Skip to main content
NCBI home page
Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1991 Jul;85(1):14–19. doi: 10.1111/j.1365-2249.1991.tb05675.x

Vascular damage in Wegener's granulomatosis and microscopic polyarteritis: presence of anti-endothelial cell antibodies and their relation to anti-neutrophil cytoplasm antibodies.

C O Savage 1, B E Pottinger 1, G Gaskin 1, C M Lockwood 1, C D Pusey 1, J D Pearson 1
PMCID: PMC1535720  PMID: 2070557

Abstract

To define mechanisms of vascular injury in Wegener's granulomatosis and microscopic polyarteritis, anti-endothelial cell antibodies (AECA) were sought in serum from 168 patients, all of whom had anti-neutrophil cytoplasm antibodies (ANCA) detectable by indirect immunofluorescence. Using an ELISA with human umbilical vein endothelial cells (HUVEC), IgG AECA were demonstrated in 59% and IgM AECA in 68% of patients. Pretreatment of HUVEC with tumour necrosis factor (TNF), IL-1 or interferon-gamma (IFN-gamma) led to increased binding. Adsorption of AECA/ANCA-containing serum with HUVEC or neutrophils demonstrated that AECA and ANCA recognized different targets. von Willebrand factor (vWf) antigen levels in the patient samples were markedly elevated, with a mean of 3.10 +/- 1.89 U/ml (control population mean 1.04 +/- 0.36 U/ml), suggesting widespread endothelial cell damage. Studies using an 111In-labelled HUVEC release assay with 29 AECA-containing sera did not demonstrate complement-mediated cytotoxicity, even following activation of HUVEC with TNF. Four out of 16 AECA-containing sera tested showed antibody-dependent cellular cytotoxicity with unfractionated peripheral blood mononuclear cells. These data suggest that patients with Wegener's granulomatosis or microscopic polyarteritis can develop AECA to constitutively expressed but cytokine modulated determinants on HUVEC. These antibodies do not appear to support complement-mediated cytotoxicity, but a proportion can support antibody-dependent cellular cytotoxicity, suggesting that they may contribute to vascular injury.

