Health  Vol.6 No.14 , July 2014
ANCA-Associated Vasculitides—An Update
Abstract: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are characterized by destruction of small vessels, granulomatous inflammation of the respiratory tract and necrotizing glomerulonephritis. This review describes the clinical diagnosis and therapy as well as the patho-physiology of ANCA-associated vasculitides with a specific focus on the interplay of ANCAs with activated neutrophils and the deleterious pathophysiological consequences of neutrophil-endothelium interaction.
Cite this paper: Kegel, J. and Kirsch, T. (2014) ANCA-Associated Vasculitides—An Update. Health, 6, 1767-1779. doi: 10.4236/health.2014.614209.

[1]   Watts, R.A. and Scott, D.G. (2009) Recent Developments in the Classification and Assessment of Vasculitis. Best Practice & Research Clinical Rheumatology, 23, 429-443.

[2]   Hoffman, G.S. (1998) Classification of the Systemic Vasculitides: Antineutrophil Cytoplasmic Antibodies, Consensus and Controversy. Clinical and Experimental Rheumatology, 16, 111-115.

[3]   Hunder, G.G., Arend, W.P., Bloch, D.A., Calabrese, L.H., Fauci, A.S., Fries, J.F., Leavitt, R.Y., Lie, J.T., Lightfoot Jr., R.W., Masi, A.T., et al. (1990) The American College of Rheumatology 1990 Criteria for the Classification of Vasculitis. Introduction. Arthritis & Rheumatology, 33, 1065-1067.

[4]   Watts, R., Lane, S., Hanslik, T., Hauser, T., Hellmich, B., Koldingsnes, W., Mahr, A., Segelmark, M., Cohen-Tervaert, J.W. and Scott, D. (2007) Development and Validation of a Consensus Methodology for the Classification of the ANCA-Associated Vasculitides and Polyarteritis Nodosa for Epidemiological Studies. Annals of the Rheumatic Diseases, 66, 222-227.

[5]   Kallenberg, C.G., Stegeman, C.A., Abdulahad, W.H. and Heeringa, P. (2013) Pathogenesis of ANCA-Associated Vasculitis: New Possibilities for Intervention. American Journal of Kidney Diseases, 62, 1176-1187.

[6]   Watts, R.A. and Scott, D.G. (2003) Epidemiology of the Vasculitides. Current Opinion in Rheumatology, 15, 11-16.

[7]   Flossmann, O., Berden, A., de Groot, K., Hagen, C., Harper, L., Heijl, C., Hoglund, P., Jayne, D., Luqmani, R., Mahr, A., Mukhtyar, C., Pusey, C., Rasmussen, N., Stegeman, C., Walsh, M. and Westman, K. (2011) Long-Term Patient Survival in ANCA-Associated Vasculitis. Annals of the Rheumatic Diseases, 70, 488-494.

[8]   Watts, R.A., Lane, S.E., Bentham, G. and Scott, D.G. (2000) Epidemiology of Systemic Vasculitis: A Ten-Year Study in the United Kingdom. Arthritis & Rheumatology, 43, 414-419.<414::AID-ANR23>3.0.CO;2-0

[9]   Falk, R.J., Gross, W.L., Guillevin, L., Hoffman, G., Jayne, D.R., Jennette, J.C., Kallenberg, C.G., Luqmani, R., Mahr, A.D., Matteson, E.L., Merkel, P.A., Specks, U. and Watts, R. (2011) Granulomatosis with Polyangiitis (Wegener’s): An Alternative Name for Wegener’s Granulomatosis. Journal of the American Society of Nephrology, 22, 587-588.

[10]   Leavitt, R.Y., Fauci, A.S., Bloch, D.A., Michel, B.A., Hunder, G.G., Arend, W.P., Calabrese, L.H., Fries, J.F., Lie, J.T., Lightfoot Jr., R.W., et al. (1990) The American College of Rheumatology 1990 Criteria for the Classification of Wegener’s Granulomatosis. Arthritis & Rheumatology, 33, 1101-1107.

[11]   Jennette, J.C., Falk, R.J., Andrassy, K., Bacon, P.A., Churg, J., Gross, W.L., Hagen, E.C., Hoffman, G.S., Hunder, G.G., Kallenberg, C.G., et al. (1994) Nomenclature of Systemic Vasculitides. Proposal of an International Consensus Conference. Arthritis & Rheumatology, 37, 187-192.

[12]   Luqmani, R.A., Suppiah, R., Grayson, P.C., Merkel, P.A. and Watts, R. (2011) Nomenclature and Classification of Vasculitis—Update on the ACR/EULAR Diagnosis and Classification of Vasculitis Study (DCVAS). Clinical & Experimental Immunology, 164, 11-13.

[13]   Jennette, J.C. and Falk, R.J. (1997) Small-Vessel Vasculitis. New England Journal of Medicine, 337, 1512-1523.

