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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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).
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.
Integrated supplementary information
IFN-α in supernatants of pDCs stimulated for 16 h with influenza virus (Flu) at a multiplicity of infection (MOI) of 3, in the presence of increasing percentages of aggregated IgE (% Agg IgE). Data are presented as mean ± s.d. Results represent three independent experiments.
(a) Graphical representation of the heavy chain (HC) and light chain (LC) composition of monoclonal dsDNA-specific IgE (IgED) and dsDNA-specific IgG (IgGD). The light chain and heavy chain variable region are identical for IgGD and IgED, while the heavy chain constant region were from IgG (blue) or IgE (red). (b) Representative gel electrophoresis analysis of the molecular weights of the heavy chain (HC) and light chain (LC) of monoclonal dsDNA-specific IgE (IgED) and dsDNA-specific IgG (IgGD). (c) Binding of IgED on plate-bound dsDNA
(a-c) pDCs were stimulated with DNA+IgED in the presence of TLR9 inhibitor (TLR9 inhib) or control ODN (Control). TNF (a), IL-8 (b) and IL-6 (c) in supernatant were measured after 16 h. Data are presented as mean ± s.e.m. from three independent experiments. * P < 0.05, *** P < 0.001.
(a) Additional images for the experiments displayed in Fig. 2. IgG (blue), IgE (green), pDCs (BDCA-2, red), and IFN-α-induced protein MxA (light blue) in LN and normal kidney biopsies. Yellow arrows indicate glomerular area. (b) Quantification of the immunofluorescence signal intensity in kidney biopsies. The relative fluorescent intensities were represented for IgG, IgE, BDCA-2, and MxA. Data are presented as mean ± s.e.m of the fluorescent intensities of LN biopsies (n = 11) and normal control kidney biopsies (n = 5). Means were compared by using Student’s t-test. *** P < 0.001.
(a) Representative plots of CD27 and CD38 expression on B cell (CD123- CD19+) cultured with pDCs (+pDC) or without pDCs (no pDC) in the presence of DNA+IgED. PCs were defined as CD123-CD19+ CD27hi CD38hi cells. Quantification of B cell (b) and PC (c) from pDC/B cell co-cultures in number of cells acquired for a fixed amount of time per well. Data are presented as mean ± s.d. of at least three independent experiments. *** P < 0.001.
TNF (a), IL-6 (b) and IL-8 (c) in supernatants of pDCs stimulated for 16 h with DNA-ICs containing increasing concentrations of dsDNA-specific antibodies. Data are presented as mean ± s.d. and are representative of seven independent experiments. ** P < 0.01.
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Henault, J., Riggs, J., Karnell, J. et al. Self-reactive IgE exacerbates interferon responses associated with autoimmunity. Nat Immunol 17, 196–203 (2016). https://doi.org/10.1038/ni.3326
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