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Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells

Nature Medicine volume 12, pages 688–692 (2006)Cite this article

Abstract

Despite a more than 20-year experience of therapeutic benefit, the relevant molecular and cellular targets of intravenous immunoglobulin (IVIg) in autoimmune disease remain unclear. Contrary to the prevailing theories of IVIg action in autoimmunity, we show that IVIg drives signaling through activating Fcγ receptors (FcγR) in the amelioration of mouse immune thrombocytopenic purpura (ITP). The actual administration of IVIg was unnecessary because as few as 105 IVIg-treated cells could, upon adoptive transfer, ameliorate ITP. IVIg did not interact with the inhibitory FcγRIIB on the initiator cell, although FcγRIIB does have a role in the late phase of IVIg action. Notably, only IVIg-treated CD11c+ dendritic cells could mediate these effects. We hypothesize that IVIg forms soluble immune complexes in vivo that prime dendritic-cell regulatory activity. In conclusion, the clinical effects of IVIg in ameliorating ITP seem to involve the acute interaction of IVIg with activating FcγR on dendritic cells.

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Figure 1: IVIg-primed leukocytes inhibit mouse ITP.
Figure 2: IVIg does not interact with the inhibitory FcγRIIB in the amelioration of mouse ITP.
Figure 3: IVIg-primed leukocytes require FcR γ chain–dependent signals to ameliorate mouse ITP.
Figure 4: IVIg-primed dendritic cells ameliorate mouse ITP.

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References

  1. Knezevic-Maramica, I. & Kruskall, M.S. Intravenous immune globulins: an update for clinicians. Transfusion 43, 1460–1480 (2003).

    Article  CAS  Google Scholar 

  2. Jolles, S., Sewell, W.A. & Misbah, S.A. Clinical uses of intravenous immunoglobulin. Clin. Exp. Immunol. 142, 1–11 (2005).

    Article  CAS  Google Scholar 

  3. McMillan, R., Longmire, R.L., Yelenosky, R., Donnell, R.L. & Armstrong, S. Quantitation of platelet-binding IgG produced in vitro by spleens from patients with idiopathic thrombocytopenic purpura. N. Engl. J. Med. 291, 812–817 (1974).

    Article  CAS  Google Scholar 

  4. Saleh, M.N., Moore, D.L., Lee, J.Y. & LoBuglio, A.F. Monocyte-platelet interaction in immune and nonimmune thrombocytopenia. Blood 74, 1328–1331 (1989).

    CAS  PubMed  Google Scholar 

  5. Semple, J.W. Immune pathophysiology of autoimmune thrombocytopenic purpura. Blood Rev. 16, 9–12 (2002).

    Article  CAS  Google Scholar 

  6. Bussel, J.B. Fc receptor blockade and immune thrombocytopenic purpura. Semin. Hematol. 37, 261–266 (2000).

    Article  CAS  Google Scholar 

  7. Fehr, J., Hofmann, V. & Kappeler, U. Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin. N. Engl. J. Med. 306, 1254–1258 (1982).

    Article  CAS  Google Scholar 

  8. Salama, A., Mueller-Eckhardt, C. & Kiefel, V. Effect of intravenous immunoglobulin in immune thrombocytopenia. Lancet 2, 193–195 (1983).

    Article  CAS  Google Scholar 

  9. Salama, A., Kiefel, V., Amberg, R. & Mueller-Eckhardt, C. Treatment of autoimmune thrombocytopenic purpura with rhesus antibodies (anti-Rh0(D)). Blut 49, 29–35 (1984).

    Article  CAS  Google Scholar 

  10. Lazarus, A.H. & Crow, A.R. Mechanism of action of IVIG and anti-D in ITP. Transfus. Apher. Sci. 28, 249–255 (2003).

    Article  Google Scholar 

  11. Samuelsson, A., Towers, T.L. & Ravetch, J.V. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291, 484–486 (2001).

    Article  CAS  Google Scholar 

  12. Crow, A.R. et al. IVIg-mediated amelioration of murine ITP via Fc{gamma}RIIB is independent of SHIP1, SHP-1, and Btk activity. Blood 102, 558–560 (2003).

    Article  CAS  Google Scholar 

  13. Siragam, V. et al. Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease? J. Clin. Invest. 115, 155–160 (2005).

    Article  CAS  Google Scholar 

  14. Korganow, A.S. et al. From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. Immunity 10, 451–461 (1999).

    Article  CAS  Google Scholar 

  15. Kouskoff, V. et al. Organ-specific disease provoked by systemic autoimmunity. Cell 87, 811–822 (1996).

    Article  CAS  Google Scholar 

  16. Bruhns, P., Samuelsson, A., Pollard, J.W. & Ravetch, J.V. Colony-stimulating factor-1-dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity 18, 573–581 (2003).

    Article  CAS  Google Scholar 

  17. Cao, X. et al. The inositol 3-phosphatase PTEN negatively regulates Fc gamma receptor signaling, but supports Toll-like receptor 4 signaling in murine peritoneal macrophages. J. Immunol. 172, 4851–4857 (2004).