[14]   Seo, P. and Stone, J.H. (2004) The Antineutrophil Cytoplasmic Antibody-Associated Vasculitides. The American Journal of Medicine, 117, 39-50.

[15]   Falk, R.J., Hogan, S., Carey, T.S. and Jennette, J.C. (1990) Clinical Course of Anti-Neutrophil Cytoplasmic Autoanti-body-Associated Glomerulonephritis and Systemic Vasculitis. The Glomerular Disease Collaborative Network. Annals of Internal Medicine, 113, 656-663.

[16]   Hoffman, G.S., Kerr, G.S., Leavitt, R.Y., Hallahan, C.W., Lebovics, R.S., Travis, W.D., Rottem, M. and Fauci, A.S. (1992) Wegener Granulomatosis: An Analysis of 158 Patients. Annals of Internal Medicine, 116, 488-498.

[17]   Jayne, D. (2009) The Diagnosis of Vasculitis. Best Practice & Research Clinical Rheumatology, 23, 445-453.

[18]   Gomez-Puerta, J.A., Hernandez-Rodriguez, J., Lopez-Soto, A. and Bosch, X. (2009) Antineutrophil Cytoplasmic Antibody-Associated Vasculitides and Respiratory Disease. Chest, 136, 1101-1111.

[19]   Jennette, J.C. and Falk, R.J. (1994) The Pathology of Vasculitis Involving the Kidney. American Journal of Kidney Diseases, 24, 130-141.

[20]   Hoffman, G.S. and Specks, U. (1998) Antineutrophil Cytoplasmic Antibodies. Arthritis & Rheumatology, 41, 1521-1537.<1521::AID-ART2>3.0.CO;2-A

[21]   Jones, R.B., Tervaert, J.W., Hauser, T., Luqmani, R., Morgan, M.D., Peh, C.A., Savage, C.O., Segelmark, M., Tesar, V., van Paassen, P., Walsh, D., Walsh, M., Westman, K. and Jayne, D.R. (2010) Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis. New England Journal of Medicine, 363, 211-220.

[22]   Stone, J.H., Merkel, P.A., Spiera, R., Seo, P., Langford, C.A., Hoffman, G.S., Kallenberg, C.G., St Clair, E.W., Turkiewicz, A., Tchao, N.K., Webber, L., Ding, L., Sejismundo, L.P., Mieras, K., Weitzenkamp, D., Ikle, D., Seyfert-Margolis, V., Mueller, M., Brunetta, P., Allen, N.B., Fervenza, F.C., Geetha, D., Keogh, K.A., Kissin, E.Y., Monach, P.A., Peikert, T., Stegeman, C., Ytterberg, S.R. and Specks, U. (2010) Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis. New England Journal of Medicine, 363, 221-232.

[23]   Holle, J.U. (2013) ANCA-Associated Vasculitis. Zeitschrift für Rheumatologie, 72, 445-456.

[24]   Voswinkel, J., Mueller, A., Kraemer, J.A., Lamprecht, P., Herlyn, K., Holl-Ulrich, K., Feller, A.C., Pitann, S., Gause, A. and Gross, W.L. (2006) B Lymphocyte Maturation in Wegener’s Granulomatosis: A Comparative Analysis of VH Genes from Endonasal Lesions. Annals of the Rheumatic Diseases, 65, 859-864.

[25]   Muller, A., Trabandt, A., Gloeckner-Hofmann, K., Seitzer, U., Csernok, E., Schonermarck, U., Feller, A.C. and Gross, W.L. (2000) Localized Wegener’s Granulomatosis: Predominance of CD26 and IFN-Gamma Expression. The Journal of Pathology, 192, 113-120.<::AID-PATH656>3.0.CO;2-M

[26]   Tadema, H., Abdulahad, W.H., Stegeman, C.A., Kallenberg, C.G. and Heeringa, P. (2011) Increased Expression of Toll-Like Receptors by Monocytes and Natural Killer Cells in ANCA-Associated Vasculitis. PLoS ONE, 6, e24315.

[27]   Bunch, D.O., McGregor, J.G., Khandoobhai, N.B., Aybar, L.T., Burkart, M.E., Hu, Y., Hogan, S.L., Poulton, C.J., Berg, E.A., Falk, R.J. and Nachman, P.H. (2013) Decreased CD5+ B Cells in Active ANCA Vasculitis and Relapse after Rituximab. Clinical Journal of the American Society of Nephrology, 8, 382-391.

[28]   Abdulahad, W.H., De Souza, A.W. and Kallenberg, C.G. (2013) L3. Are Mononuclear Cells Predominant Actors of Endothelial Damage in Vasculitis? La Presse Médicale, 42, 499-503.

[29]   Appay, V. (2004) The Physiological Role of Cytotoxic CD4(+) T-Cells: The Holy Grail? Clinical Experimental Immunology, 138, 10-13.

