Rheumatology International

, Volume 28, Issue 7, pp 661–665 | Cite as

Antiphospholipid syndrome patients display reduced titers of soluble CD21 in their sera irrespective of circulating anti-β2-glycoprotein-I autoantibodies

  • Anjana Singh
  • Miri Blank
  • Yehuda Shoenfeld
  • Harald IllgesEmail author
Orignal Article


A soluble form of the complement receptor CD21 (sCD21) is shed from the lymphocyte surface. The sCD21 is able to bind all known ligands such as CD23, sCD23, Epstein–Barr virus and C3d in immune complexes. Here, we show the serum levels of sCD21 in sera the of antiphospholipid syndrome (APS) patients. Antiphospholipid syndrome is an autoimmune disorder in which autoantibodies cause heart attack, stroke and miscarriage. Antiphospholipid syndrome may appear as primary or in association with systemic lupus erythromatosus (SLE) and other autoimmune diseases. Here, we ask whether APS patients have different sCD21 titers compared to healthy persons and whether sCD21 levels correlate with the presence of anti-β2-GPI autoantibodies. We show that autoimmune APS patients have significantly reduced amounts of sCD21 in their sera, irrespective of the presence of anti-β2-GPI autoantibodies. In our APS patients cohort additional SLE, vasculities, DVT (deep vein thrombosis), fetal loss or thrombosis did not correlate to the reduced level of sCD21.


Complement receptor 2/CD21 Antiphospholipid syndrome (APS) Systemic lupus erythomatosus (SLE) Shedding Autoantibody 



This work was supported by AUTOROME European Community grant no. LSHM-CT-2004-005264 to HI and MB. AS is a Marie Curie Fellow.


