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Etiopathogenesis of ANCA-Associated Vasculitis

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Anti-Neutrophil Cytoplasmic Antibody (ANCA) Associated Vasculitis

Part of the book series: Rare Diseases of the Immune System ((RDIS))

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Abstract

Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAVs) are autoimmune diseases in which pathogenic autoantibodies recognizing either MPO or PR3 proteins play a key role. Molecular mimicry through bacterial antigens, the presentation of peptides complementary to PR3, and the presentation of MPO and PR3 proteins through NETs can induce the production of anti-MPO or anti-PR3 autoantibodies, especially in the context of TH17/Treg dysregulation. Those antibodies, when bound to neutrophils, can activate them. The latter are responsible for the inflammatory process that damages the vessels. The deleterious role of neutrophils is further enhanced by their capacity to promote the complement alternate activation pathway through the ligation of C5a to the C5a receptors on neutrophils. Therefore, those new etiopathogenetic pathways represent promising therapeutic targets in AAV.

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References

  1. Gross WL, Schmitt WH, Csernok E. ANCA and associated diseases: immunodiagnostic and pathogenetic aspects. Clin Exp Immunol. 1993;91(1):1–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rose NR, Bona C. Defining criteria for autoimmune diseases (Witebsky’s postulates revisited). Immunol Today. 1993;14(9):426–30.

    Article  CAS  PubMed  Google Scholar 

  3. Chapman AL, Mocatta TJ, Shiva S, et al. Ceruloplasmin is an endogenous inhibitor of myeloperoxidase. J Biol Chem. 2013;288(9):6465–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Duranton J, Bieth JG. Inhibition of proteinase 3 by [alpha]1-antitrypsin in vitro predicts very fast inhibition in vivo. Am J Respir Cell Mol Biol. 2003;29(1):57–61.

    Article  CAS  PubMed  Google Scholar 

  5. Lyons PA, Rayner TF, Trivedi S, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012;367(3):214–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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(1):72–9.

    Article  CAS  PubMed  Google Scholar 

  7. Kain R, Rees AJ. What is the evidence for antibodies to LAMP-2 in the pathogenesis of ANCA associated small vessel vasculitis? Curr Opin Rheumatol. 2013;25(1):26–34.

    Article  CAS  PubMed  Google Scholar 

  8. Kain R, Tadema H, McKinney EF, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kain R, Exner M, Brandes R, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med. 2008;14(10):1088–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Roth AJ, Brown MC, Smith RN, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fervenza FC, Specks U. Vasculitis: will LAMP enlighten us about ANCA-associated vasculitis? Nat Rev Nephrol. 2012;8(6):318–20.

    Article  CAS  PubMed  Google Scholar 

  12. Yang J, Bautz DJ, Lionaki S, et al. ANCA patients have T cells responsive to complementary PR-3 antigen. Kidney Int. 2008;74(9):1159–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zycinska K, Wardyn KA, Zielonka TM, Demkow U, Traburzynski MS. Chronic crusting, nasal carriage of Staphylococcus aureus and relapse rate in pulmonary Wegener’s granulomatosis. J Physiol Pharmacol. 2008;59(Suppl 6):825–31.

    PubMed  Google Scholar 

  14. Savige J, Nassis L, Cooper T, Paspaliaris B, Martinello P, MacGregor D. Antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis after immunisation with bacterial proteins. Clin Exp Rheumatol. 2002;20(6):783–9.

    CAS  PubMed  Google Scholar 

  15. Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23(3):279–87.

    Article  CAS  PubMed  Google Scholar 

  16. Garcia-Romo GS, Caielli S, Vega B, et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med. 2011;3(73):73ra20.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kusunoki Y, Nakazawa D, Shida H, et al. Peptidylarginine deiminase inhibitor suppresses neutrophil extracellular trap formation and MPO-ANCA production. Front Immunol. 2016;7:227.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Lood C, Hughes GC. Neutrophil extracellular traps as a potential source of autoantigen in cocaine-associated autoimmunity. Rheumatology (Oxford). 2017;56(4):638–43.

    CAS  Google Scholar 

  19. Ooi JD, Chang J, Hickey MJ, et al. The immunodominant myeloperoxidase T-cell epitope induces local cell-mediated injury in antimyeloperoxidase glomerulonephritis. Proc Natl Acad Sci U S A. 2012;109(39):E2615–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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):4107–21.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chavele KM, Shukla D, Keteepe-Arachi T, et al. Regulation of myeloperoxidase-specific T cell responses during disease remission in antineutrophil cytoplasmic antibody-associated vasculitis: the role of Treg cells and tryptophan degradation. Arthritis Rheum. 2010;62(5):1539–48.

