Clinical Reviews in Allergy & Immunology

, Volume 35, Issue 1–2, pp 59–65

Antiendothelial Cells Autoantibodies in Vasculitis-Associated Systemic Diseases

Article

Abstract

Antiendothelial cell antibodies (AECA) have been detected in healthy individuals, as well as in autoimmune and systemic inflammatory diseases, including systemic vasculitides. AECA have been reported in large vessel vasculitides such as giant cell arteritis and Takayasu arteritis; medium-sized vessel vasculitides, such as polyarteritis nodosa related to hepatitis B virus infection and Kawasaki disease; and small-sized vessel vasculitides, such as Wegener’s granulomatosis, microscopic polyangiitis, and Henoch–Schonlein purpura. In Takayasu arteritis and antineutrophil cytoplasm antibody-positive vasculitides, AECA have been reported to correlate with disease activity. A cell-based enzyme-linked immunosorbent assay (ELISA) using cultured human umbilical vein endothelial cells (HUVEC) represent one of the reference techniques for AECA detection, although flow cytometry and immunobloting have also been proposed. AECA might contribute to the pathogenesis of systemic vasculitides and vasculitis-associated diseases through (1) activation of endothelial cells (EC), (2) direct cytotoxic effect due to complement-dependent cytotoxicity or indirect cytotoxic effect secondary to antibody-dependent cytotoxicity, (3) induction of coagulation, (4) induction of apoptosis through the binding of phospholipids or heat-shock protein 60, and (5) induction of EC activation. None of the identified target antigens of AECA is specific for EC, and EC-specific target antigens of AECA remain to be identified in systemic vasculitides.

