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Intravenous gammaglobulin suppresses inflammation through a novel TH2 pathway

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Abstract

High-dose intravenous immunoglobulin is a widely used therapeutic preparation of highly purified immunoglobulin G (IgG) antibodies. It is administered at high doses (1–2 grams per kilogram) for the suppression of autoantibody-triggered inflammation in a variety of clinical settings1. This anti-inflammatory activity of intravenous immunoglobulin is triggered by a minor population of IgG crystallizable fragments (Fcs), with glycans terminating in α2,6 sialic acids (sFc) that target myeloid regulatory cells expressing the lectin dendritic-cell-specific ICAM-3 grabbing non-integrin (DC-SIGN; also known as CD209)2,3,4. Here, to characterize this response in detail, we generated humanized DC-SIGN mice (hDC-SIGN), and demonstrate that the anti-inflammatory activity of intravenous immunoglobulin can be recapitulated by the transfer of bone-marrow-derived sFc-treated hDC-SIGN+ macrophages or dendritic cells into naive recipients. Furthermore, sFc administration results in the production of IL-33, which, in turn, induces expansion of IL-4-producing basophils that promote increased expression of the inhibitory Fc receptor FcγRIIB on effector macrophages. Systemic administration of the TH2 cytokines IL-33 or IL-4 upregulates FcγRIIB on macrophages, and suppresses serum-induced arthritis. Consistent with these results, transfer of IL-33-treated basophils suppressed induced arthritic inflammation. This novel DC-SIGN–TH2 pathway initiated by an endogenous ligand, sFc, provides an intrinsic mechanism for maintaining immune homeostasis that could be manipulated to provide therapeutic benefit in autoimmune diseases.

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Figure 1: Human DC-SIGN conveys sFc anti-inflammatory activity.
Figure 2: IL-4 requirements of sFc anti-inflammatory activity.
Figure 3: IL-33 triggers IL-4 anti-inflammatory activity.
Figure 4: Anti-inflammatory activity mediated by basophils.

Change history

  • 06 July 2011

    Fig. 2b and d were corrected.

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Acknowledgements

The authors thank P. Smith, M. Kibe, J. Brown and K. Velinzon for technical support, K. L. Jeffrey, C. Cheong, R. Steinman and J. J. Lee for discussions, M. Pack for providing human spleen sections, A. McKenzie for providing SIGN-R1−/− mice, T. Sparwasser for providing CD11c-hDC-SIGN mice, C. G. Park for providing hDC-SIGN and hDC-SIGN-R expressing cell lines, and H. Watarai for providing anti-IL-25R antibodies. R.M.A. is an Irvington Institute fellow of the Cancer Research Institute. F.W. is supported by the Wenner-Gren Foundations, Sweden. This work was performed with support from Virdante Pharmaceuticals and NIH grants to J.V.R.

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R.M.A., T.K., F.W. and J.V.R. designed the experiments and interpreted the results. R.M.A., T.K. and F.W. performed the experiments, and R.M.A. and J.V.R. wrote the manuscript.

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Correspondence to Jeffrey V. Ravetch.

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Anthony, R., Kobayashi, T., Wermeling, F. et al. Intravenous gammaglobulin suppresses inflammation through a novel TH2 pathway. Nature 475, 110–113 (2011). https://doi.org/10.1038/nature10134

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