[30]   Zwirner, N.W., Dole, K. and Stastny, P. (1999) Differential Surface Expression of MICA by Endothelial Cells, Fibroblasts, Keratinocytes, and Monocytes. Human Immunology, 60, 323-330.

[31]   Charles Jennette, J. and Falk, R.J. (2013) L1. Pathogenesis of ANCA-Associated Vasculitis: Observations, Theories and Speculations. La Presse Médicale, 42, 493-498.

[32]   Jennette, J.C. (2011) Nomenclature and Classification of Vasculitis: Lessons Learned from Granulomatosis with Polyangiitis (Wegener’s Granulomatosis). Clinical & Experimental Immunology, 164, 7-10.

[33]   Mark, E.J., Matsubara, O., Tan-Liu, N.S. and Fienberg, R. (1988) The Pulmonary Biopsy in the Early Diagnosis of Wegener’s (Pathergic) Granulomatosis: A Study Based on 35 Open Lung Biopsies. Human Pathology, 19, 1065-1071.

[34]   Lamprecht, P. and Gross, W.L. (2007) Current Knowledge on Cellular Interactions in the WG-Granuloma. Clinical and Experimental Rheumatology, 25, S49-S51.

[35]   van der Woude, F.J., Rasmussen, N., Lobatto, S., Wiik, A., Permin, H., van Es, L.A., van der Giessen, M., Van Der Hem, G.K. and The, T.H. (1985) Autoantibodies against Neutrophils and Monocytes: Tool for Diagnosis and Marker of Disease Activity in Wegener’s Granulomatosis. The Lancet, 1, 425-429.

[36]   Falk, R.J. and Jennette, J.C. (1988) Anti-Neutrophil Cytoplasmic Autoantibodies with Specificity for Myeloperoxidase in Patients with Systemic Vasculitis and Idiopathic Necrotizing and Crescentic Glomerulonephritis. The New England Journal of Medicine, 318, 1651-1657.

[37]   Tervaert, J.W., Goldschmeding, R., Elema, J.D., van der Giessen, M., Huitema, M.G., van der Hem, G.K., The, T.H., von dem Borne, A.E. and Kallenberg, C.G. (1990) Autoantibodies against Myeloid Lysosomal Enzymes in Crescentic Glomerulonephritis. Kidney International, 37, 799-806.

[38]   Jennette, J.C., Wilkman, A.S. and Falk, R.J. (1998) Diagnostic Predictive Value of ANCA Serology. Kidney International, 53, 796-798.

[39]   Hagen, E.C., Daha, M.R., Hermans, J., Andrassy, K., Csernok, E., Gaskin, G., Lesavre, P., Ludemann, J., Rasmussen, N., Sinico, R.A., Wiik, A. and van der Woude, F.J. (1998) Diagnostic Value of Standardized Assays for Anti-Neutrophil Cytoplasmic Antibodies in Idiopathic Systemic Vasculitis. EC/BCR Project for ANCA Assay Standardization. Kidney International, 53, 743-753.

[40]   Witko-Sarsat, V. (2013) L34. Neutrophils in ANCA-Associated Vasculitis: Still under Investigation. La Presse Médicale, 42, 595-597.

[41]   Hu, N., Westra, J., Huitema, M.G., Bijl, M., Brouwer, E., Stegeman, C.A., Heeringa, P., Limburg, P.C. and Kallenberg, C.G. (2009) Coexpression of CD177 and Membrane Proteinase 3 on Neutrophils in Antineutrophil Cytoplasmic Autoantibody-Associated Systemic Vasculitis: Anti-Proteinase 3-Mediated Neutrophil Activation Is Independent of the Role of CD177-Expressing Neutrophils. Arthritis Rheumatology, 60, 1548-1557.

[42]   Yang, J.J., Tuttle, R.H., Hogan, S.L., Taylor, J.G., Phillips, B.D., Falk, R.J. and Jennette, J.C. (2000) Target Antigens for Anti-Neutrophil Cytoplasmic Autoantibodies (ANCA) Are on the Surface of Primed and Apoptotic but Not Unstimulated Neutrophils. Clinical Experimental Immunology, 121, 165-172.

[43]   Huugen, D., Xiao, H., van Esch, A., Falk, R.J., Peutz-Kootstra, C.J., Buurman, W.A., Tervaert, J.W., Jennette, J.C. and Heeringa, P. (2005) Aggravation of Anti-Myeloperoxidase Antibody-Induced Glomerulonephritis by Bacterial Lipo-polysaccharide: Role of Tumor Necrosis Factor-Alpha. American Journal of Pathology, 167, 47-58.

