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J Clin Invest. Jan 1, 1996; 97(1): 111–119.
PMCID: PMC507068

IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro. Induction of adhesion molecule expression and involvement of endothelium-derived cytokines.

Abstract

IgG autoantibodies that bind human endothelial cells (AECA) were detected by ELISA in 30 of 42 samples of sera from patients with scleroderma. Pretreatment of human umbilical vein endothelial cells with AECA-positive scleroderma sera, or IgG purified from these sera, led to a dose- and time-dependent increase in the ability of the cells to bind human U937 monocytic cells. Threshold-active IgG concentrations were 1-10 micrograms/ml; effects were significant after 3 h and maximal after 6-12 h. IgG from AECA-negative sera or normal sera were without effect. Increased adhesion of U937 cells was accompanied by increased expression of endothelial intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. Transfer of endothelial cell-conditioned media after pretreatment with AECA and immunodepletion of IgG demonstrated the presence of transferable activity that mimicked the effects of AECA. Treatment with neutralizing anticytokine antibodies indicated that IL-1, generated by the endothelial cells in response to AECA, was involved in the upregulation of adhesion molecules and U937 cell adhesion. We conclude that AECA can play a pathogenic role in scleroderma by activating endothelial cells, in part due to autocrine or paracrine actions of IL-1.

