Archivum Immunologiae et Therapiae Experimentalis

, Volume 57, Issue 6, pp 447–458 | Cite as

CD40-activated B cells from patients with systemic lupus erythematosus can be modulated by therapeutic immunoglobulins in vitro

  • Sonia NéronEmail author
  • Gilles Boire
  • Nathalie Dussault
  • Claudia Racine
  • Artur J. de Brum-Fernandes
  • Serge Côté
  • Annie Jacques
Open Access
Original Article



Aberrant signaling within and between B and T cells, considered to be central in systemic lupus erythematosus (SLE), could depend on enhanced CD40-CD154 activation. As a result, autoreactive B cells, normally anergic, differentiate and secrete antibodies attacking several normal tissues. Thus restorating B cell homeostasis might help control this disease. In this study, two facets of SLE B cells were investigated, namely their in vitro response to CD40-CD154 and the effect of treatment with human immunoglobulins for intravenous use (IVIg).

Materials and Methods

Blood samples from SLE patients and healthy volunteers were obtained and used to isolate B cells, which were activated through CD40 in the presence or absence of IVIg. The phenotype, proliferation, and differentiation of the SLE B cells were determined and compared with those of control B cells using flow cytometry and standard ELISA.


In this model, CD40-activated SLE B cells, as control B cells, proliferated and differentiated and were characterized by the emergence of CD19loCD38++CD138+CD27++ cells. IVIg treatment of the CD40-activated SLE B cells resulted in higher differentiation, characterized by increased secretion rates of IgG and IgM, as reported previously for control B cells.


Taken as a whole, such accelerated differentiation of CD40-activated B cells suggests that IVIg may participate in re-equilibration of the antibody repertoire by replacing pathological antibodies by de novo harmless antibodies.