Keywords

Vasculitis Autoantibodies Endothelial cells 

References

  1. 1.
    Moreland LW, Gay RE, Gay S (1991) Collagen autoantibodies in patients with vasculitis and systemic lupus erythematosus. Clin Immunol Immunopathol 60(3):412–418PubMedCrossRefGoogle Scholar
  2. 2.
    Direskeneli H, D'Cruz D, Khamashta MA, Hughes GR (1994) Autoantibodies against endothelial cells, extracellular matrix, and human collagen type IV in patients with systemic vasculitis. Clin Immunol Immunopathol 70(3):206–210PubMedCrossRefGoogle Scholar
  3. 3.
    Chan TM, Frampton G, Staines NA, Hobby P, Perry GJ, Cameron JS (1992) Different mechanisms by which anti-DNA MoAbs bind to human endothelial cells and glomerular mesangial cells. Clin Exp Immunol 88(1):68–74PubMedCrossRefGoogle Scholar
  4. 4.
    Del Papa N, Guidali L, Spatola L, Bonara P, Borghi MO, Tincani A et al (1995) Relationship between anti-phospholipid and anti-endothelial cell antibodies III: beta 2 glycoprotein I mediates the antibody binding to endothelial membranes and induces the expression of adhesion molecules. Clin Exp Rheumatol 13(2):179–185PubMedGoogle Scholar
  5. 5.
    Del Papa N, Sheng YH, Raschi E, Kandiah DA, Tincani A, Khamashta MA et al (1998) Human beta 2-glycoprotein I binds to endothelial cells through a cluster of lysine residues that are critical for anionic phospholipid binding and offers epitopes for anti-beta 2-glycoprotein I antibodies. J Immunol 160(11):5572–5578PubMedGoogle Scholar
  6. 6.
    Garcia de la Pena-Lefebvre P, Chanseaud Y, Tamby MC, Reinbolt J, Batteux F, Allanore Y et al (2004) IgG reactivity with a 100-kDa tissue and endothelial cell antigen identified as topoisomerase I distinguishes between limited and diffuse systemic sclerosis patients. Clin Immunol 111(3):241–251PubMedCrossRefGoogle Scholar
  7. 7.
    Servettaz A, Tamby MC, Guilpain P, Reinbolt J, Garcia de la Pena-Lefebvre P, Allanore Y et al (2006) Anti-endothelial cell antibodies from patients with limited cutaneous systemic sclerosis bind to centromeric protein B (CENP-B). Clin Immunol 120(2):212–219PubMedCrossRefGoogle Scholar
  8. 8.
    Ronda N, Haury M, Nobrega A, Kaveri SV, Coutinho A, Kazatchkine MD (1994) Analysis of natural and disease-associated autoantibody repertoires: anti-endothelial cell IgG autoantibody activity in the serum of healthy individuals and patients with systemic lupus erythematosus. Int Immunol 6(11):1651–1660PubMedCrossRefGoogle Scholar
  9. 9.
    Ronda N, Leonardi S, Orlandini G, Gatti R, Bellosta S, Bernini F et al (1999) Natural anti-endothelial cell antibodies (AECA). J Autoimmun 13(1):121–127PubMedCrossRefGoogle Scholar
  10. 10.
    Mendonca LL, Khamashta MA, Cuadrado MJ, Bertolaccini ML, Hughes GR (2000) Natural immune response involving anti-endothelial cell antibodies in normal and lupus pregnancy. Arthritis Rheum 43(7):1511–1515PubMedCrossRefGoogle Scholar
  11. 11.
    Servettaz A, Guilpain P, Camoin L, Mayeux P, Broussard C, Tamby M et al (2007) Identification of target antigens of anti-endothelial cell antibodies in healthy individuals: a proteomic approach. Proteomics (in press)Google Scholar
  12. 12.
    Guillevin L, Mahr A, Callard P, Godmer P, Pagnoux C, Leray E et al (2005) Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore) 84(5):313–322CrossRefGoogle Scholar
  13. 13.
    Guilpain P, Chanseaud Y, Tamby MC, Mahr A, Servettaz A, Guillevin L et al (2005) [Pathogenesis of primary systemic vasculitides (I): ANCA-positive vasculitides]. Presse Med 34(14):1013–1022PubMedCrossRefGoogle Scholar
  14. 14.
    Ronda N, Meroni P, Raschi H, Borghi M (eds) (2007) Anti-endothelial cell autoantibodies. Vol. second edition: ElsevierGoogle Scholar
  15. 15.
    Chanseaud Y, Garcia de la Pena-Lefebvre P, Guilpain P, Mahr A, Tamby MC, Uzan M et al (2003) IgM and IgG antoantibodies from microscopic polyangiitis patients but not those with other small- and medium-sized vessel vasculitides recognize multiple endothelial cell antigens. Clin Immunol 109(2):165–178PubMedCrossRefGoogle Scholar
  16. 16.