    Article  CAS  PubMed  Google Scholar 

  22. Brouwer E, Stegeman CA, Huitema MG, Limburg PC, Kallenberg CG. T cell reactivity to proteinase 3 and myeloperoxidase in patients with Wegener’s granulomatosis (WG). Clin Exp Immunol. 1994;98(3):448–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW. Autoreactive T cells in healthy individuals. J Immunol. 2004;172(10):5967–72.

    Article  CAS  PubMed  Google Scholar 

  24. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87.

    Article  CAS  PubMed  Google Scholar 

  25. Miyara M, Gorochov G, Ehrenstein M, Musset L, Sakaguchi S, Amoura Z. Human FoxP3+ regulatory T cells in systemic autoimmune diseases. Autoimmun Rev. 2011;10(12):744–55.

    Article  CAS  PubMed  Google Scholar 

  26. Tan DS, Gan PY, O’Sullivan KM, et al. Thymic deletion and regulatory T cells prevent antimyeloperoxidase GN. J Am Soc Nephrol. 2013;24(4):573–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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(4):e18734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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(1):64–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Abdulahad WH, Stegeman CA, van der Geld YM, Doornbos-van der Meer B, Limburg PC, Kallenberg CG. Functional defect of circulating regulatory CD4+ T cells in patients with Wegener’s granulomatosis in remission. Arthritis Rheum. 2007;56(6):2080–91.

    Article  CAS  PubMed  Google Scholar 

  30. Marinaki S, Neumann I, Kalsch AI, et al. Abnormalities of CD4 T cell subpopulations in ANCA-associated vasculitis. Clin Exp Immunol. 2005;140(1):181–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485–517.

    Article  CAS  PubMed  Google Scholar 

  32. Eriksson P, Andersson C, Cassel P, Nystrom S, Ernerudh J. Increase in Th17-associated CCL20 and decrease in Th2-associated CCL22 plasma chemokines in active ANCA-associated vasculitis. Scand J Rheumatol. 2015;44(1):80–3.

    Article  CAS  PubMed  Google Scholar 

  33. Gan PY, Steinmetz OM, Tan DS, et al. Th17 cells promote autoimmune anti-myeloperoxidase glomerulonephritis. J Am Soc Nephrol. 2010;21(6):925–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gao Y, Zhao MH. Review article: drug-induced anti-neutrophil cytoplasmic antibody-associated vasculitis. Nephrology (Carlton). 2009;14(1):33–41.

    Article  CAS  Google Scholar 

  35. Boomsma MM, Stegeman CA, van der Leij MJ, et al. Prediction of relapses in Wegener’s granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum. 2000;43(9):2025–33.

    Article  CAS  PubMed  Google Scholar 

  36. Thai LH, Charles P, Resche-Rigon M, Desseaux K, Guillevin L. Are anti-proteinase-3 ANCA a useful marker of granulomatosis with polyangiitis (Wegener’s) relapses? Results of a retrospective study on 126 patients. Autoimmun Rev. 2014;13(3):313–8.

    Article  CAS  PubMed  Google Scholar 

  37. Roth AJ, Ooi JD, Hess JJ, et al. Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis. J Clin Invest. 2013;123(4):1773–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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.

    Article  PubMed  Google Scholar 

  39. Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363(3):211–20.

    Article  CAS  PubMed  Google Scholar 

  40. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 2007;18(7):2180–8.

    Article  CAS  PubMed  Google Scholar 

  42. Alpha-antitrypsin-alpha therapeutic corporation. AAT - Alpha Therapeutic Corporation, alpha-1 proteinase inhibitor - Alpha Therapeutic Corporation, alpha-1-antitrypsin - Alpha Therapeutic Corporation, Aralast, Respitin. Drugs R D. 2003;4(2):113–4.

    Article  Google Scholar 

  43. Soderberg D, Segelmark M. Neutrophil extracellular traps in vasculitis, friend or foe? Curr Opin Rheumatol. 2018;30(1):16–23.

    Article  PubMed  Google Scholar 

  44. Guilpain P, Servettaz A, Goulvestre C, et al. Pathogenic effects of antimyeloperoxidase antibodies in patients with microscopic polyangiitis. Arthritis Rheum. 2007;56(7):2455–63.

    Article  CAS  Google Scholar 

  45. Kessenbrock K, Krumbholz M, Schonermarck U, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med. 2009;15(6):623–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Carmona-Rivera C, Purmalek MM, Moore E, et al. A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity. JCI Insight. 2017;2(3):e89780.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kumar SV, Kulkarni OP, Mulay SR, et al. Neutrophil extracellular trap-related extracellular histones cause vascular necrosis in severe GN. J Am Soc Nephrol. 2015;26(10):2399–413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schreiber A, Rousselle A, Becker JU, von Massenhausen A, Linkermann A, Kettritz R. Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis. Proc Natl Acad Sci U S A. 2017;114(45):E9618–E25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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(1):89–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 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(9):3209–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Charles LA, Caldas ML, Falk RJ, Terrell RS, Jennette JC. Antibodies against granule proteins activate neutrophils in vitro. J Leukoc Biol. 1991;50(6):539–46.

