Skip to main content
PMC home page
Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1990 Nov;82(2):238–243. doi: 10.1111/j.1365-2249.1990.tb05433.x

Diverse target antigens recognized by circulating antibodies in anti-neutrophil cytoplasm antibody-associated renal vasculitides.

J A Savige 1, M Gallicchio 1, T Georgiou 1, D J Davies 1
PMCID: PMC1535103  PMID: 1978702

Abstract

Antibodies that are directed against cytoplasmic constituents of neutrophils and monocytes (anti-neutrophil cytoplasm antibodies, ANCA) have been described in Wegener's granulomatosis, microscopic polyarteritis (MPA) and some cases of segmental necrotizing glomerulonephritis (SNGN). Other antibodies occasionally described in Wegener's granulomatosis and MPA include anti-nuclear antibodies (ANA) and anti-glomerular basement membrane (GBM) antibodies. We have studied the diversity of the corresponding antigens in ANCA-associated renal diseases. Sera from 46 patients with active histologically proven Wegener's granulomatosis, MPA and SNGN were tested for ANCA by indirect immunofluorescent examination of normal peripheral blood neutrophils. Thirty-four sera (74%) were positive; 16 were associated with diffuse cytoplasmic staining (cANCA) and 18 with perinuclear staining (pANCA). In addition, five demonstrated antineutrophil-specific nuclear staining (ANNA). On Western blotting of the neutrophil extract, five sera recognized a 29-kD molecule recently identified as neutrophil proteinase 3. Two sera with typical cANCA bound to molecules of 36, 38 and 116 kD and another to a molecule of 22 kD. The final serum associated with pANCA bound to a molecule of about 12 kD. Thirteen sera out of 46 (28%) tested in an ELISA contained anti-myeloperoxidase antibodies; 10 of these were associated with pANCA and two others with ANNA. Three sera of 17 (18%) tested contained anti-elastase antibodies; these also contained anti-myeloperoxidase antibodies and were associated with pANCA. However, eight sera with pANCA were negative for anti-myeloperoxidase antibodies and three of these were also negative for anti-elastase antibodies, suggesting further unidentified target antigen or antigens associated with the pANCA. Fifteen of the 34 sera positive for ANCA also demonstrated anti-nuclear staining on Hep-2 cells (53%) in a speckled, homogeneous, or nucleolar pattern. ANA were significantly associated with the presence of pANCA (P less than 0.01), and levels of ANA and ANCA fell in parallel after treatment. One serum with a pANCA was also positive for anti-GBM antibodies. Inhibition studies using ELISAs for anti-GBM antibodies indicated that there was no cross-reactivity between target molecules recognized by these antibodies. The diversity of target molecules recognized by ANCA suggests that cross-reactivity with bacterial structures is less likely as the primary aetiological event in the development of these antibodies than tissue destruction; and that cross-reactivity with vascular endothelium is also unlikely as the pathogenetic basis of vessel disease.