    Youinou P, Le Dantec C, Bendaoud B, Renaudineau Y, Pers JO, Jamin C (2006) Endothelium, a target for immune-mediated assault in connective tissue disease. Autoimmun Rev 5(3):222–228PubMedCrossRefGoogle Scholar
  17. 17.
    Revelen R, D'Arbonneau F, Guillevin L, Bordron A, Youinou P, Dueymes M (2002) Comparison of cell-ELISA, flow cytometry and Western blotting for the detection of antiendothelial cell antibodies. Clin Exp Rheumatol 20(1):19–26PubMedGoogle Scholar
  18. 18.
    Renaudineau Y, Grunebaum E, Krause I, Praprotnik S, Revelen R, Youinou P et al (2001) Anti-endothelial cell antibodies (AECA) in systemic sclerosis–increased sensitivity using different endothelial cell substrates and association with other autoantibodies. Autoimmunity 33(3):171–179PubMedCrossRefGoogle Scholar
  19. 19.
    Guilpain P, Servettaz A, Tamby MC, Chanseaud Y, Tamas N, De la Pena-Lefebvre PG et al (2007) A combined SDS-PAGE and proteomics approach to identify target autoantigens in healthy individuals and patients with autoimmune diseases. Ann N Y Acad Sci 1109:538–549PubMedCrossRefGoogle Scholar
  20. 20.
    Lee KH, Chung HS, Kim HS, Oh SH, Ha MK, Baik JH et al (2003) Human alpha-enolase from endothelial cells as a target antigen of anti-endothelial cell antibody in Behcet’s disease. Arthritis Rheum 48(7):2025–2035PubMedCrossRefGoogle Scholar
  21. 21.
    Kaneko M, Ono T, Matsubara T, Yamamoto Y, Ikeda H, Yoshiki T et al (2004) Serological identification of endothelial antigens predominantly recognized in Kawasaki disease patients by recombinant expression cloning. Microbiol Immunol 48(9):703–711PubMedGoogle Scholar
  22. 22.
    Gupta S (1981) Surgical and immunological aspects of Takayasu’s disease. Ann R Coll Surg Engl 63(5):325–332PubMedGoogle Scholar
  23. 23.
    Nityanand S, Mishra K, Shrivastava S, Holm G, Lefvert AK (1997) Autoantibodies against cardiolipin and endothelial cells in Takayasu’s arteritis: prevalence and isotype distribution. Br J Rheumatol 36(8):923–924PubMedCrossRefGoogle Scholar
  24. 24.
    Eichhorn J, Sima D, Thiele B, Lindschau C, Turowski A, Schmidt H et al (1996) Anti-endothelial cell antibodies in Takayasu arteritis. Circulation 94(10):2396–2401PubMedGoogle Scholar
  25. 25.
    Fujieda M, Oishi N, Naruse K, Hashizume M, Nishiya K, Kurashige T et al (1998) Soluble thrombomodulin and antibodies to bovine glomerular endothelial cells in patients with Henoch-Schonlein purpura. Arch Dis Child 78(3):240–244PubMedGoogle Scholar
  26. 26.
    Yang YH, Wang SJ, Chuang YH, Lin YT, Chiang BL (2002) The level of IgA antibodies to human umbilical vein endothelial cells can be enhanced by TNF-alpha treatment in children with Henoch-Schonlein purpura. Clin Exp Immunol 130(2):352–357PubMedCrossRefGoogle Scholar
  27. 27.
    Kaneko K, Savage CO, Pottinger BE, Shah V, Pearson JD, Dillon MJ (1994) 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 98(2):264–269PubMedCrossRefGoogle Scholar
  28. 28.
    Leung DY, Collins T, Lapierre LA, Geha RS, Pober JS (1986) Immunoglobulin M antibodies present in the acute phase of Kawasaki syndrome lyse cultured vascular endothelial cells stimulated by gamma interferon. J Clin Invest 77(5):1428–1435PubMedCrossRefGoogle Scholar
  29. 29.
    Leung DY, Geha RS, Newburger JW, Burns JC, Fiers W, Lapierre LA et al (1986) Two monokines, interleukin 1 and tumor necrosis factor, render cultured vascular endothelial cells susceptible to lysis by antibodies circulating during Kawasaki syndrome. J Exp Med 164(6):1958–1972PubMedCrossRefGoogle Scholar
  30. 30.
    Muller Kobold AC, van Wijk RT, Franssen CF, Molema G, Kallenberg CG, Tervaert JW (1999) In vitro up-regulation of E-selectin and induction of interleukin-6 in endothelial cells by autoantibodies in Wegener’s granulomatosis and microscopic polyangiitis. Clin Exp Rheumatol 17(4):433–440PubMedGoogle Scholar
  31. 31.
    Gobel U, Eichhorn J, Kettritz R, Briedigkeit L, Sima D, Lindschau C et al (1996) Disease activity and autoantibodies to endothelial cells in patients with Wegener’s granulomatosis. Am J Kidney Dis 28(2):186–194PubMedCrossRefGoogle Scholar