[44]   Xiao, H., Heeringa, P., Hu, P., Liu, Z., Zhao, M., Aratani, Y., Maeda, N., Falk, R.J. and Jennette, J.C. (2002) Antineutrophil Cytoplasmic Autoantibodies Specific for Myeloperoxidase Cause Glomerulonephritis and Vasculitis in Mice. Journal of Clinical Investigation, 110, 955-963.

[45]   Little, M.A., Al-Ani, B., Ren, S., Al-Nuaimi, H., Leite Jr., M., Alpers, C.E., Savage, C.O. and Duffield, J.S. (2012) Anti-Proteinase 3 Anti-Neutrophil Cytoplasm Autoantibodies Recapitulate Systemic Vasculitis in Mice with a Humanized Immune System. PLoS ONE, 7, e28626.

[46]   Bansal, P.J. and Tobin, M.C. (2004) Neonatal Microscopic Polyangiitis Secondary to Transfer of Maternal Myeloperoxidase-Antineutrophil Cytoplasmic Antibody Resulting in Neonatal Pulmonary Hemorrhage and Renal Involvement. Annals of Allergy, Asthma Immunology, 93, 398-401.

[47]   Ciavatta, D.J., Yang, J., Preston, G.A., Badhwar, A.K., Xiao, H., Hewins, P., Nester, C.M., Pendergraft 3rd, W.F., Magnuson, T.R., Jennette, J.C. and Falk, R.J. (2010) Epigenetic Basis for Aberrant Upregulation of Autoantigen Genes in Humans with ANCA Vasculitis. Journal of Clinical Investigation, 120, 3209-3219.

[48]   Tomasson, G., Grayson, P.C., Mahr, A.D., Lavalley, M. and Merkel, P.A. (2012) Value of ANCA Measurements during Remission to Predict a Relapse of ANCA-Associated Vasculitis—A Meta-Analysis. Rheumatology (Oxford), 51, 100-109.

[49]   Cartin-Ceba, R., Golbin, J.M., Keogh, K.A., Peikert, T., Sanchez-Menendez, M., Ytterberg, S.R., Fervenza, F.C. and Specks, U. (2012) Rituximab for Remission Induction and Maintenance in Refractory Granulomatosis with Polyangiitis (Wegener’s): Ten-Year Experience at a Single Center. Arthritis & Rheumatism, 64, 3770-3778.

[50]   Keogan, M.T., Esnault, V.L., Green, A.J., Lockwood, C.M. and Brown, D.L. (1992) Activation of Normal Neutrophils by Anti-Neutrophil Cytoplasm Antibodies. Clinical Experimental Immunology, 90, 228-234.

[51]   Preston, G.A. and Falk, R.J. (2001) ANCA Signaling: Not Just a Matter of Respiratory Burst. Kidney International, 59, 1981-1982.

[52]   Savage, C.O., Pottinger, B.E., Gaskin, G., Pusey, C.D. and Pearson, J.D. (1992) Autoantibodies Developing to Myeloperoxidase and Proteinase 3 in Systemic Vasculitis Stimulate Neutrophil Cytotoxicity toward Cultured Endothelial Cells. American Journal of Pathology, 141, 335-342.

[53]   Cui, Z., Zhao, M.H., Segelmark, M. and Hellmark, T. (2010) Natural Autoantibodies to Myeloperoxidase, Proteinase 3, and the Glomerular Basement Membrane Are Present in Normal Individuals. Kidney International, 78, 590-597.

[54]   Holle, J.U., Gross, W.L., Holl-Ulrich, K., Ambrosch, P., Noelle, B., Both, M., Csernok, E., Moosig, F., Schinke, S. and Reinhold-Keller, E. (2010) Prospective Long-Term Follow-Up of Patients with Localised Wegener’s Granulomatosis: Does It Occur as Persistent Disease Stage? Annals of the Rheumatic Diseases, 69, 1934-1939.

[55]   Roth, A.J., Ooi, J.D., Hess, J.J., van Timmeren, M.M., Berg, E.A., Poulton, C.E., McGregor, J., Burkart, M., Hogan, S.L., Hu, Y., Winnik, W., Nachman, P.H., Stegeman, C.A., Niles, J., Heeringa, P., Kitching, A.R., Holdsworth, S., Jennette, J.C., Preston, G.A. and Falk, R.J. (2013) Epitope Specificity Determines Pathogenicity and Detectability in ANCA-Associated Vasculitis. Journal of Clinical Investigation, 123, 1773-1783.

[56]   Mulder, A.H., Heeringa, P., Brouwer, E., Limburg, P.C. and Kallenberg, C.G. (1994) Activation of Granulocytes by Anti-Neutrophil Cytoplasmic Antibodies (ANCA): A Fc Gamma RII-Dependent Process. Clinical Experimental Immunology, 98, 270-278.

