, Volume 70, Issue 3, pp 921–927 | Cite as

Anti-inflammatory intravenous immunoglobulin (IVIg) suppresses homeostatic proliferation of B cells

  • Ayane Hori
  • Takashi Fujimura
  • Seiji Kawamoto
Original Article


An intravenous injection of plasma-derived immunoglobulins is used for the treatment of severe infectious and autoimmune disorders. Despite of its clinical efficacy, precise mechanisms by which intravenous immunoglobulin (IVIg) suppresses proinflammatory immune response are still enigmatic. Here, we provide in vitro evidence that IVIg inhibits homeostatic proliferation of B cells accompanied by induction of their cell aggregation. The IVIg-driven suppression of B cell proliferation and induction of cell aggregation are both unaffected by treatment with a neutralizing antibody against low-affinity Fc receptors for IgG (CD16/FcγRIII and CD32/FcγRII), known cell surface ligands for IVIg. Our observations propose a new immunosuppressive action of IVIg, which directly acts on steady-state B cells to suppress their homeostatic expansion.


Aggregation B cells Homeostatic proliferation Intravenous immunoglobulin (IVIg) 


Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest regarding this study.


  1. Akdis M, Palomares O, van de Veen W, van Splunter M, Akdis CA (2012) TH17 and TH22 cells: a confusion of antimicrobial response with tissue inflammation versus protection. J Allergy Clin Immunol 129:1438–1449CrossRefPubMedGoogle Scholar
  2. Amran D, Renz H, Lack G, Bradley K, Gelfand EW (1994) Suppression of cytokine-dependent human T-cell proliferation by intravenous immunoglobulin. Clin Immunol Immunopathol 73:180–186CrossRefPubMedGoogle Scholar
  3. Andersson J, Skansen-Saphir U, Sparrelid E, Andersson U (1996) Intravenous immune globulin affects cytokine production in T lymphocytes and monocytes/macrophages. Clin Exp Immunol 104:10–20PubMedGoogle Scholar
  4. Anthony RM, Wermeling F, Karlsson MC, Ravetch JV (2008) Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc Natl Acad Sci USA 105:19571–19578CrossRefPubMedGoogle Scholar
  5. Ballow M (2014) Mechanisms of immune regulation by IVIG. Curr Opin Allergy Clin Immunol 14:509–515CrossRefPubMedGoogle Scholar
  6. Barahona Afonso AF, Joao CM (2016) The production processes and biological effects of intravenous immunoglobulin. Biomolecules 6:15CrossRefPubMedPubMedCentralGoogle Scholar
  7. Basta M, Langlois PF, Marques M, Frank MM, Fries LF (1989) High-dose intravenous immunoglobulin modifies complement-mediated in vivo clearance. Blood 74:326–333PubMedGoogle Scholar
  8. Bjorck P, Paulie S, Axelsson B (1992) Interleukin-4-mediated aggregation of anti-IgM-stimulated human B cells: inhibition of aggregation but enhancement of proliferation by antibodies to LFA-1. Immunology 75:122–128PubMedPubMedCentralGoogle Scholar
  9. Choi YS, Baumgarth N (2008) Dual role for B-1a cells in immunity to influenza virus infection. J Exp Med 205:3053–3064CrossRefPubMedPubMedCentralGoogle Scholar
  10. Dourmishev LA, Guleva DV, Miteva LG (2016) Intravenous immunoglobulins: mode of action and indications in autoimmune and inflammatory dermatoses. Int J Inflamm 2016:3523057CrossRefGoogle Scholar
  11. Haji-Ghassemi O, Gagnon SML, Muller-Loennies S, Evans SV (2017) Polyspecificity of anti-lipid A antibodies and its relevance to the development of autoimmunity. Adv Exp Med Biol. 966:181–202CrossRefPubMedGoogle Scholar
  12. Hartung HP (2008) Advances in the understanding of the mechanism of action of IVIg. J Neurol 255:3–6CrossRefPubMedGoogle Scholar
  13. Issekutz AC, Rowter D, Miescher S, Kasermann F (2015) Intravenous IgG (IVIG) and subcutaneous IgG (SCIG) preparations have comparable inhibitory effect on T cell activation, which is not dependent on IgG sialylation, monocytes or B cells. Clin Immunol 160:123–132CrossRefPubMedGoogle Scholar
  14. Kaneko Y, Nimmerjahn F, Ravetch JV (2006) Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313:670–673CrossRefPubMedGoogle Scholar
  15. Kim SJ, Won JH (2012) B cell homeostasis and the development of chronic graft-versus-host disease: implications for B cell-depleting therapy. Leuk Lymphoma 53:19–25CrossRefPubMedGoogle Scholar
