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. 1995 Oct;102(1):120–130. doi: 10.1111/j.1365-2249.1995.tb06645.x

Immunization with anti-neutrophil cytoplasmic antibody (ANCA) induces the production of mouse ANCA and perivascular lymphocyte infiltration.

M Blank 1, Y Tomer 1, M Stein 1, J Kopolovic 1, A Wiik 1, P L Meroni 1, G Conforti 1, Y Shoenfeld 1
PMCID: PMC1553333  PMID: 7554378

Abstract

Wegener's granulomatosis (WG) is a granulomatous necrotizing vasculitis associated with the presence of ANCA, predominantly directed against proteinase 3 (PR3). The titres of ANCA correlate with disease activity and titre increases may precede disease exacerbations. Previously, we have shown that it is possible to induce autoimmune disease (systemic lupus erythematosus (SLE) and anti-phospholipid syndrome) in naive mice following active immunization with human autoantibodies, namely anti-DNA and anti-cardiolipin, respectively. The mice developed first anti-autoantibodies and, after about 4 months anti-anti-autoantibodies (Ab3), simulating auto-antibodies (Ab1) in their binding activities, and their presence was associated with the development of disease manifestations, characteristic of the human disease. So far, there is no good animal model for WG. In the current study we have immunized mice with human ANCA with the aim of inducing experimental WG. In two separate studies 30 mice were immunized in their footpads with autoantigen-purified IgG fraction (ANCA) from the sera of two patients with untreated WG, emulsified in Freund's complete adjuvant, followed 3 weeks later by ANCA injection in PBS. In the first experiment mice immunized with ANCA developed sterile microabscesses in the lungs after 8 months, and died after 8-15 months. In the second experiment, mice immunized with ANCA developed after 4 months mouse ANCA, with specificity both to PR3 and to myeloperoxidase, as well as anti-endothelial autoantibodies (AECA), as shown by radioimmunoprecipitation. Pathologically, the immunized mice developed proteinuria but not haematuria, and histological sections of the lungs demonstrated mononuclear perivascular infiltration, while diffuse granular deposition of immunoglobulins was noted in the kidneys. Our results point to a pathogenic role of ANCA in WG, and confirm the importance of the idiotypic network in the etiopathogenesis of autoimmune conditions.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bakimer R., Fishman P., Blank M., Sredni B., Djaldetti M., Shoenfeld Y. Induction of primary antiphospholipid syndrome in mice by immunization with a human monoclonal anticardiolipin antibody (H-3). J Clin Invest. 1992 May;89(5):1558–1563. doi: 10.1172/JCI115749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bakimer R., Guilburd B., Zurgil N., Shoenfeld Y. The effect of intravenous gamma-globulin on the induction of experimental antiphospholipid syndrome. Clin Immunol Immunopathol. 1993 Oct;69(1):97–102. doi: 10.1006/clin.1993.1155. [DOI] [PubMed] [Google Scholar]
  3. Blank M., Ben-Bassat M., Shoenfeld Y. The effect of cyclosporin A on early and late stages of experimental lupus. Arthritis Rheum. 1992 Nov;35(11):1350–1355. doi: 10.1002/art.1780351116. [DOI] [PubMed] [Google Scholar]
  4. Blank M., Cohen J., Toder V., Shoenfeld Y. Induction of anti-phospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3069–3073. doi: 10.1073/pnas.88.8.3069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blank M., Krup M., Mendlovic S., Fricke H., Mozes E., Talal N., Coates A. R., Shoenfeld Y. The importance of the pathogenic 16/6 idiotype in the induction of SLE in naive mice. Scand J Immunol. 1990 Jan;31(1):45–52. doi: 10.1111/j.1365-3083.1990.tb02741.x. [DOI] [PubMed] [Google Scholar]