Full text

PDF
14

Selected References

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

  1. Belch J. J., Zoma A. A., Richards I. M., McLaughlin K., Forbes C. D., Sturrock R. D. Vascular damage and factor-VIII-related antigen in the rheumatic diseases. Rheumatol Int. 1987;7(3):107–111. doi: 10.1007/BF00270462. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Cariou R., Tobelem G., Soria C., Caen J. Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. N Engl J Med. 1986 May 1;314(18):1193–1194. doi: 10.1056/NEJM198605013141817. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Coade S. B., van Haaren E., Loizou S., Walport M. J., Denman A. M., Pearson J. D. Endothelial prostacyclin release in systemic lupus erythematosus. Thromb Haemost. 1989 Feb 28;61(1):97–100. [PubMed] [Google Scholar]
  6. Collins T., Krensky A. M., Clayberger C., Fiers W., Gimbrone M. A., Jr, Burakoff S. J., Pober J. S. Human cytolytic T lymphocyte interactions with vascular endothelium and fibroblasts: role of effector and target cell molecules. J Immunol. 1984 Oct;133(4):1878–1884. [PubMed] [Google Scholar]
  7. Donald K. J., Edwards R. L., McEvoy J. D. An ultrastructural study of the pathogenesis of tissue injury in limited Wegener's granulomatosis. Pathology. 1976 Apr;8(2):161–169. doi: 10.3109/00313027609094443. [DOI] [PubMed] [Google Scholar]
  8. Enayat M. S., Hill F. G. Qualitative VIIIR: AG function screening of multiple samples by two-dimensional crossed immunoelectrophoretic technique. Med Lab Sci. 1982 Oct;39(4):357–362. [PubMed] [Google Scholar]
  9. Falk R. J., Jennette J. C. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med. 1988 Jun 23;318(25):1651–1657. doi: 10.1056/NEJM198806233182504. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Ferraro G., Meroni P. L., Tincani A., Sinico A., Barcellini W., Radice A., Gregorini G., Froldi M., Borghi M. O., Balestrieri G. Anti-endothelial cell antibodies in patients with Wegener's granulomatosis and micropolyarteritis. Clin Exp Immunol. 1990 Jan;79(1):47–53. doi: 10.1111/j.1365-2249.1990.tb05125.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Gordon J. L., Pottinger B. E., Woo P., Rosenbaum J., Black C. M. Plasma von Willebrand factor in connective tissue disease. Ann Rheum Dis. 1987 Jun;46(6):491–492. doi: 10.1136/ard.46.6.491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hind C. R., Savage C. O., Winearls C. G., Pepys M. B. Objective monitoring of disease activity in polyarteritis by measurement of serum C reactive protein concentration. Br Med J (Clin Res Ed) 1984 Apr 7;288(6423):1027–1030. doi: 10.1136/bmj.288.6423.1027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hind C. R., Winearls C. G., Lockwood C. M., Rees A. J., Pepys M. B. Objective monitoring of activity in Wegener's granulomatosis by measurement of serum C-reactive protein concentration. Clin Nephrol. 1984 Jun;21(6):341–345. [PubMed] [Google Scholar]
  16. Jaffe E. A., Nachman R. L., Becker C. G., Minick C. R. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest. 1973 Nov;52(11):2745–2756. doi: 10.1172/JCI107470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Leung D. Y., Collins T., Lapierre L. A., Geha R. S., Pober J. S. Immunoglobulin M antibodies present in the acute phase of Kawasaki syndrome lyse cultured vascular endothelial cells stimulated by gamma interferon. J Clin Invest. 1986 May;77(5):1428–1435. doi: 10.1172/JCI112454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Leung D. Y., Moake J. L., Havens P. L., Kim M., Pober J. S. Lytic anti-endothelial cell antibodies in haemolytic-uraemic syndrome. Lancet. 1988 Jul 23;2(8604):183–186. doi: 10.1016/s0140-6736(88)92287-8. [DOI] [PubMed] [Google Scholar]
  19. Marks R. M., Czerniecki M., Andrews B. S., Penny R. The effects of scleroderma serum on human microvascular endothelial cells. Induction of antibody-dependent cellular cytotoxicity. Arthritis Rheum. 1988 Dec;31(12):1524–1534. doi: 10.1002/art.1780311209. [DOI] [PubMed] [Google Scholar]
  20. Nusinow S. R., Federici A. B., Zimmerman T. S., Curd J. G. Increased von Willebrand factor antigen in the plasma of patients with vasculitis. Arthritis Rheum. 1984 Dec;27(12):1405–1410. doi: 10.1002/art.1780271211. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Penning C. A., French M. A., Rowell N. R., Hughes P. Antibody-dependent cellular cytotoxicity of human vascular endothelium in systemic lupus erythematosus. J Clin Lab Immunol. 1985 Jul;17(3):125–130. [PubMed] [Google Scholar]
  23. Pottinger B. E., Read R. C., Paleolog E. M., Higgins P. G., Pearson J. D. von Willebrand factor is an acute phase reactant in man. Thromb Res. 1989 Feb 15;53(4):387–394. doi: 10.1016/0049-3848(89)90317-4. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Savage C. O., Winearls C. G., Jones S., Marshall P. D., Lockwood C. M. Prospective study of radioimmunoassay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis. Lancet. 1987 Jun 20;1(8547):1389–1393. doi: 10.1016/s0140-6736(87)90591-5. [DOI] [PubMed] [Google Scholar]
  26. Thornton S. C., Mueller S. N., Levine E. M. Human endothelial cells: use of heparin in cloning and long-term serial cultivation. Science. 1983 Nov 11;222(4624):623–625. doi: 10.1126/science.6635659. [DOI] [PubMed] [Google Scholar]
  27. Toothill V. J., Needham L., Gordon J. L., Pearson J. D. Desensitization of agonist-stimulated prostacyclin release in human umbilical vein endothelial cells. Eur J Pharmacol. 1988 Nov 22;157(2-3):189–196. doi: 10.1016/0014-2999(88)90382-2. [DOI] [PubMed] [Google Scholar]
  28. Toothill V. J., Van Mourik J. A., Niewenhuis H. K., Metzelaar M. J., Pearson J. D. Characterization of the enhanced adhesion of neutrophil leukocytes to thrombin-stimulated endothelial cells. J Immunol. 1990 Jul 1;145(1):283–291. [PubMed] [Google Scholar]
  29. Woolf A. D., Wakerley G., Wallington T. B., Scott D. G., Dieppe P. A. Factor VIII related antigen in the assessment of vasculitis. Ann Rheum Dis. 1987 Jun;46(6):441–447. doi: 10.1136/ard.46.6.441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. 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]

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology

RESOURCES