• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. Feb 1, 1995; 181(2): 585–597.
PMCID: PMC2191894

A novel class of autoantigens of anti-neutrophil cytoplasmic antibodies in necrotizing and crescentic glomerulonephritis: the lysosomal membrane glycoprotein h-lamp-2 in neutrophil granulocytes and a related membrane protein in glomerular endothelial cells

Abstract

Necrotizing and crescentic glomerulonephritis (NCGN) is frequently associated with circulating antineutrophil cytoplasmic autoantibodies (ANCA). It is established that ANCA are specific for soluble enzymes of granules of polymorphonuclear neutrophil granulocytes (PMN), such as myeloperoxidase (MPO) or protease 3 (PR3). The purpose of this study was to identify membrane proteins of PMNs, and/or glomerular cells, as additional autoantigenic ANCA targets. When membrane protein fractions were prepared from PMNs and isolated human glomeruli, and immunoblotted with ANCA sera of NCGN patients, two bands with apparent molecular masses of 170 and 80-110 kD (gp170/80-110) were labeled in PMNs, and a 130-kD glycoprotein (gp130) in glomeruli. Gp130 was purified, and monoclonal and rabbit antibodies (Abs) were produced which showed the same double specificity as the patient's ANCA. Using these probes, evidence was provided that gp170/80-110 is identical with human lysosomal-associated membrane protein 2 (h-lamp-2), because both proteins were immunologically cross-reactive and screening of a cDNA expression library from human promyelocytic leukemia cells with anti- gp130 Ab yielded a clone derived from h-lamp-2. Gp170/80-110 was localized primarily in granule membranes of resting PMNs, and was translocated to the cell surfaces by activation with FMLP. By contrast, gp130 was localized in the surface membranes of endothelial cells of human glomerular and renal interstitial capillaries, rather than in lysosomes, as found for h-lamp-2. Potential clinical relevance of autoantibodies to gp170/80-110 and gp130 was assessed in a preliminary trial, in which ANCA sera of patients (n = 16) with NCGN were probed with purified or recombinant antigens. Specific reactivity was detected in approximately 90% of cases with active phases of NCGN, and frequently also in combination with autoantibodies specific for PR3 or MPO. Collectively, these data provide evidence that h-lamp-2 in PMNs and a different, structurally related 130-kD membrane protein on the cell surface of renal microvascular endothelial cells are autoantigenic targets for ANCA in patients with active NCGN.