  6. Borregaard N., Heiple J. M., Simons E. R., Clark R. A. Subcellular localization of the b-cytochrome component of the human neutrophil microbicidal oxidase: translocation during activation. J Cell Biol. 1983 Jul;97(1):52–61. doi: 10.1083/jcb.97.1.52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brasile L., Kremer J. M., Clarke J. L., Cerilli J. Identification of an autoantibody to vascular endothelial cell-specific antigens in patients with systemic vasculitis. Am J Med. 1989 Jul;87(1):74–80. doi: 10.1016/s0002-9343(89)80486-3. [DOI] [PubMed] [Google Scholar]
  8. Brouwer E., Huitema M. G., Klok P. A., de Weerd H., Tervaert J. W., Weening J. J., Kallenberg C. G. Antimyeloperoxidase-associated proliferative glomerulonephritis: an animal model. J Exp Med. 1993 Apr 1;177(4):905–914. doi: 10.1084/jem.177.4.905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Carrington C. B., Liebow A. Limited forms of angiitis and granulomatosis of Wegener's type. Am J Med. 1966 Oct;41(4):497–527. doi: 10.1016/0002-9343(66)90214-2. [DOI] [PubMed] [Google Scholar]
  10. Cines D. B., Lyss A. P., Reeber M., Bina M., DeHoratius R. J. Presence of complement-fixing anti-endothelial cell antibodies in systemic lupus erythematosus. J Clin Invest. 1984 Mar;73(3):611–625. doi: 10.1172/JCI111251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Conforti G., Dominguez-Jimenez C., Zanetti A., Gimbrone M. A., Jr, Cremona O., Marchisio P. C., Dejana E. Human endothelial cells express integrin receptors on the luminal aspect of their membrane. Blood. 1992 Jul 15;80(2):437–446. [PubMed] [Google Scholar]
  12. D'Cruz D. P., Houssiau F. A., Ramirez G., Baguley E., McCutcheon J., Vianna J., Haga H. J., Swana G. T., Khamashta M. A., Taylor J. C. Antibodies to endothelial cells in systemic lupus erythematosus: a potential marker for nephritis and vasculitis. Clin Exp Immunol. 1991 Aug;85(2):254–261. doi: 10.1111/j.1365-2249.1991.tb05714.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. DeRemee R. A. The treatment of Wegener's granulomatosis with trimethoprim/sulfamethoxazole: illusion or vision? Arthritis Rheum. 1988 Aug;31(8):1068–1074. doi: 10.1002/art.1780310821. [DOI] [PubMed] [Google Scholar]
  14. Del Papa N., Meroni P. L., Tincani A., Harris E. N., Pierangeli S. S., Barcellini W., Borghi M. O., Balestrieri G., Zanussi C. Relationship between anti-phospholipid and anti-endothelial cell antibodies: further characterization of the reactivity on resting and cytokine-activated endothelial cells. Clin Exp Rheumatol. 1992 Jan-Feb;10(1):37–42. [PubMed] [Google Scholar]
  15. Efthimiou J., Spickett G., Lane D., Thompson A. Antineutrophil cytoplasmic antibodies, cystic fibrosis, and infection. Lancet. 1991 Apr 27;337(8748):1037–1038. doi: 10.1016/0140-6736(91)92694-w. [DOI] [PubMed] [Google Scholar]
  16. Egner W., Chapel H. M. Titration of antibodies against neutrophil cytoplasmic antigens is useful in monitoring disease activity in systemic vasculitides. Clin Exp Immunol. 1990 Nov;82(2):244–249. doi: 10.1111/j.1365-2249.1990.tb05434.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Falk R. J., Terrell R. S., Charles L. A., Jennette J. C. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4115–4119. doi: 10.1073/pnas.87.11.4115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fauci A. S., Haynes B. F., Katz P., Wolff S. M. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med. 1983 Jan;98(1):76–85. doi: 10.7326/0003-4819-98-1-76. [DOI] [PubMed] [Google Scholar]
