Abstract

Canonically, immunoglobulin E (IgE) mediates allergic immune responses by triggering mast cells and basophils to release histamine and type 2 helper cytokines. Here we found that in human systemic lupus erythematosus (SLE), IgE antibodies specific for double-stranded DNA (dsDNA) activated plasmacytoid dendritic cells (pDCs), a type of cell of the immune system linked to viral defense, which led to the secretion of substantial amounts of interferon-α (IFN-α). The concentration of dsDNA-specific IgE found in patient serum correlated with disease severity and greatly potentiated pDC function by triggering phagocytosis via the high-affinity FcɛRI receptor for IgE, followed by Toll-like receptor 9 (TLR9)-mediated sensing of DNA in phagosomes. Our findings expand the known pathogenic mechanisms of IgE-mediated inflammation beyond those found in allergy and demonstrate that IgE can trigger interferon responses capable of exacerbating self-destructive autoimmune responses.

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Acknowledgements

We thank S. Cohen (MedImmune) for antibody to IgE; M. Rebelatto, M. Czapiga, K. Dacosta, W. King and H. Koelkebeck for discussions; E. Grant and K. Stover for critical manuscript review; E. Grant and M. Parker and the Autoimmunity Molecular Medicine Group (Medimmune) for assistance with clinical samples; and K. Zerrouki for assistance with manuscript editing. Supported by the US National Institutes of Health (AR-43727).

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Author notes

    • Roland Kolbeck
    •  & Miguel A Sanjuan

    These authors contributed equally to this work.

Affiliations

  1. Research Department, MedImmune, Gaithersburg, Maryland, USA.

    • Jill Henault
    • , Jeffrey M Riggs
    • , Jodi L Karnell
    • , Jianqing Li
    • , Kerry A Casey
    • , Michael A Smith
    • , Deepak B Khatry
    • , Liat Izhak
    • , Ronald Herbst
    • , Rachel Ettinger
    • , Tomas Mustelin
    • , Roland Kolbeck
    •  & Miguel A Sanjuan
  2. Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA.

    • Vladimir M Liarski
    •  & Marcus R Clark
  3. Antibody Discovery and Protein Engineering Department, MedImmune, Gaithersburg, Maryland, USA.

    • Lena Shirinian
    • , Linda Xu
    •  & Lorraine Clarke
  4. Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Michelle Petri

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Contributions

J.H., J.M.R., J.L.K., V.M.L., J.L., L.S., L.I. and L.C., experimental design and conception, under the guidance of L.X., R.H., R.E. and T.M.; K.A.C., M.A. Smith and D.B.K., statistical analysis; M.P. and M.R.C., supervision of the generation and analysis of data from patients with SLE; J.H., R.K. and M.A. Sanjuan conception and direction of the project; and J.H. and M.A. Sanjuan authorship of the manuscript with input from all authors.

Competing interests

J.H., J.M.R., J.L.K., J.L., L.S., L.X., K.A.C., M.A. Smith, D.B.K., L.I., L.C., R.H., R.E., T.M., R.K. and M.A. Sanjuan are or were full-time employees of MedImmune, which is developing therapies for autoimmune diseases.

Corresponding author

Correspondence to Miguel A Sanjuan.

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https://doi.org/10.1038/ni.3326