Full Text

The Full Text of this article is available as a PDF (5.3M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Cameron JS. New horizons in renal vasculitis. Klin Wochenschr. 1991 Sep 3;69(13):536–551. [PubMed]
  • Churg J. Nomenclature of vasculitic syndromes: a historical perspective. Am J Kidney Dis. 1991 Aug;18(2):148–153. [PubMed]
  • Niles JL. Value of tests for antineutrophil cytoplasmic autoantibodies in the diagnosis and treatment of vasculitis. Curr Opin Rheumatol. 1993 Jan;5(1):18–24. [PubMed]
  • Waldherr R, Eberlein-Gonska M, Noronha IL. Histopathological differentiation of systemic necrotizing vasculitides. APMIS Suppl. 1990;19:17–18. [PubMed]
  • Wiik A. Current classification and definitions of autoantibodies to neutrophil granulocytes. APMIS Suppl. 1990;19:24–25. [PubMed]
  • Falk RJ, Jennette JC. 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. [PubMed]
  • Jennette JC. Antineutrophil cytoplasmic autoantibody-associated diseases: a pathologist's perspective. Am J Kidney Dis. 1991 Aug;18(2):164–170. [PubMed]
  • Falk RJ. ANCA-associated renal disease. Kidney Int. 1990 Nov;38(5):998–1010. [PubMed]
  • Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, Hagen EC, Hoffman GS, Hunder GG, Kallenberg CG, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994 Feb;37(2):187–192. [PubMed]
  • Davies DJ, Moran JE, Niall JF, Ryan GB. Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? Br Med J (Clin Res Ed) 285(6342):606–606. [PMC free article] [PubMed]
  • Gaskin G, Savage CO, Ryan JJ, Jones S, Rees AJ, Lockwood CM, Pusey CD. Anti-neutrophil cytoplasmic antibodies and disease activity during long-term follow-up of 70 patients with systemic vasculitis. Nephrol Dial Transplant. 1991;6(10):689–694. [PubMed]
  • Tervaert JW, Limburg PC, Elema JD, Huitema MG, Horst G, The TH, Kallenberg CG. Detection of autoantibodies against myeloid lysosomal enzymes: a useful adjunct to classification of patients with biopsy-proven necrotizing arteritis. Am J Med. 1991 Jul;91(1):59–66. [PubMed]
  • Specks U, Wheatley CL, McDonald TJ, Rohrbach MS, DeRemee RA. Anticytoplasmic autoantibodies in the diagnosis and follow-up of Wegener's granulomatosis. Mayo Clin Proc. 1989 Jan;64(1):28–36. [PubMed]
  • Andrassy K, Koderisch J, Rufer M, Erb A, Waldherr R, Ritz E. Detection and clinical implication of anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis and rapidly progressive glomerulonephritis. Clin Nephrol. 1989 Oct;32(4):159–167. [PubMed]
  • Lesavre P, Noël LH, Chauveau D, Geffriaud C, Grünfeld JP. Antigen specificities and clinical distribution of ANCA in kidney diseases. Klin Wochenschr. 1991 Sep 3;69(13):552–557. [PubMed]
  • Goldschmeding R, van der Schoot CE, ten Bokkel Huinink D, Hack CE, van den Ende ME, Kallenberg CG, von dem Borne AE. 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. [PMC free article] [PubMed]
  • Jenne DE, Tschopp J, Lüdemann J, Utecht B, Gross WL. Wegener's autoantigen decoded. Nature. 1990 Aug 9;346(6284):520–520. [PubMed]
  • Niles JL, McCluskey RT, Ahmad MF, Arnaout MA. Wegener's granulomatosis autoantigen is a novel neutrophil serine proteinase. Blood. 1989 Nov 1;74(6):1888–1893. [PubMed]
  • Tervaert JW, Mulder L, Stegeman C, Elema J, Huitema M, The H, Kallenberg C. Occurrence of autoantibodies to human leucocyte elastase in Wegener's granulomatosis and other inflammatory disorders. Ann Rheum Dis. 1993 Feb;52(2):115–120. [PMC free article] [PubMed]
  • Coremans IE, Hagen EC, Daha MR, van der Woude FJ, van der Voort EA, Kleijburg-van der Keur C, Breedveld FC. Antilactoferrin antibodies in patients with rheumatoid arthritis are associated with vasculitis. Arthritis Rheum. 1992 Dec;35(12):1466–1475. [PubMed]
  • Dolman KM, Damsma I, Tool AT, Sonnenberg A, von dem Borne AE, Goldschmeding R. A novel specificity of anticytoplasmic autoantibodies directed against eosinophil peroxidase. Clin Exp Immunol. 1993 Apr;92(1):58–64. [PMC free article] [PubMed]
  • Moodie FD, Leaker B, Cambridge G, Totty NF, Segal AW. Alpha-enolase: a novel cytosolic autoantigen in ANCA positive vasculitis. Kidney Int. 1993 Mar;43(3):675–681. [PubMed]
  • Chan TM, Frampton G, Jayne DR, Perry GJ, Lockwood CM, Cameron JS. Clinical significance of anti-endothelial cell antibodies in systemic vasculitis: a longitudinal study comparing anti-endothelial cell antibodies and anti-neutrophil cytoplasm antibodies. Am J Kidney Dis. 1993 Sep;22(3):387–392. [PubMed]
  • Savage CO, Pottinger BE, Gaskin G, Lockwood CM, Pusey CD, Pearson JD. 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. [PMC free article] [PubMed]
  • Ferraro G, Meroni PL, Tincani A, Sinico A, Barcellini W, Radice A, Gregorini G, Froldi M, Borghi MO, Balestrieri G. Anti-endothelial cell antibodies in patients with Wegener's granulomatosis and micropolyarteritis. Clin Exp Immunol. 1990 Jan;79(1):47–53. [PMC free article] [PubMed]
  • Wiik A. Delineation of a standard procedure for indirect immunofluorescence detection of ANCA. APMIS Suppl. 1989;6:12–13. [PubMed]
  • Rasmussen N, Wiik A, Høier-Madsen M, Borregaard N, van der Woude F. Anti-neutrophil cytoplasm antibodies 1988. Lancet. 1988 Mar 26;1(8587):706–707. [PubMed]
  • Kerjaschki D, Ojha PP, Susani M, Horvat R, Binder S, Hovorka A, Hillemanns P, Pytela R. A beta 1-integrin receptor for fibronectin in human kidney glomeruli. Am J Pathol. 1989 Feb;134(2):481–489. [PMC free article] [PubMed]