Full text

PDF
238

Images in this article

241Fig. 1
on p.241
241Fig. 2
on p.241

Selected References

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

  1. Bowman C., Lockwood C. M. Clinical application of a radio-immunoassay for auto-antibodies to glomerular basement membrane. J Clin Lab Immunol. 1985 Aug;17(4):197–202. [PubMed] [Google Scholar]
  2. Briggs R. C., Glass W. F., 2nd, Montiel M. M., Hnilica L. S. Lactoferrin: nuclear localization in the human neutrophilic granulocyte? J Histochem Cytochem. 1981 Oct;29(10):1128–1136. doi: 10.1177/29.10.7028857. [DOI] [PubMed] [Google Scholar]
  3. CALABRESI P., EDWARDS E. A., SCHILLING R. F. Fluorescent antiglobulin studies in leukopenic and related disorders. J Clin Invest. 1959 Nov;38:2091–2100. doi: 10.1172/JCI103987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Davies D. J., Moran J. E., Niall J. F., Ryan G. B. Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? 1982 Aug 28-Sep 4Br Med J (Clin Res Ed) 285(6342):606–606. doi: 10.1136/bmj.285.6342.606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Elling P. On the incidence of antinuclear factors in rheumatoid arthritis. A comparative study, with special reference to the reaction with polymorphonuclear granulocytes. Acta Rheumatol Scand. 1967;13(2):101–112. doi: 10.3109/rhe1.1967.13.issue-1-4.10. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Fauci A. S., Wolff S. M. Wegener's granulomatosis: studies in eighteen patients and a review of the literature. Medicine (Baltimore) 1973 Nov;52(6):535–561. doi: 10.1097/00005792-197311000-00002. [DOI] [PubMed] [Google Scholar]
  8. Howell S. B., Epstein W. V. Circulating immunoglobulin complexes in Wegener's granulomatosis. Am J Med. 1976 Feb;60(2):259–268. doi: 10.1016/0002-9343(76)90435-6. [DOI] [PubMed] [Google Scholar]
  9. Klassen J., Elwood C., Grossberg A. L., Milgrom F., Montes M., Sepulveda M., Andres G. A. Evolution of membranous nephropathy into anti-glomerular-basement-membrane glomerulonephritis. N Engl J Med. 1974 Jun 13;290(24):1340–1344. doi: 10.1056/NEJM197406132902403. [DOI] [PubMed] [Google Scholar]
  10. Kurki P., Helve T., von Bonsdorff M., Törnroth T., Pettersson E., Riska H., Miettinen A. Transformation of membranous glomerulonephritis into crescentic glomerulonephritis with glomerular basement membrane antibodies. Serial determinations of anti-GBM before the transformation. Nephron. 1984;38(2):134–137. doi: 10.1159/000183294. [DOI] [PubMed] [Google Scholar]
  11. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  12. Lüdemann G., Gross W. L. Autoantibodies against cytoplasmic structures of neutrophil granulocytes in Wegener's granulomatosis. Clin Exp Immunol. 1987 Aug;69(2):350–357. [PMC free article] [PubMed] [Google Scholar]
  13. Lüdemann J., Csernok E., Ulmer M., Lemke H., Utecht B., Rautmann A., Gross W. L. Anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis: immunodiagnostic value, monoclonal antibodies and characterization of the target antigen. Neth J Med. 1990 Apr;36(3-4):157–162. [PubMed] [Google Scholar]
  14. 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]
  15. Parlevliet K. J., Henzen-Logmans S. C., Oe P. L., Bronsveld W., Balm A. J., Donker A. J. Antibodies to components of neutrophil cytoplasm: a new diagnostic tool in patients with Wegener's granulomatosis and systemic vasculitis. Q J Med. 1988 Jan;66(249):55–63. [PubMed] [Google Scholar]
  16. Pinching A. J., Lockwood C. M., Pussell B. A., Rees A. J., Sweny P., Evans D. J., Bowley N., Peters D. K. Wegener's granulomatosis: observations on 18 patients with severe renal disease. Q J Med. 1983 Autumn;52(208):435–460. [PubMed] [Google Scholar]
  17. Ronco P., Verroust P., Mignon F., Kourilsky O., Vanhille P., Meyrier A., Mery J. P., Morel-Maroger L. Immunopathological studies of polyarteritis nodosa and Wegener's granulomatosis: a report of 43 patients with 51 renal biopsies. Q J Med. 1983 Spring;52(206):212–223. [PubMed] [Google Scholar]
  18. 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]
  19. Snook J. A., Chapman R. W., Fleming K., Jewell D. P. Anti-neutrophil nuclear antibody in ulcerative colitis, Crohn's disease and primary sclerosing cholangitis. Clin Exp Immunol. 1989 Apr;76(1):30–33. [PMC free article] [PubMed] [Google Scholar]
  20. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Wahls T. L., Bonsib S. M., Schuster V. L. Coexistent Wegener's granulomatosis and anti-glomerular basement membrane disease. Hum Pathol. 1987 Feb;18(2):202–205. doi: 10.1016/s0046-8177(87)80340-4. [DOI] [PubMed] [Google Scholar]
  22. 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