  19. Fishman P., Bakimer R., Blank M., Sredni D., Djaldetti M., Shoenfeld Y. The putative role of cytokines in the induction of primary anti-phospholipid syndrome in mice. Clin Exp Immunol. 1992 Nov;90(2):266–270. doi: 10.1111/j.1365-2249.1992.tb07940.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Frampton G., Jayne D. R., Perry G. J., Lockwood C. M., Cameron J. S. Autoantibodies to endothelial cells and neutrophil cytoplasmic antigens in systemic vasculitis. Clin Exp Immunol. 1990 Nov;82(2):227–232. doi: 10.1111/j.1365-2249.1990.tb05431.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gabay J. E., Scott R. W., Campanelli D., Griffith J., Wilde C., Marra M. N., Seeger M., Nathan C. F. Antibiotic proteins of human polymorphonuclear leukocytes. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5610–5614. doi: 10.1073/pnas.86.14.5610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Goldschmeding R., van der Schoot C. E., ten Bokkel Huinink D., Hack C. E., van den Ende M. E., Kallenberg C. G., von dem Borne A. E. Wegener's granulomatosis autoantibodies identify a novel diisopropylfluorophosphate-binding protein in the lysosomes of normal human neutrophils. J Clin Invest. 1989 Nov;84(5):1577–1587. doi: 10.1172/JCI114335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hay E. M., Beaman M., Ralston A. J., Ackrill P., Bernstein R. M., Holt P. J. Wegener's granulomatosis occurring in siblings. Br J Rheumatol. 1991 Apr;30(2):144–145. doi: 10.1093/rheumatology/30.2.144. [DOI] [PubMed] [Google Scholar]
  24. Hoffman G. S., Kerr G. S., Leavitt R. Y., Hallahan C. W., Lebovics R. S., Travis W. D., Rottem M., Fauci A. S. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992 Mar 15;116(6):488–498. doi: 10.7326/0003-4819-116-6-488. [DOI] [PubMed] [Google Scholar]
  25. Jayne D. R., Esnault V. L., Lockwood C. M. ANCA anti-idiotype antibodies and the treatment of systemic vasculitis with intravenous immunoglobulin. J Autoimmun. 1993 Apr;6(2):207–219. doi: 10.1006/jaut.1993.1018. [DOI] [PubMed] [Google Scholar]
  26. Kallenberg C. G., Tervaert J. W., van der Woude F. J., Goldschmeding R., von dem Borne A. E., Weening J. J. Autoimmunity to lysosomal enzymes: new clues to vasculitis and glomerulonephritis? Immunol Today. 1991 Feb;12(2):61–64. doi: 10.1016/0167-5699(91)90159-q. [DOI] [PubMed] [Google Scholar]
  27. 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 R. W., Jr The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum. 1990 Aug;33(8):1101–1107. doi: 10.1002/art.1780330807. [DOI] [PubMed] [Google Scholar]
  28. Lüdemann J., Utecht B., Gross W. L. Anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis recognize an elastinolytic enzyme. J Exp Med. 1990 Jan 1;171(1):357–362. doi: 10.1084/jem.171.1.357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lüdemann J., Utecht B., Gross W. L. Detection and quantitation of anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis by ELISA using affinity-purified antigen. J Immunol Methods. 1988 Nov 10;114(1-2):167–174. doi: 10.1016/0022-1759(88)90169-x. [DOI] [PubMed] [Google Scholar]
  30. Mendlovic S., Brocke S., Fricke H., Shoenfeld Y., Bakimer R., Mozes E. The genetic regulation of the induction of experimental SLE. Immunology. 1990 Feb;69(2):228–236. [PMC free article] [PubMed] [Google Scholar]
  31. Mendlovic S., Brocke S., Shoenfeld Y., Ben-Bassat M., Meshorer A., Bakimer R., Mozes E. Induction of a systemic lupus erythematosus-like disease in mice by a common human anti-DNA idiotype. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2260–2264. doi: 10.1073/pnas.85.7.2260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mozes E., Kohn L. D., Hakim F., Singer D. S. Resistance of MHC class I-deficient mice to experimental systemic lupus erythematosus. Science. 1993 Jul 2;261(5117):91–93. doi: 10.1126/science.8316860. [DOI] [PubMed] [Google Scholar]
