosh SM, Karp SL, Adler SG, Meehan SM. ANCA-associated crescentic glomerulonephritis with mesangial IgA deposits. Am J Kidney Dis. 2000; 36(4): 709-18.
145. Mentzel HJ, Neumann T, Fitzek C, Sauner D, Reichenbach JR, KaiserWA. MR Imaging inWegener granulomatosis of the spinal cord. AJNR Am J Neuroradiol. 2003; 24(1): 18-21. (Pubitemid 36110095)
146. Stassen PM, Derks RP, Kallenberg CG, Stegeman CA. Venous thromboembolism in ANCA-associated vasculitis-incidence and risk factors. Rheumatol (Oxford). 2008; 47(4): 530-4.
147. Markiewski MM, Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD. Complement and coagulation: strangers or partners in crime? Trends Immunol [Res Support, NIH, Extramural Research Support, Non-US Gov't Rev]. 2007; 28(4): 184-92. (Pubitemid 46476881)
148. 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(1): 52-64. (Pubitemid 47339189)
149. Huugen D, van Esch A, Xiao H, Peutz-Kootstra CJ, Buurman WA, Tervaert JW, et al. Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice. Kidney Int. 2007; 71(7): 646-54. (Pubitemid 46494558)
150. Schreiber A, Xiao H, Jennette JC, SchneiderW, Luft FC, Kettritz R. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J Am Soc Nephrol. 2009; 20(2): 289-98.
151. Xing GQ, Chen M, Liu G, Heeringa P, Zhang JJ, Zheng X, et al. Complement activation is involved in renal damage in human antineutrophil cytoplasmic autoantibody associated pauciimmune vasculitis. J Clin Immunol. 2009; 29(3): 282-91.
152. 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. 2005; 45(4): 758-61. (Pubitemid 40460764)
153. 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
154. Sinico RA, Di Toma L, Maggiore U, Tosoni C, Bottero P, Sabadini E, et al. Renal involvement in Churg-Strauss syndrome. Am J Kidney Dis. 2006; 47(5): 770-9.
155. Finkielman JD, Lee AS, Hummel AM, Viss MA, Jacob GL, Homburger HA, et al. ANCA are detectable in nearly all patients with active severe Wegener's granulomatosis. Am J Med. 2007; 120(7): 643-14. e9.
156. Finkielman JD, Merkel PA, Schroeder D, Hoffman GS, Spiera R, St Clair EW, et al. Antiproteinase 3 Antineutrophil Cytoplasmic Antibodies and Disease Activity in Wegener Granulomatosis. Ann Intern Med. 2007; 147(9): 611-9. (Pubitemid 351664480)