  1. 1.
    Timens W, Boes A, Rozeboom-Uiterwijk T, Poppema S (1989) Immaturity of the human splenic marginal zone in infancy. Possible contribution to the deficient infant immune response. J Immunol 143(10):3200–3206PubMedGoogle Scholar
  2. 2.
    Aubry JP, Pochon S, Graber P, Jansen KU, Bonnefoy JY (1992) CD21 is a ligand for CD23 and regulates IgE production. Nature 358(6386):505–507PubMedCrossRefGoogle Scholar
  3. 3.
    Masilamani M, Kassahn D, Mikkat S, Glocker MO, Illges H (2003) B cell activation leads to shedding of complement receptor type II (CR2/CD21). Eur J Immunol 33(9):2391–2397PubMedCrossRefGoogle Scholar
  4. 4.
    Masilamani M, von Seydlitz E, Bastmeyer M, Illges H (2002) T cell activation induced by cross-linking CD3 and CD28 leads to silencing of Epstein–Barr virus/C3d receptor (CR2/CD21) gene and protein expression. Immunobiology 206(5):528–536PubMedCrossRefGoogle Scholar
  5. 5.
    Ling N, Hansel T, Richardson P, Brown B (1991) Cellular origins of serum complement receptor type 2 in normal individuals and in hypogammaglobulinaemia. Clin Exp Immunol 84(1):16–22PubMedCrossRefGoogle Scholar
  6. 6.
    Myones BL, Ross GD (1987) Identification of a spontaneously shed fragment of B cell complement receptor type two (CR2) containing the C3d-binding site. Complement 4(2):87–98PubMedGoogle Scholar
  7. 7.
    Weis JJ, Tedder TF, Fearon DT (1984) Identification of a 145,000 Mr membrane protein as the C3d receptor (CR2) of human B lymphocytes. Proc Natl Acad Sci USA 81(3):881–885PubMedCrossRefGoogle Scholar
  8. 8.
    Huemer HP, Larcher C, Prodinger WM, Petzer AL, Mitterer M, Falser N (1993) Determination of soluble CD21 as a parameter of B cell activation. Clin Exp Immunol 93(2):195–199PubMedCrossRefGoogle Scholar
  9. 9.
    Reynes M, Aubert JP, Cohen JH, Audouin J, Tricottet V, Diebold J, Kazatchkine MD (1985) Human follicular dendritic cells express CR1, CR2, and CR3 complement receptor antigens. J Immunol 135(4):2687–2694PubMedGoogle Scholar
  10. 10.
    Tsoukas CD, Lambris JD (1988) Expression of CR2/EBV receptors on human thymocytes detected by monoclonal antibodies. Eur J Immunol 18(8):1299–1302PubMedCrossRefGoogle Scholar
  11. 11.
    Hebell T, Ahearn JM, Fearon DT (1991) Suppression of the immune response by a soluble complement receptor of B lymphocytes. Science 254(5028):102–105PubMedCrossRefGoogle Scholar
  12. 12.
    Qin D, Wu J, Carroll MC, Burton GF, Szakal AK, Tew JG (1998) Evidence for an important interaction between a complement-derived CD21 ligand on follicular dendritic cells and CD21 on B cells in the initiation of IgG responses. J Immunol 161(9):4549–4554PubMedGoogle Scholar
  13. 13.
    Fischer E, Delibrias C, Kazatchkine MD (1991) Expression of CR2 (the C3dg/EBV receptor, CD21) on normal human peripheral blood T lymphocytes. J Immunol 146(3):865–869PubMedGoogle Scholar
  14. 14.
    Fingeroth JD, Weis JJ, Tedder TF, Strominger JL, Biro PA, Fearon DT (1984) Epstein–Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proc Natl Acad Sci USA 81(14):4510–4514PubMedCrossRefGoogle Scholar
  15. 15.
    Lowe J, Brown B, Hardie D, Richardson P, Ling N (1989) Soluble forms of CD21 and CD23 antigens in the serum in B cell chronic lymphocytic leukaemia. Immunol Lett 20(2):103–109PubMedCrossRefGoogle Scholar
  16. 16.
    Delibrias CC, Fischer E, Bismuth G, Kazatchkine MD (1992) Expression, molecular association, and functions of C3 complement receptors CR1 (CD35) and CR2 (CD21) on the human T cell line HPB-ALL. J Immunol 149(3):768–774PubMedGoogle Scholar
  17. 17.
    Moore MD, DiScipio RG, Cooper NR, Nemerow GR (1989) Hydrodynamic, electron microscopic, and ligand-binding analysis of the Epstein–Barr virus/C3dg receptor (CR2). J Biol Chem 264(34):20576–20582PubMedGoogle Scholar
  18. 18.
    Masilamani M, Nowack R, Witte T, Schlesier M, Warnatz K, Glocker MO, Peter HH, Illges H (2004) Reduction of soluble complement receptor 2/CD21 in systemic lupus erythomatosus and Sjogren’s syndrome but not juvenile arthritis. Scand J Immunol 60(6):625–630PubMedCrossRefGoogle Scholar
  19. 19.
    Fremeaux-Bacchi V, Fischer E, Lecoanet-Henchoz S, Mani JC, Bonnefoy JY, Kazatchkine MD (1998) Soluble CD21 (sCD21) forms biologically active complexes with CD23: sCD21 is present in normal plasma as a complex with trimeric CD23 and inhibits soluble CD23-induced IgE synthesis by B cells. Int Immunol 10(10):1459–1466PubMedCrossRefGoogle Scholar
