Therapeutic preparations of normal polyspecific IgG (IVIg) induce apoptosis in human lymphocytes and monocytes: a novel mechanism of action of IVIg involving the Fas apoptotic pathway

J Immunol. 1998 Oct 1;161(7):3781-90.


Therapeutic preparations of normal human IgG for i.v. use (i.v.Ig) exhibit a broad spectrum of immunoregulatory activities in vitro and in vivo. I.v.Ig has been shown to inhibit the proliferation of activated B and T lymphocytes and of several autonomously growing cell lines. In this study, we demonstrate that i.v.Ig induces apoptosis in leukemic cells of lymphocyte and monocyte lineage and in CD40-activated normal tonsillar B cells, involving, at least in part, Fas (CD95/APO-1) and activation of caspases. I.v.Ig-induced apoptosis was higher in Fas-sensitive HuT78 cells than in Fas-resistant HuT78.B1 mutant cells, and soluble Fas inhibited IVIg-induced apoptosis. I.v.Ig immunoprecipitated Fas from Fas-expressing transfectants and recognized purified Fas/glutathione-S-transferase fusion proteins upon immunoblotting. Affinity-purified anti-Fas Abs from i.v.Ig induced apoptosis of CEM T cells at a 120-fold lower concentration than unfractionated i.v.Ig. Inhibitors of cysteine proteases of the caspase family, caspase 1 (IL-1beta-converting enzyme) and caspase 3 (Yama/CPP32b), partially inhibited i.v.Ig-induced apoptosis of CEM cells. Furthermore, cleavage of poly(A)DP-ribose polymerase into an 85-kDa signature death fragment was observed in CEM cells following i.v.Ig treatment. Thus, normal IgG induces apoptosis in lymphocytes and monocytes. Our results provide evidence for a role of Fas, bring new insights into the mechanisms of action of i.v.Ig in autoimmune diseases, and suggest a role of normal Ig in controlling cell death and proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Specificity*
  • Apoptosis / immunology*
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology
  • CD40 Antigens / physiology
  • Cell Death / immunology
  • Cell Division / immunology
  • Cell Line
  • Cysteine Endopeptidases / metabolism
  • Enzyme Activation / immunology
  • Humans
  • Immune Sera / chemistry
  • Immune Sera / genetics
  • Immune Sera / isolation & purification
  • Immunoglobulins, Intravenous / chemistry
  • Immunoglobulins, Intravenous / pharmacology*
  • Immunoglobulins, Intravenous / therapeutic use
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred MRL lpr
  • Monocytes / cytology*
  • Monocytes / immunology
  • Palatine Tonsil / cytology
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / immunology
  • Tumor Cells, Cultured
  • fas Receptor / genetics
  • fas Receptor / immunology
  • fas Receptor / physiology*


  • CD40 Antigens
  • Immune Sera
  • Immunoglobulins, Intravenous
  • fas Receptor
  • Cysteine Endopeptidases