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Selected References

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  • Campbell PM, LeRoy EC. Pathogenesis of systemic sclerosis: a vascular hypothesis. Semin Arthritis Rheum. 1975 May;4(4):351–368. [PubMed]
  • Rosenbaum J, Pottinger BE, Woo P, Black CM, Loizou S, Byron MA, Pearson JD. 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]
  • Leung DY, Collins T, Lapierre LA, Geha RS, Pober JS. 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. [PMC free article] [PubMed]
  • Kaneko K, Savage CO, Pottinger BE, Shah V, Pearson JD, Dillon MJ. Antiendothelial cell antibodies can be cytotoxic to endothelial cells without cytokine pre-stimulation and correlate with ELISA antibody measurement in Kawasaki disease. Clin Exp Immunol. 1994 Nov;98(2):264–269. [PMC free article] [PubMed]
  • Leung DY, Moake JL, Havens PL, Kim M, Pober JS. Lytic anti-endothelial cell antibodies in haemolytic-uraemic syndrome. Lancet. 1988 Jul 23;2(8604):183–186. [PubMed]
  • Penning CA, Cunningham J, French MA, Harrison G, Rowell NR, 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]
  • Hashemi S, Smith CD, Izaguirre CA. Anti-endothelial cell antibodies: detection and characterization using a cellular enzyme-linked immunosorbent assay. J Lab Clin Med. 1987 Apr;109(4):434–440. [PubMed]
  • Marks RM, Czerniecki M, Andrews BS, 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. [PubMed]
  • Holt CM, Lindsey N, Moult J, Malia RG, Greaves M, Hume A, Rowell NR, Hughes P. Antibody-dependent cellular cytotoxicity of vascular endothelium: characterization and pathogenic associations in systemic sclerosis. Clin Exp Immunol. 1989 Dec;78(3):359–365. [PMC free article] [PubMed]
  • Tannenbaum SH, Finko R, Cines DB. Antibody and immune complexes induce tissue factor production by human endothelial cells. J Immunol. 1986 Sep 1;137(5):1532–1537. [PubMed]
  • Hasselaar P, Derksen RH, Oosting JD, Blokzijl L, de Groot PG. Synergistic effect of low doses of tumor necrosis factor and sera from patients with systemic lupus erythematosus on the expression of procoagulant activity by cultured endothelial cells. Thromb Haemost. 1989 Sep 29;62(2):654–660. [PubMed]
  • Pober JS, Cotran RS. Cytokines and endothelial cell biology. Physiol Rev. 1990 Apr;70(2):427–451. [PubMed]
  • Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood. 1994 Oct 1;84(7):2068–2101. [PubMed]
  • Hughes CC, Savage CO, Pober JS. The endothelial cell as a regulator of T-cell function. Immunol Rev. 1990 Oct;117:85–102. [PubMed]
  • Mantovani A, Bussolino F, Dejana E. Cytokine regulation of endothelial cell function. FASEB J. 1992 May;6(8):2591–2599. [PubMed]
  • Fleischmajer R, Perlish JS, Reeves JR. Cellular infiltrates in scleroderma skin. Arthritis Rheum. 1977 May;20(4):975–984. [PubMed]
  • Roumm AD, Whiteside TL, Medsger TA, Jr, Rodnan GP. Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations. Arthritis Rheum. 1984 Jun;27(6):645–653. [PubMed]
  • Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol. 1992 Mar;166(3):255–263. [PubMed]
  • Rudnicka L, Majewski S, Blaszczyk M, Skiendzielewska A, Makiela B, Skopinska M, Jablonska S. Adhesion of peripheral blood mononuclear cells to vascular endothelium in patients with systemic sclerosis (scleroderma). Arthritis Rheum. 1992 Jul;35(7):771–775. [PubMed]
  • Claman HN, Giorno RC, Seibold JR. Endothelial and fibroblastic activation in scleroderma. The myth of the "uninvolved skin". Arthritis Rheum. 1991 Dec;34(12):1495–1501. [PubMed]
  • Majewski S, Hunzelmann N, Johnson JP, Jung C, Mauch C, Ziegler-Heitbrock HW, Riethmüller G, Krieg T. Expression of intercellular adhesion molecule-1 (ICAM-1) in the skin of patients with systemic scleroderma. J Invest Dermatol. 1991 Oct;97(4):667–671. [PubMed]
  • Sollberg S, Peltonen J, Uitto J, Jimenez SA. Elevated expression of beta 1 and beta 2 integrins, intercellular adhesion molecule 1, and endothelial leukocyte adhesion molecule 1 in the skin of patients with systemic sclerosis of recent onset. Arthritis Rheum. 1992 Mar;35(3):290–298. [PubMed]
  • Koch AE, Kronfeld-Harrington LB, Szekanecz Z, Cho MM, Haines GK, Harlow LA, Strieter RM, Kunkel SL, Massa MC, Barr WG, et al. In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Their role in early and late disease. Pathobiology. 1993;61(5-6):239–246. [PubMed]
  • Kahaleh MB, Osborn I, LeRoy EC. Increased factor VIII/von Willebrand factor antigen and von Willebrand factor activity in scleroderma and in Raynaud's phenomenon. Ann Intern Med. 1981 Apr;94(4 Pt 1):482–484. [PubMed]
