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Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells

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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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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Authors and Affiliations

Authors

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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