B cell SLE differentiation intravenous immunoglobulins IVIg 


  1. Agenes F, Rosado MM, Freitas AA (2000) Peripheral B cell survival. Cell Mol Life Sci 57: 1220–1228CrossRefPubMedGoogle Scholar
  2. Anolik JH, Barnard J, Cappione A et al (2004) Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum 50: 3580–3590CrossRefPubMedGoogle Scholar
  3. Anthony RM, Nimmerjahn F, Ashline DJ et al (2008) Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science 320: 373–376CrossRefPubMedGoogle Scholar
  4. Arce E, Jackson DG, Gill MA et al (2001) Increased frequency of pre-germinal center b cells and plasma cell precursors in the blood of children with systemic lupus erythematosus. J Immunol 167: 2361–2369PubMedGoogle Scholar
  5. Banchereau J, de Paoli P, Valle A et al (1991) Long-term human B cell lines dependent on interleukin-4 and antibody to CD40. Science 251: 70–72CrossRefPubMedGoogle Scholar
  6. Branch DW, Porter TF, Paidas MJ et al (2001) Obstetric uses of intravenous immunoglobulin: Successes, failures, and promises. J Allergy Clin Immunol 108: S133–S138CrossRefPubMedGoogle Scholar
  7. Cambridge G, Leandro MJ, Teodorescu M et al (2006) B cell depletion therapy in systemic lupus erythematosus – effect on autoantibody and antimicrobial antibody profiles. Arthritis Rheum 54: 3612–3622CrossRefPubMedGoogle Scholar
  8. Cappione AJ, Pugh-Bernard AE, Anolik JH et al (2004) Lupus IgG V(H)4.34 antibodies bind to a 220-kDa glycoform of CD45/B220 on the surface of human B lymphocytes. J Immunol 172: 4298–4307PubMedGoogle Scholar
  9. Carter RH, Zhao H, Liu X et al (2005) Expression and occupancy of BAFF-R on B cells in systemic lupus erythematosus. Arthritis Rheum 52: 3943–3954CrossRefPubMedGoogle Scholar
  10. de Grandmont MJ, Racine C, Roy A et al (2003) Intravenous immunoglobulins induce the in vitro differentiation of human B lymphocytes and the secretion of IgG. Blood 101: 3065–3073CrossRefPubMedGoogle Scholar
  11. Dilillo DJ, Hamaguchi Y, Ueda Y et al (2008) Maintenance of long-lived plasma cells and serological memory despite mature and memory b cell depletion during CD20 immunotherapy in mice. J Immunol 180: 361–371PubMedGoogle Scholar
  12. Driver CB, Ishimori M, Weisman MH (2008) The B cell in systemic lupus erythematosus: a rational target for more effective therapy. Ann Rheum Dis 67: 1374–1381CrossRefPubMedGoogle Scholar
  13. Dussault N, Ducas E, Racine C et al (2008) Immunomodulation of human B cells following treatment with intravenous immunoglobulins involves increased phosphorylation of extracellular signal-regulated kinases 1 and 2. Int Immunol 20: 1369–1379CrossRefPubMedGoogle Scholar
  14. Fecteau JF, Néron S (2003) CD40 stimulation of human peripheral B lymphocytes: distinct response from nanve and memory cells. J Immunol 171: 4621–4629PubMedGoogle Scholar
  15. Gladman DD, Goldsmith CH, Urowitz MB et al (2000) The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index for systemic lupus erythematosus international comparison. J Rheumatol 27: 373–376PubMedGoogle Scholar
  16. Gonzalez-Amaro R, Portales-Perez D, Baranda L et al (1998) Role of IL-10 in the abnormalities of early cell activation events of lymphocytes from patients with systemic lupus erythematosus. J Autoimmun 11: 395–402CrossRefPubMedGoogle Scholar
  17. Grammer AC, Lipsky PE (2002) CD154-CD40 interactions mediate differentiation to plasma cells in healthy individuals and persons with systemic lupus erythematosus. Arthritis Rheum 46: 1417–1429CrossRefPubMedGoogle Scholar
  18. Grammer AC, Lipsky PE (2003) B cell abnormalities in systemic lupus erythematosus. Arthritis Res Ther 5(suppl 4):S22–27Google Scholar
  19. Grammer AC, Slota R, Fischer R et al (2003) Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. J Clin Invest 112: 1506–1520PubMedGoogle Scholar
  20. Harada Y, Kawano MM, Huang N et al (1996) Identification of early plasma cells in peripheral blood and their clinical significance. Br J Haematol 92: 184–191CrossRefPubMedGoogle Scholar
  21. Harigai M, Hara M, Fukasawa C et al (1999) Responsiveness of peripheral blood B cells to recombinant CD40 ligand in patients with systemic lupus erythematosus. Lupus 8: 227–233CrossRefPubMedGoogle Scholar
  22. Hawker G, Gabriel S, Bombardier C et al (1993) A reliability study of SLEDAI: a disease activity index for systemic lupus erythematosus. J Rheumatol 20: 657–660PubMedGoogle Scholar
  23. Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40: 1725CrossRefPubMedGoogle Scholar