  32. 32.
    Chan TM, Frampton G, Jayne DR, Perry GJ, Lockwood CM, Cameron JS (1993) 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 22(3):387–392PubMedGoogle Scholar
  33. 33.
    Del Papa N, Conforti G, Gambini D, La Rosa L, Tincani A, D’Cruz D et al (1994) Characterization of the endothelial surface proteins recognized by anti-endothelial antibodies in primary and secondary autoimmune vasculitis. Clin Immunol Immunopathol 70(3):211–216PubMedCrossRefGoogle Scholar
  34. 34.
    Belizna C, Tervaert JW (1997) Specificity, pathogenecity, and clinical value of antiendothelial cell antibodies. Semin Arthritis Rheum 27(2):98–109PubMedCrossRefGoogle Scholar
  35. 35.
    Fujieda M, Oishi N, Kurashige T (1997) Antibodies to endothelial cells in Kawasaki disease lyse endothelial cells without cytokine pretreatment. Clin Exp Immunol 107(1):120–126PubMedCrossRefGoogle Scholar
  36. 36.
    Tripathy NK, Upadhyaya S, Sinha N, Nityanand S (2001) Complement and cell mediated cytotoxicity by antiendothelial cell antibodies in Takayasu’s arteritis. J Rheumatol 28(4):805–808PubMedGoogle Scholar
  37. 37.
    Savage CO, Pottinger BE, Gaskin G, Lockwood CM, Pusey CD, Pearson JD (1991) 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 85(1):14–19PubMedCrossRefGoogle Scholar
  38. 38.
    Mayet WJ, Schwarting A, Meyer zum Buschenfelde KH (1994) Cytotoxic effects of antibodies to proteinase 3 (C-ANCA) on human endothelial cells. Clin Exp Immunol 97(3):458–465PubMedGoogle Scholar
  39. 39.
    Del Papa N, Guidali L, Sironi M, Shoenfeld Y, Mantovani A, Tincani A et al (1996) Anti-endothelial cell IgG antibodies from patients with Wegener’s granulomatosis bind to human endothelial cells in vitro and induce adhesion molecule expression and cytokine secretion. Arthritis Rheum 39(5):758–766PubMedCrossRefGoogle Scholar
  40. 40.
    Ballieux BE, Zondervan KT, Kievit P, Hagen EC, van Es LA, van der Woude FJ et al (1994) Binding of proteinase 3 and myeloperoxidase to endothelial cells: ANCA-mediated endothelial damage through ADCC? Clin Exp Immunol 97(1):52–60PubMedCrossRefGoogle Scholar
  41. 41.
    Savage CO, Gaskin G, Pusey CD, Pearson JD (1993) Anti-neutrophil cytoplasm antibodies can recognize vascular endothelial cell-bound anti-neutrophil cytoplasm antibody-associated autoantigens. Exp Nephrol 1(3):190–195PubMedGoogle Scholar
  42. 42.
    Carvalho D, Savage CO, Isenberg D, Pearson JD (1999) IgG anti-endothelial cell autoantibodies from patients with systemic lupus erythematosus or systemic vasculitis stimulate the release of two endothelial cell-derived mediators, which enhance adhesion molecule expression and leukocyte adhesion in an autocrine manner. Arthritis Rheum 42(4):631–640PubMedCrossRefGoogle Scholar
  43. 43.
    Papa ND, Raschi E, Moroni G, Panzeri P, Borghi MO, Ponticelli C et al (1999) Anti-endothelial cell IgG fractions from systemic lupus erythematosus patients bind to human endothelial cells and induce a pro-adhesive and a pro-inflammatory phenotype in vitro. Lupus 8(6):423–429PubMedCrossRefGoogle Scholar
  44. 44.
    Lee KH, Cho HJ, Kim HS, Lee WJ, Lee S, Bang D (2002) Activation of extracellular signal regulated kinase ½ in human dermal microvascular endothelial cells stimulated by anti-endothelial cell antibodies in sera of patients with Behcet’s disease. J Dermatol Sci 30(1):63–72PubMedCrossRefGoogle Scholar
  45. 45.
    Min W, Pober JS (1997) TNF initiates E-selectin transcription in human endothelial cells through parallel TRAF-NF-kappa B and TRAF-RAC/CDC42-JNK-c-Jun/ATF2 pathways. J Immunol 159(7):3508–3518PubMedGoogle Scholar
  46. 46.
    Chauhan SK, Tripathy NK, Nityanand S (2006) Antigenic targets and pathogenicity of anti-aortic endothelial cell antibodies in Takayasu arteritis. Arthritis Rheum 54(7):2326–2333PubMedCrossRefGoogle Scholar
  47. 47.
    Blank M, Krause I, Goldkorn T, Praprotnik S, Livneh A, Langevitz P et al (1999) Monoclonal anti-endothelial cell antibodies from a patient with Takayasu arteritis activate endothelial cells from large vessels. Arthritis Rheum 42(7):1421–1432PubMedCrossRefGoogle Scholar