  • Kerjaschki D, Horvat R, Binder S, Susani M, Dekan G, Ojha PP, Hillemanns P, Ulrich W, Donini U. Identification of a 400-kd protein in the brush borders of human kidney tubules that is similar to gp330, the nephritogenic antigen of rat Heymann nephritis. Am J Pathol. 1987 Oct;129(1):183–191. [PMC free article] [PubMed]
  • Kerjaschki D, Ullrich R, Diem K, Pietromonaco S, Orlando RA, Farquhar MG. Identification of a pathogenic epitope involved in initiation of Heymann nephritis. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11179–11183. [PMC free article] [PubMed]
  • Csernok E, Lüdemann J, Gross WL, Bainton DF. Ultrastructural localization of proteinase 3, the target antigen of anti-cytoplasmic antibodies circulating in Wegener's granulomatosis. Am J Pathol. 1990 Nov;137(5):1113–1120. [PMC free article] [PubMed]
  • Young RA, Davis RW. Efficient isolation of genes by using antibody probes. Proc Natl Acad Sci U S A. 1983 Mar;80(5):1194–1198. [PMC free article] [PubMed]
  • Maina CV, Riggs PD, Grandea AG, 3rd, Slatko BE, Moran LS, Tagliamonte JA, McReynolds LA, Guan CD. An Escherichia coli vector to express and purify foreign proteins by fusion to and separation from maltose-binding protein. Gene. 1988 Dec 30;74(2):365–373. [PubMed]
  • Kerjaschki D, Schulze M, Binder S, Kain R, Ojha PP, Susani M, Horvat R, Baker PJ, Couser WG. Transcellular transport and membrane insertion of the C5b-9 membrane attack complex of complement by glomerular epithelial cells in experimental membranous nephropathy. J Immunol. 1989 Jul 15;143(2):546–552. [PubMed]
  • Collins SJ, Ruscetti FW, Gallagher RE, Gallo RC. Terminal differentiation of human promyelocytic leukemia cells induced by dimethyl sulfoxide and other polar compounds. Proc Natl Acad Sci U S A. 1978 May;75(5):2458–2462. [PMC free article] [PubMed]
  • Keller GA, Tokuyasu KT, Dutton AH, Singer SJ. An improved procedure for immunoelectron microscopy: ultrathin plastic embedding of immunolabeled ultrathin frozen sections. Proc Natl Acad Sci U S A. 1984 Sep;81(18):5744–5747. [PMC free article] [PubMed]
  • Kekow J, Gross WL. Wegener's granulomatosis and ANCA-associated diseases in 1992. Br J Rheumatol. 1993 Feb;32(2):150–153. [PubMed]
  • Kallenberg CG, Brouwer E, Weening JJ, Tervaert JW. Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiological potential. Kidney Int. 1994 Jul;46(1):1–15. [PubMed]
  • Falk RJ, Terrell RS, Charles LA, Jennette JC. 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. [PMC free article] [PubMed]
  • Carlsson SR, Roth J, Piller F, Fukuda M. Isolation and characterization of human lysosomal membrane glycoproteins, h-lamp-1 and h-lamp-2. Major sialoglycoproteins carrying polylactosaminoglycan. J Biol Chem. 1988 Dec 15;263(35):18911–18919. [PubMed]
  • Chen JW, Cha Y, Yuksel KU, Gracy RW, August JT. Isolation and sequencing of a cDNA clone encoding lysosomal membrane glycoprotein mouse LAMP-1. Sequence similarity to proteins bearing onco-differentiation antigens. J Biol Chem. 1988 Jun 25;263(18):8754–8758. [PubMed]
  • Lewis V, Green SA, Marsh M, Vihko P, Helenius A, Mellman I. Glycoproteins of the lysosomal membrane. J Cell Biol. 1985 Jun;100(6):1839–1847. [PMC free article] [PubMed]
  • Fukuda M. Lysosomal membrane glycoproteins. Structure, biosynthesis, and intracellular trafficking. J Biol Chem. 1991 Nov 15;266(32):21327–21330. [PubMed]
  • Holness CL, da Silva RP, Fawcett J, Gordon S, Simmons DL. Macrosialin, a mouse macrophage-restricted glycoprotein, is a member of the lamp/lgp family. J Biol Chem. 1993 May 5;268(13):9661–9666. [PubMed]
  • Saitoh O, Piller F, Fox RI, Fukuda M. T-lymphocytic leukemia expresses complex, branched O-linked oligosaccharides on a major sialoglycoprotein, leukosialin. Blood. 1991 Apr 1;77(7):1491–1499. [PubMed]
  • Sawada R, Lowe JB, Fukuda M. E-selectin-dependent adhesion efficiency of colonic carcinoma cells is increased by genetic manipulation of their cell surface lysosomal membrane glycoprotein-1 expression levels. J Biol Chem. 1993 Jun 15;268(17):12675–12681. [PubMed]
  • Holcombe RF, Baethge BA, Stewart RM, Betzing K, Hall VC, Fukuda M, Wolf RE. Cell surface expression of lysosome-associated membrane proteins (LAMPs) in scleroderma: relationship of lamp2 to disease duration, anti-Sc170 antibodies, serum interleukin-8, and soluble interleukin-2 receptor levels. Clin Immunol Immunopathol. 1993 Apr;67(1):31–39. [PubMed]
  • Bainton DF, Miller LJ, Kishimoto TK, Springer TA. Leukocyte adhesion receptors are stored in peroxidase-negative granules of human neutrophils. J Exp Med. 1987 Dec 1;166(6):1641–1653. [PMC free article] [PubMed]
  • Harter C, Mellman I. Transport of the lysosomal membrane glycoprotein lgp120 (lgp-A) to lysosomes does not require appearance on the plasma membrane. J Cell Biol. 1992 Apr;117(2):311–325. [PMC free article] [PubMed]
  • Silverstein RL, Febbraio M. Identification of lysosome-associated membrane protein-2 as an activation-dependent platelet surface glycoprotein. Blood. 1992 Sep 15;80(6):1470–1475. [PubMed]
  • Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • Protein
    Protein
    Published protein sequences
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...