  33. Muller W. A., Gimbrone M. A., Jr Plasmalemmal proteins of cultured vascular endothelial cells exhibit apical-basal polarity: analysis by surface-selective iodination. J Cell Biol. 1986 Dec;103(6 Pt 1):2389–2402. doi: 10.1083/jcb.103.6.2389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Murty G. E., Mains B. T., Middleton D., Maxwell A. P., Savage D. A. HLA antigen frequencies and Wegener's granulomatosis. Clin Otolaryngol Allied Sci. 1991 Oct;16(5):448–451. doi: 10.1111/j.1365-2273.1991.tb01037.x. [DOI] [PubMed] [Google Scholar]
  35. Naparstek Y., Duggan D., Schattner A., Madaio M. P., Goni F., Frangione B., Stollar B. D., Kabat E. A., Schwartz R. S. Immunochemical similarities between monoclonal antibacterial Waldenstrom's macroglobulins and monoclonal anti-DNA lupus autoantibodies. J Exp Med. 1985 Jun 1;161(6):1525–1538. doi: 10.1084/jem.161.6.1525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Niles J. L., McCluskey R. T., Ahmad M. F., Arnaout M. A. Wegener's granulomatosis autoantigen is a novel neutrophil serine proteinase. Blood. 1989 Nov 1;74(6):1888–1893. [PubMed] [Google Scholar]
  37. Nölle B., Specks U., Lüdemann J., Rohrbach M. S., DeRemee R. A., Gross W. L. Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener granulomatosis. Ann Intern Med. 1989 Jul 1;111(1):28–40. doi: 10.7326/0003-4819-111-1-28. [DOI] [PubMed] [Google Scholar]
  38. Penning C. A., Cunningham J., French M. A., Harrison G., Rowell N. R., Hughes P. Antibody-dependent cellular cytotoxicity of human vascular endothelium in systemic sclerosis. Clin Exp Immunol. 1984 Sep;57(3):548–556. [PMC free article] [PubMed] [Google Scholar]
  39. Pinching A. J., Rees A. J., Pussell B. A., Lockwood C. M., Mitchison R. S., Peters D. K. Relapses in Wegener's granulomatosis: the role of infection. Br Med J. 1980 Sep 27;281(6244):836–838. doi: 10.1136/bmj.281.6244.836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Rasmussen N., Wiik A. Indirect immunofluorescence examination for IgG-ANCA in sera submitted for the 1st international workshop on ANCA, 1988. APMIS Suppl. 1989;6:16–20. [PubMed] [Google Scholar]
  41. Rosenbaum J., Pottinger B. E., Woo P., Black C. M., Loizou S., Byron M. A., Pearson J. D. Measurement and characterisation of circulating anti-endothelial cell IgG in connective tissue diseases. Clin Exp Immunol. 1988 Jun;72(3):450–456. [PMC free article] [PubMed] [Google Scholar]
  42. Saeki Y., Mima T., Sakoda S., Fujimura H., Arita N., Nomura T., Kishimoto T. Transfer of multiple sclerosis into severe combined immunodeficiency mice by mononuclear cells from cerebrospinal fluid of the patients. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6157–6161. doi: 10.1073/pnas.89.13.6157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Savage C. O., Cooke S. P. The role of the endothelium in systemic vasculitis. J Autoimmun. 1993 Apr;6(2):237–249. doi: 10.1006/jaut.1993.1021. [DOI] [PubMed] [Google Scholar]
  44. Savage C. O., Pottinger B. E., Gaskin G., Lockwood C. M., Pusey C. D., Pearson J. D. Vascular damage in Wegener's granulomatosis and microscopic polyarteritis: presence of anti-endothelial cell antibodies and their relation to anti-neutrophil cytoplasm antibodies. Clin Exp Immunol. 1991 Jul;85(1):14–19. doi: 10.1111/j.1365-2249.1991.tb05675.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Savage C. O., Pottinger B. E., Gaskin G., Lockwood C. M., Pusey C. D., Pearson J. D. Vascular damage in Wegener's granulomatosis and microscopic polyarteritis: presence of anti-endothelial cell antibodies and their relation to anti-neutrophil cytoplasm antibodies. Clin Exp Immunol. 1991 Jul;85(1):14–19. doi: 10.1111/j.1365-2249.1991.tb05675.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Schmitt W. H., Csernok E., Gross W. L. ANCA and infection. Lancet. 1991 Jun 8;337(8754):1416–1417. doi: 10.1016/0140-6736(91)93102-f. [DOI] [PubMed] [Google Scholar]