    Article  CAS  PubMed  Google Scholar 

  52. 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):4115–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Williams JM, Ben-Smith A, Hewins P, et al. Activation of the G(i) heterotrimeric G protein by ANCA IgG F(abʿ) 2 fragments is necessary but not sufficient to stimulate the recruitment of those downstream mediators used by intact ANCA IgG. J Am Soc Nephrol. 2003;14(3):661–9.

    Article  CAS  PubMed  Google Scholar 

  54. 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(3):1271–80.

    CAS  PubMed  Google Scholar 

  55. 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;336:121–3.

    Article  CAS  PubMed  Google Scholar 

  56. 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.

    Article  CAS  PubMed  Google Scholar 

  57. 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(7):955–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pfister H, Ollert M, Frohlich LF, et al. Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo. Blood. 2004;104(5):1411–8.

    Article  CAS  PubMed  Google Scholar 

  59. Salama AD, Little MA. Animal models of antineutrophil cytoplasm antibody-associated vasculitis. Curr Opin Rheumatol. 2012;24(1):1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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(1):47–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 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):3355–64.

    Article  PubMed  Google Scholar 

  62. van der Geld YM, Hellmark T, Selga D, et al. Rats and mice immunised with chimeric human/mouse proteinase 3 produce autoantibodies to mouse Pr3 and rat granulocytes. Ann Rheum Dis. 2007;66(12):1679–82.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Little MA, Al-Ani B, Ren S, Al-Nuaimi H, Leite M Jr, Alpers CE, et al. Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system. PLoS One. 2012;7(1):e28626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Chen M, Xing GQ, Yu F, Liu G, Zhao MH. Complement deposition in renal histopathology of patients with ANCA-associated pauci-immune glomerulonephritis. Nephrol Dial Transplant. 2009;24(4):1247–52.

    Article  CAS  PubMed  Google Scholar 

  65. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Xiao H, Dairaghi DJ, Powers JP, et al. C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol. 2014;25(2):225–31.

    Article  CAS  PubMed  Google Scholar 

  67. 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(2):289–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Dick J, Gan PY, Ford SL, et al. C5a receptor 1 promotes autoimmunity, neutrophil dysfunction and injury in experimental anti-myeloperoxidase glomerulonephritis. Kidney Int. 2018;93(3):615–25.

    Article  CAS  PubMed  Google Scholar 

  69. Jayne DRW, Bruchfeld AN, Harper L, et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol. 2017;28(9):2756–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Manenti L, Urban ML, Maritati F, Galetti M, Vaglio A. Complement blockade in ANCA-associated vasculitis: an index case, current concepts and future perspectives. Intern Emerg Med. 2017;12(6):727–31.

    Article  PubMed  Google Scholar 

  71. Shingu M, Nonaka S, Nishimukai H, Nobunaga M, Kitamura H, Tomo-Oka K. Activation of complement in normal serum by hydrogen peroxide and hydrogen peroxide-related oxygen radicals produced by activated neutrophils. Clin Exp Immunol. 1992;90(1):72–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hilhorst M, van Paassen P, Tervaert JW. Proteinase 3-ANCA vasculitis versus myeloperoxidase-ANCA vasculitis. J Am Soc Nephrol. 2015;26(10):2314–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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):1651–7.

    Article  CAS  PubMed  Google Scholar 

  74. Jennette JC, Hoidal JR, Falk RJ. Specificity of anti-neutrophil cytoplasmic autoantibodies for proteinase 3. Blood. 1990;75(11):2263–4.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sorbonne Université, Inserm, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), AP-HP Hôpital Pitié-Salpêtrière, Paris, France

    Delphine Sterlin & Makoto Miyara

  2. Immunology Department, AP-HP Hôpital Pitié-Salpêtrière, Paris, France

    Delphine Sterlin & Makoto Miyara

  3. Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), AP-HP Hôpital Pitié-Salpêtrière, INSERM, Sorbonne Université, Paris, France

    Alexis Mathian

  4. Internal Medicine Department, French National Reference Center for Rare Systemic Autoimmune Diseases, AP-HP Hôpital Pitié-Salpêtrière, Paris, France

    Alexis Mathian

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  1. Delphine Sterlin
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Correspondence to Makoto Miyara .

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  1. Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Monza e Brianza, Italy

    Renato Alberto Sinico

  2. Department of Medicine, Paris Descartes University Hospital Cochin, Paris, France

    Loïc Guillevin

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Sterlin, D., Mathian, A., Miyara, M. (2020). Etiopathogenesis of ANCA-Associated Vasculitis. In: Sinico, R., Guillevin, L. (eds) Anti-Neutrophil Cytoplasmic Antibody (ANCA) Associated Vasculitis. Rare Diseases of the Immune System. Springer, Cham. https://doi.org/10.1007/978-3-030-02239-6_3

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