ANCA-Associated Vasculitis: Pathogenesis, Models, and Preclinical Testing

Walton, 1958, Giant-cell granuloma of the respiratory tract (Wegener’s granulomatosis), Br Med J, 2, 265, 10.1136/bmj.2.5091.265

Little, 2010, Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis, Ann Rheum Dis, 69, 1036, 10.1136/ard.2009.109389

Davies, 1982, Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology?, Br Med J (Clin Res Ed), 285, 606, 10.1136/bmj.285.6342.606

Stilmant, 1979, Crescentic glomerulonephritis without immune deposits: clinicopathologic features, Kidney Int, 15, 184, 10.1038/ki.1979.24

Falk, 1990, Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro, Proc Natl Acad Sci U S A, 87, 4115, 10.1073/pnas.87.11.4115

Nowack, 2000, Upregulation of CD14 and CD18 on monocytes in vitro by antineutrophil cytoplasmic autoantibodies, J Am Soc Nephrol, 11, 1639, 10.1681/ASN.V1191639

Xiao, 2002, Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice, J Clin Invest, 110, 955, 10.1172/JCI0215918

Huugen, 2007, Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice, Kidney Int, 71, 646, 10.1038/sj.ki.5002103

Ruth, 2006, Anti-neutrophil cytoplasmic antibodies and effector CD4+ cells play nonredundant roles in anti-myeloperoxidase crescentic glomerulonephritis, J Am Soc Nephrol, 17, 1940, 10.1681/ASN.2006020108

Ooi, 2012, The immunodominant myeloperoxidase T-cell epitope induces local cell-mediated injury in antimyeloperoxidase glomerulonephritis, Proc Natl Acad Sci U S A, 109, E2615, 10.1073/pnas.1210147109

Chang, 2017, CD8+ T cells effect glomerular injury in experimental anti-myeloperoxidase GN, J Am Soc Nephrol, 28, 47, 10.1681/ASN.2015121356

Brinkmann, 2004, Neutrophil extracellular traps kill bacteria, Science, 303, 1532, 10.1126/science.1092385

Kessenbrock, 2009, Netting neutrophils in autoimmune small-vessel vasculitis, Nat Med, 15, 623, 10.1038/nm.1959

Sangaletti, 2012, Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity, Blood, 120, 3007, 10.1182/blood-2012-03-416156

O’Sullivan, 2015, Renal participation of myeloperoxidase in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, Kidney Int, 88, 1030, 10.1038/ki.2015.202

Hilhorst, 2015, Proteinase 3-ANCA vasculitis versus myeloperoxidase-ANCA vasculitis, J Am Soc Nephrol, 26, 2314, 10.1681/ASN.2014090903

Scott, 2013, Epidemiology and clinical features of systemic vasculitis, Clin Exp Nephrol, 17, 607, 10.1007/s10157-013-0830-8

Lyons, 2012, Genetically distinct subsets within ANCA-associated vasculitis, N Engl J Med, 367, 214, 10.1056/NEJMoa1108735

Xie, 2013, Association of granulomatosis with polyangiitis (Wegener’s) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis, Arthritis Rheum, 65, 2457, 10.1002/art.38036

Ciavatta, 2010, Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis, J Clin Invest, 120, 3209, 10.1172/JCI40034

Zycinska, 2009, Co-trimoxazole and prevention of relapses of PR3-ANCA positive vasculitis with pulmonary involvement, Eur J Med Res, 14, 265, 10.1186/2047-783X-14-S4-265

Kain, 2008, Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis, Nat Med, 14, 1088, 10.1038/nm.1874

Huugen, 2005, Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-alpha, Am J Pathol, 167, 47, 10.1016/S0002-9440(10)62952-5

Summers, 2010, TLR9 and TLR4 are required for the development of autoimmunity and lupus nephritis in pristane nephropathy, J Autoimmun, 35, 291, 10.1016/j.jaut.2010.05.004

Summers, 2011, Toll-like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll-like receptor 9 drives Th1 autoimmunity in murine vasculitis, Arthritis Rheum, 63, 1124, 10.1002/art.30208

Miller, 2012, Epidemiology of environmental exposures and human autoimmune diseases: findings from a National Institute of Environmental Health Sciences Expert Panel Workshop, J Autoimmun, 39, 259, 10.1016/j.jaut.2012.05.002

Furuta, 2013, Antineutrophil cytoplasm antibody-associated vasculitis: recent developments, Kidney Int, 84, 244, 10.1038/ki.2013.24

Tan, 2013, Thymic deletion and regulatory T cells prevent antimyeloperoxidase GN, J Am Soc Nephrol, 24, 573, 10.1681/ASN.2012090898