[57]   Witko-Sarsat, V., Lesavre, P., Lopez, S., Bessou, G., Hieblot, C., Prum, B., Noel, L.H., Guillevin, L., Ravaud, P., Sermet-Gaudelus, I., Timsit, J., Grunfeld, J.P. and Halbwachs-Mecarelli, L. (1999) A Large Subset of Neutrophils Expressing Membrane Proteinase 3 Is a Risk Factor for Vasculitis and Rheumatoid Arthritis. Journal of the American Society of Nephrology, 10, 1224-1233.

[58]   Schreiber, A., Busjahn, A., Luft, F.C. and Kettritz, R. (2003) Membrane Expression of Proteinase 3 Is Genetically Determined. Journal of the American Society of Nephrology, 14, 68-75.

[59]   Yang, J.J., Pendergraft, W.F., Alcorta, D.A., Nachman, P.H., Hogan, S.L., Thomas, R.P., Sullivan, P., Jennette, J.C., Falk, R.J. and Preston, G.A. (2004) Circumvention of Normal Constraints on Granule Protein Gene Expression in Peripheral Blood Neutrophils and Monocytes of Patients with Antineutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis. Journal of the American Society of Nephrology, 15, 2103-2114.

[60]   Cassatella, M.A. (2013) L33. Neutrophil in Immunity: A Key Modulator. La Presse Médicale, 42, 594-595.

[61]   Pelletier, M., Maggi, L., Micheletti, A., Lazzeri, E., Tamassia, N., Costantini, C., Cosmi, L., Lunardi, C., Annunziato, F., Romagnani, S. and Cassatella, M.A. (2010) Evidence for a Cross-Talk between Human Neutrophils and Th17 Cells. Blood, 115, 335-343.

[62]   Krumbholz, M., Specks, U., Wick, M., Kalled, S.L., Jenne, D. and Meinl, E. (2005) BAFF Is Elevated in Serum of Patients with Wegener’s Granulomatosis. Journal of Autoimmunity, 25, 298-302.

[63]   Holden, N.J., Williams, J.M., Morgan, M.D., Challa, A., Gordon, J., Pepper, R.J., Salama, A.D., Harper, L. and Savage, C.O.S. (2011) ANCA-Stimulated Neutrophils Release BLyS and Promote B Cell Survival: A Clinically Relevant Cellular Process. Annals of the Rheumatic Diseases, 70, 2229-2233.

[64]   Harper, L., Cockwell, P., Adu, D. and Savage, C.O. (2001) Neutrophil Priming and Apoptosis in Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis. Kidney International, 59, 1729-1738.

[65]   van Rossum, A.P., Limburg, P.C. and Kallenberg, C.G. (2005) Activation, Apoptosis, and Clearance of Neutrophils in Wegener’s Granulomatosis. Annals of the New York Academy of Sciences, 1051, 1-11.

[66]   Cabrini, M., Nahmod, K. and Geffner, J. (2010) New Insights into the Mechanisms Controlling Neutrophil Survival. Current Opinion in Hematology, 17, 31-35.

[67]   Lauber, K., Blumenthal, S.G., Waibel, M. and Wesselborg, S. (2004) Clearance of Apoptotic Cells: Getting Rid of the Corpses. Molecular Cell, 14, 277-287.

[68]   Harper, L., Ren, Y., Savill, J., Adu, D. and Savage, C.O. (2000) Antineutrophil Cytoplasmic Antibodies Induce Reactive Oxygen-Dependent Dysregulation of Primed Neutrophil Apoptosis and Clearance by Macrophages. American Journal of Pathology, 157, 211-220.

[69]   Fernandez-Boyanapalli, R., McPhillips, K.A., Frasch, S.C., Janssen, W.J., Dinauer, M.C., Riches, D.W., Henson, P.M., Byrne, A. and Bratton, D.L. (2010) Impaired Phagocytosis of Apoptotic Cells by Macrophages in Chronic Granulomatous Disease Is Reversed by IFN-Gamma in a Nitric Oxide-Dependent Manner. The Journal of Immunology, 185, 4030-4041.

[70]   Gilligan, H.M., Bredy, B., Brady, H.R., Hebert, M.J., Slayter, H.S., Xu, Y., Rauch, J., Shia, M.A., Koh, J.S. and Levine, J.S. (1996) Antineutrophil Cytoplasmic Autoantibodies Interact with Primary Granule Constituents on the Surface of Apoptotic Neutrophils in the Absence of Neutrophil Priming. The Journal of Experimental Medicine, 184, 2231-2241.

[71]   Moosig, F., Csernok, E., Kumanovics, G. and Gross, W.L. (2000) Opsonization of Apoptotic Neutrophils by Anti-Neutrophil Cytoplasmic Antibodies (ANCA) Leads to Enhanced Uptake by Macrophages and Increased Release of Tumour Necrosis Factor-Alpha (TNF-Alpha). Clinical Experimental Immunology, 122, 499-503.