  24. Isenberg DA, McClure C, Farewell V et al (1998) Correlation of 9G4 idiotope with disease activity in patients with systemic lupus erythematosus. Ann Rheum Dis 57: 566–570CrossRefPubMedGoogle Scholar
  25. Jacobi AM, Odendahl M, Reiter K et al (2003) Correlation between circulating CD27(high) plasma cells and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 48: 1332–1342CrossRefPubMedGoogle Scholar
  26. Kaveri SV, Dietrich G, Hurez V et al (1991) Intravenous immunoglobulins (IVIg) in the treatment of autoimmune diseases. Clin Exp Immunol 86: 192–198PubMedCrossRefGoogle Scholar
  27. Kazatchkine MD, Dietrich G, Hurez V et al (1994) V region-mediated selection of autoreactive repertoires by intravenous immunoglobulin (i.v.Ig). Immunol Rev 139: 79–107CrossRefPubMedGoogle Scholar
  28. Klinman DM, Shirai A, Conover J et al (1994) Cross-reactivity of IgG anti-DNA-secreting B cells in patients with systemic lupus erythematosus. Eur J Immunol 24: 53–58CrossRefPubMedGoogle Scholar
  29. Koshy M, Berger D, Crow MK (1996) Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J Clin Invest 98: 826–837CrossRefPubMedGoogle Scholar
  30. Le Pottier L, Bendaoud B, Dueymes M et al (2007) BAFF, a new target for intravenous immunoglobulin in autoimmunity and cancer. J Clin Immunol 27: 257–265CrossRefPubMedGoogle Scholar
  31. Liang MH, Socher SA, Larson MG et al (1989) Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 32: 1107–1118CrossRefPubMedGoogle Scholar
  32. Mandik-Nayak L, Ridge N, Fields M et al (2008) Role of B cells in systemic lupus erythematosus and rheumatoid arthritis. Curr Opin Immunol 20: 639–645CrossRefPubMedGoogle Scholar
  33. McHeyzer-Williams LJ, Malherbe LP, McHeyzer-Williams MG (2006) Checkpoints in memory B-cell evolution. Immunol Rev 211: 255–268CrossRefPubMedGoogle Scholar
  34. Morell A (1997) Pharmacokinetics of intravenous immunoglobulin preparations. In: Lee ML, Strand V (eds) Intravenous immunoglobulins in clinical practice. Marcel Dekker, Inc., New-York, NY, pp 1–18Google Scholar
  35. Mori I, Parizot C, Dorgham K et al (2008) Prominent plasmacytosis following intravenous immunoglobulin correlates with clinical improvement in Guillain-Barre syndrome. PLoS ONE 3: e2109CrossRefPubMedGoogle Scholar
  36. Nagafuchi H, Shimoyama Y, Kashiwakura J et al (2003) Preferential expression of B7.2 (CD86), but not B7.1 (CD80), on B cells induced by CD40/CD40L interaction is essential for anti-DNA autoantibody production in patients with systemic lupus erythematosus. Clin Exp Rheumatol 21: 71–77PubMedGoogle Scholar
  37. Negi VS, Elluru S, Siberil S et al (2007) Intravenous immunoglobulin: An update on the clinical use and mechanisms of action. J Clin Immunol 27: 233–245CrossRefPubMedGoogle Scholar
  38. Néron S, Dussault N, Racine C (2006) Whole-blood leukoreduction filters are a source for cryopreserved cells for phenotypic and functional investigations on peripheral blood lymphocytes. Transfusion 46: 537–544CrossRefPubMedGoogle Scholar
  39. Néron S, Pelletier A, Chevrier MC et al (1996) Induction of LFA-1 independent human B cell proliferation and differentiation by binding of CD40 with its ligand. Immunol Invest 25: 79–89CrossRefPubMedGoogle Scholar
  40. Néron S, Racine C, Roy A et al (2005) Differential responses of human B-lymphocyte subpopulations to graded levels of CD40-CD154 interaction. Immunology 116: 454–463PubMedGoogle Scholar
  41. Néron S, Thibault L, Dussault N et al (2007) Characterization of mononuclear cells remaining in the leukoreduction system chambers of apheresis instruments after routine platelet collection: a new source of viable human blood cells. Transfusion 47: 1042–1049CrossRefPubMedGoogle Scholar
  42. Nimmerjahn F, Ravetch JV (2008) Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 8: 34–47CrossRefPubMedGoogle Scholar
  43. Odendahl M, Jacobi A, Hansen A et al (2000) Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 165: 5970–5979PubMedGoogle Scholar
  44. Pugh-Bernard AE, Cambier JC (2006) B cell receptor signaling in human systemic lupus erythematosus. Curr Opin Rheumatol 18: 451–455CrossRefPubMedGoogle Scholar
  45. Pugh-Bernard AE, Silverman GJ, Cappione AJ et al (2001) Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance. J Clin Invest 108: 1061–1070PubMedGoogle Scholar
  46. Putterman C (2004) New approaches to the renal pathogenicity of anti-DNA antibodies in systemic lupus erythematosus. Autoimmun Rev 3: 7–11CrossRefPubMedGoogle Scholar
  47. Radbruch A, Muehlinghaus G, Luger EO et al (2006) Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol 6: 741–750CrossRefPubMedGoogle Scholar
