Skip to main content

Antiendothelial Cells Autoantibodies in Vasculitis-Associated Systemic Diseases

Clinical Reviews in Allergy & Immunology volume 35, pages 59–65 (2008)Cite this 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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Moreland LW, Gay RE, Gay S (1991) Collagen autoantibodies in patients with vasculitis and systemic lupus erythematosus. Clin Immunol Immunopathol 60(3):412–418

    PubMed  Article  CAS  Google Scholar 

  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):206–210

    PubMed  Article  CAS  Google Scholar 

  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):68–74

    PubMed  CAS  Article  Google Scholar 

  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):179–185

    PubMed  CAS  Google Scholar 

  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):5572–5578

    PubMed  CAS  Google Scholar 

  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):241–251

    PubMed  Article  CAS  Google Scholar 

  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):212–219

    PubMed  Article  CAS  Google Scholar 

  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):1651–1660

    PubMed  Article  CAS  Google Scholar 

  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):121–127

    PubMed  Article  CAS  Google Scholar 

  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):1511–1515

    PubMed  Article  CAS  Google Scholar 

  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)

  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):313–322

    Article  Google Scholar 

  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):1013–1022

    PubMed  Article  CAS  Google Scholar 

  14. Ronda N, Meroni P, Raschi H, Borghi M (eds) (2007) Anti-endothelial cell autoantibodies. Vol. second edition: Elsevier

  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):165–178

    PubMed  Article  CAS  Google Scholar 

  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):222–228

    PubMed  Article  CAS  Google Scholar 

  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):19–26

    PubMed  CAS  Google Scholar 

  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):171–179

    PubMed  Article  CAS  Google Scholar 

  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 1109:538–549

    PubMed  Article  CAS  Google Scholar 

  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):2025–2035

    PubMed  Article  CAS  Google Scholar 

  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):703–711

    PubMed  CAS  Google Scholar 

  22. Gupta S (1981) Surgical and immunological aspects of Takayasu’s disease. Ann R Coll Surg Engl 63(5):325–332

    PubMed  CAS  Google Scholar 

  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):923–924

    PubMed  Article  CAS  Google Scholar 

  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):2396–2401

    PubMed  CAS  Google Scholar 

  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):240–244

    PubMed  CAS  Google Scholar 

  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):352–357

    PubMed  Article  CAS  Google Scholar 

  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):264–269

    PubMed  CAS  Article  Google Scholar 

  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):1428–1435

    PubMed  Article  CAS  Google Scholar 

  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):1958–1972

    PubMed  Article  CAS  Google Scholar 

  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):433–440

    PubMed  CAS  Google Scholar 

  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):186–194

    PubMed  Article  CAS  Google Scholar 

  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):387–392

    PubMed  CAS  Google Scholar 

  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):211–216

    PubMed  Article  CAS  Google Scholar 

  34. Belizna C, Tervaert JW (1997) Specificity, pathogenecity, and clinical value of antiendothelial cell antibodies. Semin Arthritis Rheum 27(2):98–109

    PubMed  Article  CAS  Google Scholar 

  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):120–126

    PubMed  Article  CAS  Google Scholar 

  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):805–808

    PubMed  CAS  Google Scholar 

  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):14–19

    PubMed  CAS  Article  Google Scholar 

  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):458–465

    PubMed  CAS  Google Scholar 

  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):758–766

    PubMed  Article  CAS  Google Scholar 

  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):52–60

    PubMed  CAS  Article  Google Scholar 

  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):190–195

    PubMed  CAS  Google Scholar 

  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):631–640

    PubMed  Article  CAS  Google Scholar 

  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):423–429

    PubMed  Article  CAS  Google Scholar 

  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):63–72

    PubMed  Article  CAS  Google Scholar 

  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):3508–3518

    PubMed  CAS  Google Scholar 

  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):2326–2333

    PubMed  Article  CAS  Google Scholar 

  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):1421–1432

    PubMed  Article  CAS  Google Scholar 

  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):1788–1790

    PubMed  CAS  Google Scholar 

  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):247–253

    PubMed  Article  CAS  Google Scholar 

  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):1511–1513

    PubMed  Article  CAS  Google Scholar 

  51. Tannenbaum SH, Finko R, Cines DB (1986) Antibody and immune complexes induce tissue factor production by human endothelial cells. J Immunol 137(5):1532–1537

    PubMed  CAS  Google Scholar 

  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):27–31

    PubMed  Google Scholar 

  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):2550–2562

    PubMed  Article  CAS  Google Scholar 

  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):1738–1747

    PubMed  Article  CAS  Google Scholar 

  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):227–232

    PubMed  Article  CAS  Google Scholar 

  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):1488–1493

    PubMed  Article  CAS  Google Scholar 

  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):3221–3231

    PubMed  Article  CAS  Google Scholar 

  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):1409–1419

    PubMed  Article  CAS  Google Scholar 

  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):424–8

    PubMed  Article  Google Scholar 

  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):4028–4038

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

Philippe Guilpain is on a grant from the Fondation pour la Recherche Médicale (FRM).

Author information

Authors and Affiliations

  1. Faculty of Medicine, Paris Descartes University, UPRES EA 4058, Paris, France

    Philippe Guilpain & Luc Mouthon

  2. Faculty of Medicine, Department of Internal Medicine and Reference Center for Vasculitides and Systemic Sclerosis, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris Descartes University, Paris, France

    Philippe Guilpain & Luc Mouthon

  3. Laboratoire d’Immunologie, Paris Descartes University, UPRES EA 4058, Pavillon Gustave Roussy, 4e étage, 8 rue Méchain, 75014, Paris, France

    Luc Mouthon

Authors
  1. Philippe Guilpain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luc Mouthon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luc Mouthon.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Guilpain, P., Mouthon, L. Antiendothelial Cells Autoantibodies in Vasculitis-Associated Systemic Diseases. Clinic Rev Allerg Immunol 35, 59–65 (2008). https://doi.org/10.1007/s12016-007-8069-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-007-8069-3

Keywords

  • Vasculitis
  • Autoantibodies
  • Endothelial cells