  48. 48.
    Seko Y, Sato O, Takagi A, Tada Y, Matsuo H, Yagita H et al (1996) Restricted usage of T-cell receptor Valpha-Vbeta genes in infiltrating cells in aortic tissue of patients with Takayasu’s arteritis. Circulation 93(10):1788–1790PubMedGoogle Scholar
  49. 49.
    Yang YH, Huang YH, Lin YL, Wang LC, Chuang YH, Yu HH et al (2006) Circulating IgA from acute stage of childhood Henoch-Schonlein purpura can enhance endothelial interleukin (IL)-8 production through MEK/ERK signalling pathway. Clin Exp Immunol 144(2):247–253PubMedCrossRefGoogle Scholar
  50. 50.
    Yang YH, Lai HJ, Huang CM, Wang LC, Lin YT, Chiang BL (2004) Sera from children with active Henoch-Schonlein purpura can enhance the production of interleukin 8 by human umbilical venous endothelial cells. Ann Rheum Dis 63(11):1511–1513PubMedCrossRefGoogle Scholar
  51. 51.
    Tannenbaum SH, Finko R, Cines DB (1986) Antibody and immune complexes induce tissue factor production by human endothelial cells. J Immunol 137(5):1532–1537PubMedGoogle Scholar
  52. 52.
    Kornberg A, Renaudineau Y, Blank M, Youinou P, Shoenfeld Y (2000) Anti-beta 2-glycoprotein I antibodies and anti-endothelial cell antibodies induce tissue factor in endothelial cells. Isr Med Assoc J 2(Suppl):27–31PubMedGoogle Scholar
  53. 53.
    Sgonc R, Gruschwitz MS, Boeck G, Sepp N, Gruber J, Wick G (2000) Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum 43(11):2550–2562PubMedCrossRefGoogle Scholar
  54. 54.
    Bordron A, Dueymes M, Levy Y, Jamin C, Ziporen L, Piette JC et al (1998) Anti-endothelial cell antibody binding makes negatively charged phospholipids accessible to antiphospholipid antibodies. Arthritis Rheum 41(10):1738–1747PubMedCrossRefGoogle Scholar
  55. 55.
    Matsuda J, Gotoh M, Gohchi K, Kawasugi K, Tsukamoto M, Saitoh N (1997) Anti-endothelial cell antibodies to the endothelial hybridoma cell line (EAhy926) in systemic lupus erythematosus patients with antiphospholipid antibodies. Br J Haematol 97(1):227–232PubMedCrossRefGoogle Scholar
  56. 56.
    Nakamura N, Shidara Y, Kawaguchi N, Azuma C, Mitsuda N, Onishi S et al (1994) Lupus anticoagulant autoantibody induces apoptosis in umbilical vein endothelial cells: involvement of annexin V. Biochem Biophys Res Commun 205(2):1488–1493PubMedCrossRefGoogle Scholar
  57. 57.
    Dieude M, Senecal JL, Raymond Y (2004) Induction of endothelial cell apoptosis by heat-shock protein 60-reactive antibodies from anti-endothelial cell autoantibody-positive systemic lupus erythematosus patients. Arthritis Rheum 50(10):3221–3231PubMedCrossRefGoogle Scholar
  58. 58.
    Rudolphi U, Rzepka R, Batsford S, Kaufmann SH, von der Mark K, Peter HH et al (1997) The B cell repertoire of patients with rheumatoid arthritis. II. Increased frequecies of IgG+ and IgA− B cells specific for mycobacterial heat-shock protein 60 or human type II collagen in synovial fluid and tissue. Arthritis Rheum 40(8):1409–1419PubMedCrossRefGoogle Scholar
  59. 59.
    de Graeff-Meeder ER, Rijkers GT, Voorhorst-Ogink MM, Kuis W, van der Zee R, van Eden W et al (1993) Antibodies to human HSP60 in patients with juvenile chronic arthritis, diabetes mellitus, and cystic fibrosis. Pediatr Res 34(4):424–8PubMedCrossRefGoogle Scholar
  60. 60.
    Jamin C, Dugue C, Alard JE, Jousse S, Saraux A, Guillevin L et al (2005) Induction of endothelial cell apoptosis by the binding of anti-endothelial cell antibodies to Hsp60 in vasculitis-associated systemic autoimmune diseases. Arthritis Rheum 52(12):4028–4038PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Faculty of MedicineParis Descartes UniversityParisFrance
  2. 2.Faculty of Medicine, Department of Internal Medicine and Reference Center for Vasculitides and Systemic Sclerosis, Cochin Hospital, Assistance Publique Hôpitaux de ParisParis Descartes UniversityParisFrance
  3. 3.Laboratoire d’ImmunologieParis Descartes UniversityParisFrance

Personalised recommendations