  48. Roy A, Krzykwa E, Lemieux R et al (2001) Increased efficiency of gamma-irradiated versus mitomycin C-treated feeder cells for the expansion of normal human cells in long-term cultures. J Hematother Stem Cell Res 10: 873–880CrossRefPubMedGoogle Scholar
  49. Sato S, Fujimoto M, Hasegawa M et al (2004) Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum 50: 1918–1927CrossRefPubMedGoogle Scholar
  50. Seite JF, Shoenfeld Y, Youinou P et al (2008) What is the contents of the magic draft IVIg?. Autoimmun Rev 7: 435–439CrossRefPubMedGoogle Scholar
  51. Sherer Y, Shoenfeld Y (2006a) Intravenous immunoglobulin for immunomodulation of systemic lupus erythematosus. Autoimmun Rev 5: 153–155CrossRefPubMedGoogle Scholar
  52. Sherer Y, Shoenfeld Y (2006b) Mechanisms of disease: atherosclerosis in autoimmune diseases. Nat Clin Pract Rheumatol 2: 99–106CrossRefPubMedGoogle Scholar
  53. Shoenfeld Y, Katz U (2005) IVIg therapy in autoimmunity and related disorders: our experience with a large cohort of patients. Autoimmunity 38: 123–137CrossRefPubMedGoogle Scholar
  54. Shoenfeld Y, Rauova L, Gilburd B et al (2002) Efficacy of IVIG affinity-purified anti-double-stranded DNA anti-idiotypic antibodies in the treatment of an experimental murine model of systemic lupus erythematosus. Int Immunol 14: 1303–1311CrossRefPubMedGoogle Scholar
  55. Sun KH, Yu CL, Tang SJ et al (2000) Monoclonal anti-double- stranded DNA autoantibody stimulates the expression and release of IL-1beta, IL-6, IL-8, IL-10 and TNF-alpha from normal human mononuclear cells involving in the lupus pathogenesis. Immunology 99: 352–360CrossRefPubMedGoogle Scholar
  56. Tangye SG, Bryant VL, Cuss AK et al (2006) BAFF, APRIL and human B cell disorders. Semin Immunol 18: 305–317CrossRefPubMedGoogle Scholar
  57. Tha-In T, Bayry J, Metselaar HJ et al (2008) Modulation of the cellular immune system by intravenous immunoglobulin. Trends Immunol 29: 608–615CrossRefPubMedGoogle Scholar
  58. Toubi E, Kessel A, Shoenfeld Y (2005) High-dose intravenous immunoglobulins: an option in the treatment of systemic lupus erythematosus. Hum Immunol 66: 395–402CrossRefPubMedGoogle Scholar
  59. Toubi E, Shoenfeld Y (2004a) BLyS/BAFF: a potential target in the treatment of active systemic lupus erythematosus. Isr Med Assoc J 6: 99–102PubMedGoogle Scholar
  60. Toubi E, Shoenfeld Y (2004b) The role of CD40-CD154 interactions in autoimmunity and the benefit of disrupting this pathway. Autoimmunity 37: 457–464CrossRefPubMedGoogle Scholar
  61. Van Kooten C, Banchereau J (2000) CD40-CD40 ligand. J Leukoc Biol 67: 2–17PubMedGoogle Scholar
  62. Vani J, Elluru S, Negi VS et al (2008) Role of natural antibodies in immune homeostasis: IVIg perspective. Autoimmun Rev 7: 440–444CrossRefPubMedGoogle Scholar
  63. Wei C, Anolik J, Cappione A et al (2007) A new population of cells lacking expression of CD27 represents a notable component of the B cell memory compartment in systemic lupus erythematosus. J Immunol 178: 6624–6633PubMedGoogle Scholar
  64. Wouters CH, Diegenant C, Ceuppens JL et al (2004) The circulating lymphocyte profiles in patients with discoid lupus erythematosus and systemic lupus erythematosus suggest a pathogenetic relationship. Br J Dermatol 150: 693–700CrossRefPubMedGoogle Scholar
  65. Zandman-Goddard G, Levy Y, Shoenfeld Y (2005) Intravenous immunoglobulin therapy and systemic lupus erythematosus. Clin Rev Allergy Immunol 29: 219–228CrossRefPubMedGoogle Scholar
  66. Zhang J, Roschke V, Baker KP et al (2001) Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol 166: 6–10PubMedGoogle Scholar
  67. Zimmerman R, Radhakrishnan J, Valeri A et al (2001) Advances in the treatment of lupus nephritis. Ann Rev Med 52: 63–78CrossRefPubMedGoogle Scholar
  68. Zouali M (2005) Taming lupus. Sci Am 292: 58–65CrossRefPubMedGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2009

Authors and Affiliations

  • Sonia Néron
    • 1
    • 2
    Email author
  • Gilles Boire
    • 3
  • Nathalie Dussault
    • 1
  • Claudia Racine
    • 1
  • Artur J. de Brum-Fernandes
    • 3
  • Serge Côté
    • 1
    • 2
  • Annie Jacques
    • 1
  1. 1.Recherche et développement, Héma-Québec, Ingénierie cellulaireQuébecCanada
  2. 2.Département de biochimie et microbiologie, Faculté des sciences et de génieUniversité LavalQuébecCanada
  3. 3.Service de rhumatologie, Faculté de médecine et des sciences de la santéUniversité de Sherbrookeet Centre hospitalier universitaire de SherbrookeSherbrookeCanada

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