[72]   Csernok, E., Moosig, F. and Gross, W.L. (2008) Pathways to ANCA Production: From Differentiation of Dendritic Cells by Proteinase 3 to B Lymphocyte Maturation in Wegener’s Granuloma. Clinical Reviews in Allergy Immunology, 34, 300-306.

[73]   Deutsch, M., Guejes, L., Zurgil, N., Shovman, O., Gilburd, B., Afrimzon, E. and Shoenfeld, Y. (2004) Antineutrophil Cytoplasmic Autoantibodies Penetrate into Human Polymorphonuclear Leukocytes and Modify Their Apoptosis. Clinical and Experimental Rheumatology, 22, S35-S40.

[74]   Hsieh, S.C., Yu, H.S., Cheng, S.H., Li, K.J., Lu, M.C., Wu, C.H., Tsai, C.Y. and Yu, C.L. (2007) Anti-Myeloperoxidase Antibodies Enhance Phagocytosis, IL-8 Production, and Glucose Uptake of Polymorphonuclear Neutrophils Rather than Anti-Proteinase 3 Antibodies Leading to Activation-Induced Cell Death of the Neutrophils. Clinical Rheumatology, 26, 216-224.

[75]   Patry, Y.C., Trewick, D.C., Gregoire, M., Audrain, M.A., Moreau, A.M., Muller, J.Y., Meflah, K. and Esnault, V.L. (2001) Rats Injected with Syngenic Rat Apoptotic Neutrophils Develop Antineutrophil Cytoplasmic Antibodies. Journal of the American Society of Nephrology, 12, 1764-1768.

[76]   Rauova, L., Gilburd, B., Zurgil, N., Blank, M., Guegas, L.L., Brickman, C.M., Cebecauer, L., Deutsch, M., Wiik, A. and Shoenfeld, Y. (2002) Induction of Biologically Active Antineutrophil Cytoplasmic Antibodies by Immunization with Human Apoptotic Polymorphonuclear Leukocytes. Clinical Immunology, 103, 69-78.

[77]   Fuchs, T.A., Abed, U., Goosmann, C., Hurwitz, R., Schulze, I., Wahn, V., Weinrauch, Y., Brinkmann, V. and Zychlinsky, A. (2007) Novel Cell Death Program Leads to Neutrophil Extracellular Traps. The Journal of Cell Biology, 176, 231-241.

[78]   Lande, R., Gregorio, J., Facchinetti, V., Chatterjee, B., Wang, Y.H., Homey, B., Cao, W., Su, B., Nestle, F.O., Zal, T., Mellman, I., Schroder, J.M., Liu, Y.J. and Gilliet, M. (2007) Plasmacytoid Dendritic Cells Sense Self-DNA Coupled with Antimicrobial Peptide. Nature, 449, 564-569.

[79]   Kessenbrock, K., Krumbholz, M., Schonermarck, U., Back, W., Gross, W.L., Werb, Z., Grone, H.J., Brinkmann, V. and Jenne, D.E. (2009) Netting Neutrophils in Autoimmune Small-Vessel Vasculitis. Nature Medicine, 15, 623-625.

[80]   Halbwachs, L. and Lesavre, P. (2012) Endothelium-Neutrophil Interactions in ANCA-Associated Diseases. Journal of the American Society of Nephrology, 23, 1449-1461.

[81]   Hu, N., Westra, J. and Kallenberg, C.G. (2011) Dysregulated Neutrophil—Endothelial Interaction in Antineutrophil Cytoplasmic Autoantibody (ANCA)-Associated Vasculitides: Implications for Pathogenesis and Disease Intervention. Autoimmunity Reviews, 10, 536-543.

[82]   Johnson-Leger, C., Aurrand-Lions, M. and Imhof, B.A. (2000) The Parting of the Endothelium: Miracle, or Simply a Junctional Affair? Journal of Cell Science, 113, 921-933.

[83]   Zeng, M., Zhang, H., Lowell, C. and He, P. (2002) Tumor Necrosis Factor-Alpha-Induced Leukocyte Adhesion and Microvessel Permeability. American Journal of Physiology-Heart and Circulatory Physiology, 283, H2420-H2430.

[84]   Carvalho-Tavares, J., Hickey, M.J., Hutchison, J., Michaud, J., Sutcliffe, I.T. and Kubes, P. (2000) A Role for Platelets and Endothelial Selectins in Tumor Necrosis Factor-Alpha-Induced Leukocyte Recruitment in the Brain Microvasculature. Circulation Research, 87, 1141-1148.