Cui, 2010, Natural autoantibodies to myeloperoxidase, proteinase 3, and the glomerular basement membrane are present in normal individuals, Kidney Int, 78, 590, 10.1038/ki.2010.198

Summers, 2010, Intrinsic renal cell and leukocyte-derived TLR4 aggravate experimental anti-MPO glomerulonephritis, Kidney Int, 78, 1263, 10.1038/ki.2010.327

Millet, 2015, Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis, J Clin Invest, 125, 4107, 10.1172/JCI78182

Pendergraft, 2004, Autoimmunity is triggered by cPR-3(105-201), a protein complementary to human autoantigen proteinase-3, Nat Med, 10, 72, 10.1038/nm968

Nogueira, 2010, Serum IL-17 and IL-23 levels and autoantigen-specific Th17 cells are elevated in patients with ANCA-associated vasculitis, Nephrol Dial Transplant, 25, 2209, 10.1093/ndt/gfp783

Kuligowski, 2009, Antimyeloperoxidase antibodies rapidly induce alpha-4-integrin-dependent glomerular neutrophil adhesion, Blood, 113, 6485, 10.1182/blood-2008-12-192617

Tomasson, 2012, Value of ANCA measurements during remission to predict a relapse of ANCA-associated vasculitis--a meta-analysis, Rheumatology (Oxford), 51, 100, 10.1093/rheumatology/ker280

Kallenberg CG. Clinical relevance of ANCA. Autoantibody Manual. 1997;1-12.

Roth, 2013, Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis, J Clin Invest, 123, 1773, 10.1172/JCI65292

Nagao, 2011, Direct activation of glomerular endothelial cells by anti-moesin activity of anti-myeloperoxidase antibody, Nephrol Dial Transplant, 26, 2752, 10.1093/ndt/gfr032

Cockwell, 1999, Interleukin-8: a pathogenetic role in antineutrophil cytoplasmic autoantibody-associated glomerulonephritis, Kidney Int, 55, 852, 10.1046/j.1523-1755.1999.055003852.x

Harper, 2001, Neutrophil priming and apoptosis in anti-neutrophil cytoplasmic autoantibody-associated vasculitis, Kidney Int, 59, 1729, 10.1046/j.1523-1755.2001.0590051729.x

O’Brien, 2015, Intermediate monocytes in ANCA vasculitis: increased surface expression of ANCA autoantigens and IL-1beta secretion in response to anti-MPO antibodies, Sci Rep, 5, 11888, 10.1038/srep11888

Jayne, 2007, Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis, J Am Soc Nephrol, 18, 2180, 10.1681/ASN.2007010090

Schlieben, 2005, Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs, Am J Kidney Dis, 45, 758, 10.1053/j.ajkd.2005.01.001

Jones, 2015, Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial, Ann Rheum Dis, 74, 1178, 10.1136/annrheumdis-2014-206404

Geetha, 2015, Rituximab versus cyclophosphamide for ANCA-associated vasculitis with renal involvement, J Am Soc Nephrol, 26, 976, 10.1681/ASN.2014010046

Xu, 2011, Comparison of characteristics of natural autoantibodies against myeloperoxidase and anti-myeloperoxidase autoantibodies from patients with microscopic polyangiitis, Rheumatology (Oxford), 50, 1236, 10.1093/rheumatology/ker085

Mulder, 1994, Activation of granulocytes by anti-neutrophil cytoplasmic antibodies (ANCA): a Fc gamma RII-dependent process, Clin Exp Immunol, 98, 270, 10.1111/j.1365-2249.1994.tb06137.x

Brouwer, 1991, Predominance of IgG1 and IgG4 subclasses of anti-neutrophil cytoplasmic autoantibodies (ANCA) in patients with Wegener’s granulomatosis and clinically related disorders, Clin Exp Immunol, 83, 379, 10.1111/j.1365-2249.1991.tb05647.x

Nowack, 2001, ANCA titres, even of IgG subclasses, and soluble CD14 fail to predict relapses in patients with ANCA-associated vasculitis, Nephrol Dial Transplant, 16, 1631, 10.1093/ndt/16.8.1631

Kuhl, 2010, Mapping of conformational epitopes on human proteinase 3, the autoantigen of Wegener’s granulomatosis, J Immunol, 185, 387, 10.4049/jimmunol.0903887

Gou, 2013, Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis, Kidney Int, 83, 129, 10.1038/ki.2012.313

Xiao, 2014, C5a receptor (CD88) blockade protects against MPO-ANCA GN, J Am Soc Nephrol, 25, 225, 10.1681/ASN.2013020143