  • Kahaleh MB. Endothelin, an endothelial-dependent vasoconstrictor in scleroderma. Enhanced production and profibrotic action. Arthritis Rheum. 1991 Aug;34(8):978–983. [PubMed]
  • Yamane K, Kashiwagi H, Suzuki N, Miyauchi T, Yanagisawa M, Goto K, Masaki T. Elevated plasma levels of endothelin-1 in systemic sclerosis. Arthritis Rheum. 1991 Feb;34(2):243–244. [PubMed]
  • Carson CW, Beall LD, Hunder GG, Johnson CM, Newman W. Serum ELAM-1 is increased in vasculitis, scleroderma, and systemic lupus erythematosus. J Rheumatol. 1993 May;20(5):809–814. [PubMed]
  • Vancheeswaran R, Magoulas T, Efrat G, Wheeler-Jones C, Olsen I, Penny R, Black CM. Circulating endothelin-1 levels in systemic sclerosis subsets--a marker of fibrosis or vascular dysfunction? J Rheumatol. 1994 Oct;21(10):1838–1844. [PubMed]
  • Ohdama S, Takano S, Miyake S, Kubota T, Sato K, Aoki N. Plasma thrombomodulin as a marker of vascular injuries in collagen vascular diseases. Am J Clin Pathol. 1994 Jan;101(1):109–113. [PubMed]
  • Gruschwitz MS, Hornstein OP, von Den Driesch P. Correlation of soluble adhesion molecules in the peripheral blood of scleroderma patients with their in situ expression and with disease activity. Arthritis Rheum. 1995 Feb;38(2):184–189. [PubMed]
  • Jaffe EA, Nachman RL, Becker CG, Minick CR. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest. 1973 Nov;52(11):2745–2756. [PMC free article] [PubMed]
  • Thornton SC, Mueller SN, Levine EM. Human endothelial cells: use of heparin in cloning and long-term serial cultivation. Science. 1983 Nov 11;222(4624):623–625. [PubMed]
  • Larrick JW, Fischer DG, Anderson SJ, Koren HS. Characterization of a human macrophage-like cell line stimulated in vitro: a model of macrophage functions. J Immunol. 1980 Jul;125(1):6–12. [PubMed]
  • Guyre PM, Morganelli PM, Miller R. Recombinant immune interferon increases immunoglobulin G Fc receptors on cultured human mononuclear phagocytes. J Clin Invest. 1983 Jul;72(1):393–397. [PMC free article] [PubMed]
  • Harris P, Ralph P. Human leukemic models of myelomonocytic development: a review of the HL-60 and U937 cell lines. J Leukoc Biol. 1985 Apr;37(4):407–422. [PubMed]
  • Libby P, Ordovas JM, Auger KR, Robbins AH, Birinyi LK, Dinarello CA. Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells. Am J Pathol. 1986 Aug;124(2):179–185. [PMC free article] [PubMed]
  • Kurt-Jones EA, Fiers W, Pober JS. Membrane interleukin 1 induction on human endothelial cells and dermal fibroblasts. J Immunol. 1987 Oct 1;139(7):2317–2324. [PubMed]
  • Sironi M, Breviario F, Proserpio P, Biondi A, Vecchi A, Van Damme J, Dejana E, Mantovani A. IL-1 stimulates IL-6 production in endothelial cells. J Immunol. 1989 Jan 15;142(2):549–553. [PubMed]
  • Kovacs EJ, DiPietro LA. Fibrogenic cytokines and connective tissue production. FASEB J. 1994 Aug;8(11):854–861. [PubMed]
  • van der Zee JM, Siegert CE, de Vreede TA, Daha MR, Breedveld FC. Characterization of anti-endothelial cell antibodies in systemic lupus erythematosus (SLE). Clin Exp Immunol. 1991 May;84(2):238–244. [PMC free article] [PubMed]
  • Del Papa N, Conforti G, Gambini D, La Rosa L, Tincani A, D'Cruz D, Khamashta M, Hughes GR, Balestrieri G, Meroni PL. Characterization of the endothelial surface proteins recognized by anti-endothelial antibodies in primary and secondary autoimmune vasculitis. Clin Immunol Immunopathol. 1994 Mar;70(3):211–216. [PubMed]
  • Bendtzen K, Svenson M, Jønsson V, Hippe E. Autoantibodies to cytokines--friends or foes? Immunol Today. 1990 May;11(5):167–169. [PubMed]
  • Suzuki H, Takemura H, Yoshizaki K, Koishihara Y, Ohsugi Y, Okano A, Akiyama Y, Tojo T, Kishimoto T, Kashiwagi H. IL-6-anti-IL-6 autoantibody complexes with IL-6 activity in sera from some patients with systemic sclerosis. J Immunol. 1994 Jan 15;152(2):935–942. [PubMed]
  • Reitamo S, Remitz A, Varga J, Ceska M, Effenberger F, Jimenez S, Uitto J. Demonstration of interleukin 8 and autoantibodies to interleukin 8 in the serum of patients with systemic sclerosis and related disorders. Arch Dermatol. 1993 Feb;129(2):189–193. [PubMed]
  • Needleman BW, Wigley FM, Stair RW. Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor alpha, and interferon-gamma levels in sera from patients with scleroderma. Arthritis Rheum. 1992 Jan;35(1):67–72. [PubMed]

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