[85]   Radford, D.J., Savage, C.O. and Nash, G.B. (2000) Treatment of Rolling Neutrophils with Antineutrophil Cytoplasmic Antibodies Causes Conversion to Firm Integrin-Mediated Adhesion. Arthritis Rheumatology, 43, 1337-1345.<1337::AID-ANR16>3.0.CO;2-M

[86]   Radford, D.J., Luu, N.T., Hewins, P., Nash, G.B. and Savage, C.O. (2001) Antineutrophil Cytoplasmic Antibodies Stabilize Adhesion and Promote Migration of Flowing Neutrophils on endothelial Cells. Arthritis Rheumatology, 44, 2851-2861.<2851::AID-ART473>3.0.CO;2-2

[87]   Calderwood, J.W., Williams, J.M., Morgan, M.D., Nash, G.B. and Savage, C.O. (2005) ANCA Induces Beta2 Integrin and CXC Chemokine-Dependent Neutrophil-Endothelial Cell Interactions That Mimic Those of Highly Cytokine-Activated Endothelium. Journal of Leukocyte Biology, 77, 33-43.

[88]   Haller, H., Eichhorn, J., Pieper, K., Gobel, U. and Luft, F.C. (1996) Circulating Leukocyte Integrin Expression in Wegener’s Granulomatosis. Journal of the American Society of Nephrology, 7, 40-48.

[89]   Arrizabalaga, P., Sole, M., Iglesias, C., Escaramis, G. and Ascaso, C. (2006) Renal Expression of ICAM-1 and VCAM-1 in ANCA-Associated Glomerulonephritis—Are There Differences among Serologic Subgroups? Clinical Nephrology, 65, 79-86.

[90]   Cockwell, P., Brooks, C.J., Adu, D. and Savage, C.O. (1999) Interleukin-8: A Pathogenetic Role in Antineutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis. Kidney International, 55, 852-863.

[91]   Brachemi, S., Mambole, A., Fakhouri, F., Mouthon, L., Guillevin, L., Lesavre, P. and Halbwachs-Mecarelli, L. (2007) Increased Membrane Expression of Proteinase 3 during Neutrophil Adhesion in the Presence of Anti Proteinase 3 Antibodies. Journal of the American Society of Nephrology, 18, 2330-2339.

[92]   Porges, A.J., Redecha, P.B., Kimberly, W.T., Csernok, E., Gross, W.L. and Kimberly, R.P. (1994) Anti-Neutrophil Cytoplasmic Antibodies Engage and Activate Human Neutrophils via Fc Gamma RIIa. The Journal of Immunology, 153, 1271-1280.

[93]   Reumaux, D., Vossebeld, P.J., Roos, D. and Verhoeven, A.J. (1995) Effect of Tumor Necrosis Factor-Induced Integrin Activation on Fc Gamma Receptor II-Mediated Signal Transduction: Relevance for Activation of Neutrophils by Anti-Proteinase 3 or Anti-Myeloperoxidase Antibodies. Blood, 86, 3189-3195.

[94]   Schreiber, A., Luft, F.C. and Kettritz, R. (2004) Membrane Proteinase 3 Expression and ANCA-Induced Neutrophil Activation. Kidney International, 65, 2172-2183.

[95]   Jerke, U., Rolle, S., Dittmar, G., Bayat, B., Santoso, S., Sporbert, A., Luft, F. and Kettritz, R. (2011) Complement Receptor Mac-1 Is an Adaptor for NB1 (CD177)-Mediated PR3-ANCA Neutrophil Activation. The Journal of Biological Chemistry, 286, 7070-7081.

[96]   Bayat, B., Werth, S., Sachs, U.J., Newman, D.K., Newman, P.J. and Santoso, S. (2010) Neutrophil Transmigration Mediated by the Neutrophil-Specific Antigen CD177 Is Influenced by the Endothelial S536N Dimorphism of Platelet Endothelial Cell Adhesion Molecule-1. The Journal of Immunology, 184, 3889-3896.

[97]   McDonald, D.M. (1994) Endothelial Gaps and Permeability of Venules in Rat Tracheas Exposed to Inflammatory Stimuli. American Journal of Physiology, 266, L61-L83.

[98]   Valeski, J.E. and Baldwin, A.L. (1999) Effect of Early Transient Adherent Leukocytes on Venular Permeability and Endothelial Actin Cytoskeleton. American Journal of Physiology, 277, H569-H575.

[99]   DiStasi, M.R. and Ley, K. (2009) Opening the Flood-Gates: How Neutrophil-Endothelial Interactions Regulate Permeability. Trends in Immunology, 30, 547-556.

[100]   Berden, A.E., Ferrario, F., Hagen, E.C., Jayne, D.R., Jennette, J.C., Joh, K., Neumann, I., Noel, L.H., Pusey, C.D., Waldherr, R., Bruijn, J.A. and Bajema, I.M. (2010) Histopathologic Classification of ANCA-Associated Glomerulonephritis. Journal of the American Society of Nephrology, 21, 1628-1636.

[101]   Falk, R.J., Terrell, R.S., Charles, L.A. and Jennette, J.C. (1990) Anti-Neutrophil Cytoplasmic Autoantibodies Induce Neutrophils to Degranulate and Produce Oxygen Radicals in Vitro. Proceedings of the National Academy of Sciences of the United States of America, 87, 4115-4119.