  47. Sela O., el-Roeiy A., Isenberg D. A., Kennedy R. C., Colaco C. B., Pinkhas J., Shoenfeld Y. A common anti-DNA idiotype in sera of patients with active pulmonary tuberculosis. Arthritis Rheum. 1987 Jan;30(1):50–56. doi: 10.1002/art.1780300107. [DOI] [PubMed] [Google Scholar]
  48. Shoenfeld Y. Idiotypic induction of autoimmunity: a new aspect of the idiotypic network. FASEB J. 1994 Dec;8(15):1296–1301. doi: 10.1096/fasebj.8.15.8001742. [DOI] [PubMed] [Google Scholar]
  49. Shoenfeld Y., Mozes E. Pathogenic idiotypes of autoantibodies in autoimmunity: lessons from new experimental models of SLE. FASEB J. 1990 Jun;4(9):2646–2651. doi: 10.1096/fasebj.4.9.2140806. [DOI] [PubMed] [Google Scholar]
  50. Shoenfeld Y., Rauch J., Massicotte H., Datta S. K., André-Schwartz J., Stollar B. D., Schwartz R. S. Polyspecificity of monoclonal lupus autoantibodies produced by human-human hybridomas. N Engl J Med. 1983 Feb 24;308(8):414–420. doi: 10.1056/NEJM198302243080802. [DOI] [PubMed] [Google Scholar]
  51. Tervaert J. W., Huitema M. G., Hené R. J., Sluiter W. J., The T. H., van der Hem G. K., Kallenberg C. G. Prevention of relapses in Wegener's granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre. Lancet. 1990 Sep 22;336(8717):709–711. doi: 10.1016/0140-6736(90)92205-v. [DOI] [PubMed] [Google Scholar]
  52. Tervaert J. W., van der Woude F. J., Fauci A. S., Ambrus J. L., Velosa J., Keane W. F., Meijer S., van der Giessen M., van der Hem G. K., The T. H. Association between active Wegener's granulomatosis and anticytoplasmic antibodies. Arch Intern Med. 1989 Nov;149(11):2461–2465. doi: 10.1001/archinte.149.11.2461. [DOI] [PubMed] [Google Scholar]
  53. Tomer Y., Davies T. F. Infection, thyroid disease, and autoimmunity. Endocr Rev. 1993 Feb;14(1):107–120. doi: 10.1210/edrv-14-1-107. [DOI] [PubMed] [Google Scholar]
  54. Tomer Y., Mendlovic S., Kukulansky T., Mozes E., Shoenfeld Y., Globerson A. Effects of aging on the induction of experimental systemic lupus erythematosus (SLE) in mice. Mech Ageing Dev. 1991 May;58(2-3):233–244. doi: 10.1016/0047-6374(91)90095-h. [DOI] [PubMed] [Google Scholar]
  55. Vismara A., Meroni P. L., Tincani A., Harris E. N., Barcellini W., Brucato A., Khamashta M., Hughes G. R., Zanussi C., Balestrieri G. Relationship between anti-cardiolipin and anti-endothelial cell antibodies in systemic lupus erythematosus. Clin Exp Immunol. 1988 Nov;74(2):247–253. [PMC free article] [PubMed] [Google Scholar]
  56. Wiik A. Delineation of a standard procedure for indirect immunofluorescence detection of ANCA. APMIS Suppl. 1989;6:12–13. [PubMed] [Google Scholar]
  57. Wiik A., van der Woude F. J. The new ACPA/ANCA nomenclature. Neth J Med. 1990 Apr;36(3-4):107–108. [PubMed] [Google Scholar]
  58. del Papa N., Meroni P. L., Barcellini W., Sinico A., Radice A., Tincani A., D'Cruz D., Nicoletti F., Borghi M. O., Khamashta M. A. Antibodies to endothelial cells in primary vasculitides mediate in vitro endothelial cytotoxicity in the presence of normal peripheral blood mononuclear cells. Clin Immunol Immunopathol. 1992 Jun;63(3):267–274. doi: 10.1016/0090-1229(92)90232-d. [DOI] [PubMed] [Google Scholar]
  59. el-Roiey A., Sela O., Isenberg D. A., Feldman R., Colaco B. C., Kennedy R. C., Shoenfeld Y. The sera of patients with Klebsiella infections contain a common anti-DNA idiotype (16/6) Id and anti-polynucleotide activity. Clin Exp Immunol. 1987 Mar;67(3):507–515. [PMC free article] [PubMed] [Google Scholar]
  60. 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., The T. H. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet. 1985 Feb 23;1(8426):425–429. doi: 10.1016/s0140-6736(85)91147-x. [DOI] [PubMed] [Google Scholar]

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