  16. Le Pottier L, Sapir T, Bendaoud B, Youinou P, Shoenfeld Y, Pers JO (2007) Intravenous immunoglobulin and cytokines: focus on tumor necrosis factor family members BAFF and APRIL. Ann N Y Acad Sci 1110:426–432CrossRefPubMedGoogle Scholar
  17. Mitrevski M, Marrapodi R, Camponeschi A, Cavaliere FM, Lazzeri C, Todi L, Visentini M (2015) Intravenous immunoglobulin and immunomodulation of B-cell—in vitro and in vivo effects. Front Immunol 6:4CrossRefPubMedPubMedCentralGoogle Scholar
  18. Mollnes TE, Andreassen IH, Hogasen K, Hack CE, Harboe M (1997) Effect of whole and fractionated intravenous immunoglobulin on complement in vitro. Mol Immunol 34:719–729CrossRefPubMedGoogle Scholar
  19. Nagelkerke SQ, Kuijpers TW (2015) Immunomodulation by IVIg and the role of Fc-gamma receptors: classic mechanisms of action after all? Front Immunol 5:674CrossRefPubMedPubMedCentralGoogle Scholar
  20. Pedros C, Duguet F, Saoudi A, Chabod M (2016) Disrupted regulatory T cell homeostasis in inflammatory bowel diseases. World J Gastroenterol 22:974–995CrossRefPubMedPubMedCentralGoogle Scholar
  21. Pollreisz A, Assinger A, Hacker S, Hoetzenecker K, Schmid W, Lang G, Wolfsberger M, Steinlechner B, Bielek E, Lalla E, Klepetko W, Volf I, Ankersmit HJ (2008) Intravenous immunoglobulins induce CD32-mediated platelet aggregation in vitro. Br J Dermatol 159:578–584CrossRefPubMedGoogle Scholar
  22. Ray A, Dittel BN (2017) Mechanisms of regulatory B cell function in autoimmune and inflammatory diseases beyond IL-10. J Clin Med 6:pii:E12Google Scholar
  23. Rigal D, Vermot-Desroches C, Heitz S, Bernaud J, Alfonsi F, Monier JC (1994) Effects of intravenous immunoglobulins (IVIG) on peripheral blood B, NK, and T cell subpopulations in women with recurrent spontaneous abortions: specific effects on LFA-1 and CD56 molecules. Clin Immunol Immunopathol 71:309–314CrossRefPubMedGoogle Scholar
  24. Seite JF, Goutsmedt C, Youinou P, Pers JO, Hillion S (2014) Intravenous immunoglobulin induces a functional silencing program similar to anergy in human B cells. J Allergy Clin Immunol 133:181–188CrossRefPubMedGoogle Scholar
  25. Seite JF, Guerrier T, Cornec D, Jamin C, Youinou P, Hillion S (2011) TLR9 responses of B cells are repressed by intravenous immunoglobulin through the recruitment of phosphatase. J Autoimmun 37:190–197CrossRefPubMedGoogle Scholar
  26. Sigman K, Ghibu F, Sommerville W, Toledano BJ, Bastein Y, Cameron L, Hamid QA, Mazer B (1998) Intravenous immunoglobulin inhibits IgE production in human B lymphocytes. J Allergy Clin Immunol 102:421–427CrossRefPubMedGoogle Scholar
  27. Tha-In T, Bayry J, Metselaar HJ, Kaveri SV, Kwekkeboom J (2008) Modulation of the cellular immune system by intravenous immunoglobulin. Trends Immunol 29:608–615CrossRefPubMedGoogle Scholar
  28. Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, Hunziker T, Saurat JH, Tschopp J, French LE (1998) Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282:490–493CrossRefPubMedGoogle Scholar
  29. Von Behring E (1890) Untersuchungen ueber das Zustandekommen der Diphtherie-Immunität bei Thieren. Dtsch Med Wochenschr 16:1145–1148 (in Germany) CrossRefGoogle Scholar
  30. Von Behring E, Kitasato S (1890) Ueber das Zustandekommen der Diphtherie-Immunität und der Tetanus-Immunität bei Thieren. Dtsch Med Wochenschr 16:1113–1114 (in Germany) CrossRefGoogle Scholar
  31. Wunsch M, Hohmann C, Milles B, Rostermund C, Lehmann PV, Schroeter M, Bayas A, Ulzheimer J, Mäurer M, Ergün S, Kuerten S (2016) The correlation between the virus- and brain antigen-specific B cell response in the blood of patients with multiple sclerosis. Viruses 8:105CrossRefPubMedPubMedCentralGoogle Scholar
  32. Yanes RE, Gustafson CE, Weyand CM, Goronzy JJ (2017) Lymphocyte generation and population homeostasis throughout life. Semin Hematol 54:33–38CrossRefPubMedGoogle Scholar
  33. Zuercher AW, Spirig R, Baz Morelli A, Kasermann F (2016) IVIG in autoimmune disease: potential next generation biologics. Autoimmun Rev 15:781–785CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Hiroshima Research Center for Healthy Aging (HiHA), Department of Molecular Biotechnology, Graduate School of Advanced Sciences of MatterHiroshima UniversityHigashi-HiroshimaJapan

Personalised recommendations