Freeley, 2016, Experimentally-induced anti-myeloperoxidase vasculitis does not require properdin, MASP-2 or bone marrow-derived C5, J Pathol, 240, 61, 10.1002/path.4754

Cunningham, 1999, Prominence of cell-mediated immunity effectors in “pauci-immune” glomerulonephritis, J Am Soc Nephrol, 10, 499, 10.1681/ASN.V103499

Schmitt, 2004, Treatment of refractory Wegener’s granulomatosis with antithymocyte globulin (ATG): an open study in 15 patients, Kidney Int, 65, 1440, 10.1111/j.1523-1755.2004.00534.x

Gan, 2013, Myeloperoxidase (MPO)-specific CD4+ T cells contribute to MPO-anti-neutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis, Cell Immunol, 282, 21, 10.1016/j.cellimm.2013.04.007

Hoshino, 2008, MPO-ANCA induces IL-17 production by activated neutrophils in vitro via classical complement pathway-dependent manner, J Autoimmun, 31, 79, 10.1016/j.jaut.2008.03.006

Gan, 2010, Th17 cells promote autoimmune anti-myeloperoxidase glomerulonephritis, J Am Soc Nephrol, 21, 925, 10.1681/ASN.2009070763

Ghali, 2016, Regulatory T cells in immune-mediated renal disease, Nephrology (Carlton), 21, 86, 10.1111/nep.12574

Gan, 2016, Myeloperoxidase peptide-based nasal tolerance in experimental ANCA-associated GN, J Am Soc Nephrol, 27, 385, 10.1681/ASN.2015010089

Radford, 2001, Antineutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelial cells, Arthritis Rheum, 44, 2851, 10.1002/1529-0131(200112)44:12<2851::AID-ART473>3.0.CO;2-2

Calderwood, 2005, ANCA induces beta2 integrin and CXC chemokine-dependent neutrophil-endothelial cell interactions that mimic those of highly cytokine-activated endothelium, J Leukoc Biol, 77, 33, 10.1189/jlb.0104054

Little, 2005, Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo, Blood, 106, 2050, 10.1182/blood-2005-03-0921

Nolan, 2008, Mechanisms of ANCA-mediated leukocyte-endothelial cell interactions in vivo, J Am Soc Nephrol, 19, 973, 10.1681/ASN.2007111166

McKinney, 2015, T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection, Nature, 523, 612, 10.1038/nature14468

McKinney, 2016, T cell exhaustion and immune-mediated disease-the potential for therapeutic exhaustion, Curr Opin Immunol, 43, 74, 10.1016/j.coi.2016.09.005

Holdsworth, 2016, Biologics for the treatment of autoimmune renal diseases, Nat Rev Nephrol, 12, 217, 10.1038/nrneph.2016.18

Porges, 1994, Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa, J Immunol, 153, 1271

Schreiber, 2013, The neutrophil in antineutrophil cytoplasmic autoantibody-associated vasculitis, J Leukoc Biol, 94, 623, 10.1189/jlb.1012525

Kettritz, 2001, Role of mitogen-activated protein kinases in activation of human neutrophils by antineutrophil cytoplasmic antibodies, J Am Soc Nephrol, 12, 37, 10.1681/ASN.V12137

Jerke, 2011, Complement receptor Mac-1 is an adaptor for NB1 (CD177)-mediated PR3-ANCA neutrophil activation, J Biol Chem, 286, 7070, 10.1074/jbc.M110.171256

Le Roux, 2012, Elevated soluble Flt1 inhibits endothelial repair in PR3-ANCA-associated vasculitis, J Am Soc Nephrol, 23, 155, 10.1681/ASN.2010080858

Salama, 2012, Animal models of antineutrophil cytoplasm antibody-associated vasculitis, Curr Opin Rheumatol, 24, 1, 10.1097/BOR.0b013e32834d2d52

Xiao, 2005, The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies, Am J Pathol, 167, 39, 10.1016/S0002-9440(10)62951-3

Xiao, 2013, Genetically determined severity of anti-myeloperoxidase glomerulonephritis, Am J Pathol, 182, 1219, 10.1016/j.ajpath.2012.12.006

Freeley, 2013, Granulocyte colony stimulating factor exacerbates antineutrophil cytoplasmic antibody vasculitis, Ann Rheum Dis, 72, 1053, 10.1136/annrheumdis-2012-202160

Xiao, 2007, Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies, Am J Pathol, 170, 52, 10.2353/ajpath.2007.060573