[102]   Westlin, W.F. and Gimbrone Jr., M.A. (1993) Neutrophil-Mediated Damage to Human Vascular Endothelium. Role of Cytokine Activation. American Journal of Pathology, 142, 117-128.

[103]   Yang, J.J., Kettritz, R., Falk, R.J., Jennette, J.C. and Gaido, M.L. (1996) Apoptosis of Endothelial Cells Induced by the Neutrophil Serine Proteases Proteinase 3 and Elastase. American Journal of Pathology, 149, 1617-1626.

[104]   Preston, G.A., Zarella, C.S., Pendergraft 3rd, W.F., Rudolph, E.H., Yang, J.J., Sekura, S.B., Jennette, J.C. and Falk, R.J. (2002) Novel Effects of Neutrophil-Derived Proteinase 3 and Elastase on the Vascular Endothelium Involve in Vivo Cleavage of NF-Kappab and Proapoptotic Changes in JNK, ERK, and p38 MAPK Signaling Pathways. Journal of the American Society of Nephrology, 13, 2840-2849.

[105]   Pendergraft 3rd, W.F., Rudolph, E.H., Falk, R.J., Jahn, J.E., Grimmler, M., Hengst, L., Jennette, J.C. and Preston, G.A. (2004) Proteinase 3 Sidesteps Caspases and Cleaves p21Waf1/Cip1/Sdi1 to Induce Endothelial Cell Apoptosis. Kidney International, 65, 75-84.

[106]   Rahman, A. and Fazal, F. (2009) Hug Tightly and Say Goodbye: Role of Endothelial ICAM-1 in Leukocyte Transmigration. Antioxidants Redox Signaling, 11, 823-839.

[107]   Woywodt, A., Streiber, F., de Groot, K., Regelsberger, H., Haller, H. and Haubitz, M. (2003) Circulating Endothelial Cells as Markers for ANCA-Associated Small-Vessel Vasculitis. The Lancet, 361, 206-210.

[108]   Tadema, H., Abdulahad, W.H., Lepse, N., Stegeman, C.A., Kallenberg, C.G. and Heeringa, P. (2011) Bacterial DNA Motifs Trigger ANCA Production in ANCA-Associated Vasculitis in Remission. Rheumatology (Oxford), 50, 689-696.

[109]   Stegeman, C.A., Tervaert, J.W., Sluiter, W.J., Manson, W.L., de Jong, P.E. and Kallenberg, C.G. (1994) Association of Chronic Nasal Carriage of Staphylococcus aureus and Higher Relapse Rates in Wegener Granulomatosis. Annals of Internal Medicine, 120, 12-17.

[110]   Pendergraft 3rd, W.F., Preston, G.A., Shah, R.R., Tropsha, A., Carter Jr., C.W., Jennette, J.C. and Falk, R.J. (2004) Autoimmunity Is Triggered by cPR-3(105-201), a Protein Complementary to Human Autoantigen Proteinase-3. Nature Medicine, 10, 72-79.

[111]   Tadema, H., Kallenberg, C.G., Stegeman, C.A. and Heeringa, P. (2011) Reactivity against Complementary Proteinase-3 Is Not Increased in Patients with PR3-ANCA-Associated Vasculitis. PLoS ONE, 6, e17972.

[112]   Hogan, S.L., Cooper, G.S., Savitz, D.A., Nylander-French, L.A., Parks, C.G., Chin, H., Jennette, C.E., Lionaki, S., Jennette, J.C. and Falk, R.J. (2007) Association of Silica Exposure with Anti-Neutrophil Cytoplasmic Autoantibody Small-Vessel Vasculitis: A Population-Based, Case-Control Study. Clinical Journal of the American Society of Nephrology, 2, 290-299.

[113]   Hogan, S.L., Satterly, K.K., Dooley, M.A., Nachman, P.H., Jennette, J.C. and Falk, R.J. (2001) Silica Exposure in Anti-Neutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis and Lupus Nephritis. Journal of the American Society of Nephrology, 12, 134-142.

[114]   Kallenberg, C.G. (1995) Overlapping Syndromes, Undifferentiated Connective Tissue Disease, and Other Fibrosing Conditions. Current Opinion in Rheumatology, 7, 568-573.

[115]   Leigh, J., Wang, H., Bonin, A., Peters, M. and Ruan, X. (1997) Silica-Induced Apoptosis in Alveolar and Granulomatous Cells in Vivo. Environmental Health Perspectives, 105, 1241-1245.

[116]   Chen, M. and Kallenberg, C.G.M. (2010) The Environment, Geoepidemiology and ANCA-Associated Vasculitides. Autoimmunity Reviews, 9, A293-A298.