  20. 20.
    Ulgiati D, Pham C, Holers VM (2002) Functional analysis of the human complement receptor 2 (CR2/CD21) promoter: characterization of basal transcriptional mechanisms. J Immunol 168(12):6279–6285PubMedGoogle Scholar
  21. 21.
    Hannan J, Young K, Szakonyi G, Overduin MJ, Perkins SJ, Chen X, Holers VM (2002) Structure of complement receptor (CR) 2 and CR2-C3d complexes. Biochem Soc Trans 30(Pt 6):983–989PubMedGoogle Scholar
  22. 22.
    Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van Breda-Vriesman PJ, Barbui T, Zwaal RF, Bevers EM (1990) Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 335(8705):1544–1547PubMedCrossRefGoogle Scholar
  23. 23.
    Masilamani M, von Kempis J, Illges H (2004) Decreased levels of serum soluble complement receptor-II (CR2/CD21) in patients with rheumatoid arthritis. Rheumatology 43(2):186–190Google Scholar
  24. 24.
    Sammaritano LR, Gharavi AE (1992) Antiphospholipid antibody syndrome. Clin Lab Med 12(1):41–59PubMedGoogle Scholar
  25. 25.
    Shoenfeld Y (2003) Systemic antiphospholipid syndrome. Lupus 12(7):497–498PubMedCrossRefGoogle Scholar
  26. 26.
    Blank M, Tincani A, Shoenfeld Y (1994) Induction of experimental antiphospholipid syndrome in naive mice with purified IgG antiphosphatidylserine antibodies. J Rheumatol 21(1):100–104PubMedGoogle Scholar
  27. 27.
    George J, Blank M, Levy Y, Meroni P, Damianovich M, Tincani A, Shoenfeld Y (1998) Differential effects of anti-beta2-glycoprotein I antibodies on endothelial cells and on the manifestations of experimental antiphospholipid syndrome. Circulation 97(9):900–906PubMedGoogle Scholar
  28. 28.
    Blank M, Cohen J, Toder V, Shoenfeld Y (1991) Induction of anti-phospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies. Proc Natl Acad Sci USA 88(8):3069–3073PubMedCrossRefGoogle Scholar
  29. 29.
    Blank M, Shoenfeld Y, Cabilly S, Heldman Y, Fridkin M, Katchalski-Katzir E (1999) Prevention of experimental antiphospholipid syndrome and endothelial cell activation by synthetic peptides. Proc Natl Acad Sci USA 96(9):5164–5168PubMedCrossRefGoogle Scholar
  30. 30.
    Blank M, George J, Barak V, Tincani A, Koike T, Shoenfeld Y (1998) Oral tolerance to low dose beta 2-glycoprotein I: immunomodulation of experimental antiphospholipid syndrome. J Immunol 161(10):5303–5312PubMedGoogle Scholar
  31. 31.
    Meroni P, Ronda N, Raschi E, Borghi MO (2005) Humoral autoimmunity against endothelium: theory or reality? Trends Immunol 26(5):275–281PubMedCrossRefGoogle Scholar
  32. 32.
    Blank M, Krause I, Fridkin M, Keller N, Kopolovic J, Goldberg I, Tobar A, Shoenfeld Y (2002) Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J Clin Invest 109(6):797–804PubMedGoogle Scholar
  33. 33.
    Masilamani M, Apell HJ, Illges H (2002) Purification and characterization of soluble CD21 from human plasma by affinity chromatography and density gradient centrifugation. J Immunol Methods 270(1):11–18PubMedGoogle Scholar
  34. 34.
    Lyubchenko T, dal Porto J, Cambier JC, Holers VM (2005) Coligation of the B cell receptor with complement receptor type 2 (CR2/CD21) using its natural ligand C3dg: activation without engagement of an inhibitory signaling pathway. J Immunol 174(6):3264–3272PubMedGoogle Scholar
  35. 35.
    Szakonyi G, Guthridge JM, Li D, Young K, Holers VM, Chen XS (2001) Structure of complement receptor 2 in complex with its C3d ligand. Science 292(5522):1725–1728PubMedCrossRefGoogle Scholar
  36. 36.
    Carel JC, Myones BL, Frazier B, Holers VM (1990) Structural requirements for C3d, g/Epstein–Barr virus receptor (CR2/CD21) ligand binding, internalization, and viral infection. J Biol Chem 265(21):12293–12299PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Anjana Singh
    • 1
  • Miri Blank
    • 2
  • Yehuda Shoenfeld
    • 2
  • Harald Illges
    • 1
    Email author
  1. 1.Department of Natural Sciences, Immunology and Cell BiologyUniversity of Applied SciencesRheinbachGermany
  2. 2.Center for Autoimmune diseases, Department of Medicine “B” and Human Microbiology, Sheba Medical Center, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael

Personalised recommendations