Ooi, 2014, T cell mediated autoimmune glomerular disease in mice, Curr Protoc Immunol, 107, 1, 10.1002/0471142735.im1527s107

Brouwer, 1993, Antimyeloperoxidase-associated proliferative glomerulonephritis: an animal model, J Exp Med, 177, 905, 10.1084/jem.177.4.905

Little, 2009, Experimental autoimmune vasculitis: an animal model of anti-neutrophil cytoplasmic autoantibody-associated systemic vasculitis, Am J Pathol, 174, 1212, 10.2353/ajpath.2009.080458

Little, 2006, Therapeutic effect of anti-TNF-alpha antibodies in an experimental model of anti-neutrophil cytoplasm antibody-associated systemic vasculitis, J Am Soc Nephrol, 17, 160, 10.1681/ASN.2005060616

Heeringa, 1996, Autoantibodies to myeloperoxidase aggravate mild anti-glomerular-basement-membrane-mediated glomerular injury in the rat, Am J Pathol, 149, 1695

Gan, 2012, Mast cells contribute to peripheral tolerance and attenuate autoimmune vasculitis, J Am Soc Nephrol, 23, 1955, 10.1681/ASN.2012060572

Schreiber, 2006, Bone marrow-derived cells are sufficient and necessary targets to mediate glomerulonephritis and vasculitis induced by anti-myeloperoxidase antibodies, J Am Soc Nephrol, 17, 3355, 10.1681/ASN.2006070718

Schreiber, 2010, Phosphoinositol 3-kinase-gamma mediates antineutrophil cytoplasmic autoantibody-induced glomerulonephritis, Kidney Int, 77, 118, 10.1038/ki.2009.420

Schreiber, 2012, Neutrophil serine proteases promote IL-1beta generation and injury in necrotizing crescentic glomerulonephritis, J Am Soc Nephrol, 23, 470, 10.1681/ASN.2010080892

Pfister, 2004, Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo, Blood, 104, 1411, 10.1182/blood-2004-01-0267

Little, 2013, L7. Animal models of PR3-ANCA vasculitis: approaches and controversies, Presse Med, 42, 512, 10.1016/j.lpm.2013.01.007

van der Geld, 2007, Rats and mice immunised with chimeric human/mouse proteinase 3 produce autoantibodies to mouse Pr3 and rat granulocytes, Ann Rheum Dis, 66, 1679, 10.1136/ard.2006.064626

Little, 2012, Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system, PLoS One, 7, e28626, 10.1371/journal.pone.0028626

Primo, 2010, Anti-PR3 immune responses induce segmental and necrotizing glomerulonephritis, Clin Exp Immunol, 159, 327, 10.1111/j.1365-2249.2009.04072.x

Roth, 2012, Anti-LAMP-2 antibodies are not prevalent in patients with antineutrophil cytoplasmic autoantibody glomerulonephritis, J Am Soc Nephrol, 23, 545, 10.1681/ASN.2011030273

Neumann, 2003, SCG/Kinjoh mice: a model of ANCA-associated crescentic glomerulonephritis with immune deposits, Kidney Int, 64, 140, 10.1046/j.1523-1755.2003.00061.x

Odobasic, 2014, Glomerulonephritis induced by heterologous anti-GBM globulin as a planted foreign antigen, Curr Protoc Immunol, 106, 1, 10.1002/0471142735.im1526s106

Odobasic, 2007, Endogenous myeloperoxidase promotes neutrophil-mediated renal injury, but attenuates T cell immunity inducing crescentic glomerulonephritis, J Am Soc Nephrol, 18, 760, 10.1681/ASN.2006040375

Schreiber, 2016, Lessons from a double-transgenic neutrophil approach to induce antiproteinase 3 antibody-mediated vasculitis in mice, J Leukoc Biol, 100, 1443, 10.1189/jlb.5A0116-037R

Anders, 2016, Hurdles to the introduction of new therapies for immune-mediated kidney diseases, Nat Rev Nephrol, 12, 205, 10.1038/nrneph.2015.206

Stegeman, 1994, Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis, Ann Intern Med, 120, 12, 10.7326/0003-4819-120-1-199401010-00003

Bontscho, 2011, Myeloperoxidase-specific plasma cell depletion by bortezomib protects from anti-neutrophil cytoplasmic autoantibodies-induced glomerulonephritis, J Am Soc Nephrol, 22, 336, 10.1681/ASN.2010010034

BS, 2011, Effects of p38 mitogen-activated protein kinase inhibition on anti-neutrophil cytoplasmic autoantibody pathogenicity in vitro and in vivo, Ann Rheum Dis, 70, 356, 10.1136/ard.2010.129106