    Article  CAS  Google Scholar 

  18. Latour, S., Bonnerot, C., Fridman, W.H. & Daeron, M. Induction of tumor necrosis factor-alpha production by mast cells via Fc gamma R. Role of the Fc gamma RIII gamma subunit. J. Immunol. 149, 2155–2162 (1992).

    CAS  Google Scholar 

  19. De Andres, B. et al. Phosphoinositide breakdown is associated with Fc-gamma RII-mediated activation of 5′-lipoxygenase in murine eosinophils. J. Immunol. 146, 1566–1570 (1991).

    CAS  PubMed  Google Scholar 

  20. Timms, J.F. et al. Identification of major binding proteins and substrates for the SH2-containing protein tyrosine phosphatase SHP-1 in macrophages. Mol. Cell. Biol. 18, 3838–3850 (1998).

    Article  CAS  Google Scholar 

  21. Boruchov, A.M. et al. Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. J. Clin. Invest. 115, 2914–2923 (2005).

    Article  CAS  Google Scholar 

  22. Song, S., Crow, A.R., Siragam, V., Freedman, J. & Lazarus, A.H. Monoclonal antibodies that mimic the action of anti-D in the amelioration of murine ITP act by a mechanism distinct from that of IVIg. Blood 105, 1546–1548 (2005).

    Article  CAS  Google Scholar 

  23. Crow, A.R., Song, S., Semple, J.W., Freedman, J. & Lazarus, A.H. IVIg inhibits reticuloendothelial system function and ameliorates murine passive-immune thrombocytopenia independent of anti-idiotype reactivity. Br. J. Haematol. 115, 679–686 (2001).

    Article  CAS  Google Scholar 

  24. Braun-Moscovici, Y. & Furst, D.E. Immunoglobulin for rheumatic diseases in the twenty-first century: take it or leave it? Curr. Opin. Rheumatol. 15, 237–245 (2003).

    Article  Google Scholar 

  25. Arnal, C. et al. Treatment of severe immune thrombocytopenia associated with systemic lupus erythematosus: 59 cases. J. Rheumatol. 29, 75–83 (2002).

    CAS  PubMed  Google Scholar 

  26. Spisek, R., Gasova, Z. & Bartunkova, J. Maturation state of dendritic cells during the extracorporeal photopheresis and its relevance for the treatment of chronic graft-versus-host disease. Transfusion 46, 55–65 (2006).

    Article  CAS  Google Scholar 

  27. Song, S., Crow, A.R., Freedman, J. & Lazarus, A.H. Monoclonal IgG can ameliorate immune thrombocytopenia in a murine model of ITP: an alternative to IVIG. Blood 101, 3708–3713 (2003).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J. Semple for discussion and critical review of this manuscript, H. Le-Tien and A. Starkey for assistance and discussion, and the St. Michael's Hospital Research Vivarium staff. This work was supported by grants from the Canadian Institutes of Health Research (to A.L.), and The Canadian Blood Services-Canadian Institutes of Health Research Request for Proposals Program Fund (to A.L.). V. Siragam was the recipient of a Post Doctoral Fellowship Award from the Canadian Blood Services. D. Brinc was supported by Graduate Fellowship Award from the Canadian Blood Services.

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Author notes

  1. Vinayakumar Siragam and Andrew R Crow: These authors contributed equally to this work.

Authors and Affiliations

  1. Canadian Blood Services, 1800 Alta Vista Drive, Ottawa, K1G 4J5, Ontario, Canada

    Vinayakumar Siragam, Andrew R Crow, Davor Brinc, John Freedman & Alan H Lazarus

  2. Department of Laboratory Medicine, Transfusion Medicine Research, St. Michael's Hospital, 30 Bond Street, Toronto, M5B 1W8, Ontario, Canada

    Vinayakumar Siragam, Andrew R Crow, Davor Brinc, Seng Song & John Freedman

  3. Department of Medicine, University of Toronto, 190 Elizabeth Street, Toronto, M5G 2C4, Ontario

    John Freedman

  4. Toronto Platelet Immunobiology Group, Toronto, Ontario, Canada

    John Freedman

Authors
  1. Vinayakumar Siragam
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  2. Andrew R Crow
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  3. Davor Brinc
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  4. Seng Song
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  5. John Freedman
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  6. Alan H Lazarus
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Contributions

V.K.S. and A.R.C. helped conceptualize and design the study, co-wrote the manuscript, performed the research and analyzed the data. D.B. and S.S. helped conceptualize and design the study and performed the research. J.F. helped conceptualize the study and co-wrote the manuscript. A.H.L. conceptualized and designed the study, obtained grant support and co-wrote the manuscript.

Corresponding author

Correspondence to Alan H Lazarus.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

IVIg primed B cells and T cells do not inhibit mouse ITP. (PDF 818 kb)

Supplementary Fig. 2

The requirement for IVIg can be bypassed using soluble immune complexes. (PDF 1208 kb)

Supplementary Fig. 3

IVIg does not reverse thrombocytopenia in SLE-ITP mice. (PDF 992 kb)

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Siragam, V., Crow, A., Brinc, D. et al. Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells. Nat Med 12, 688–692 (2006). https://doi.org/10.1038/nm1416

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