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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Rönnblom, L. & Elkon, K.B. Cytokines as therapeutic targets in SLE. Nat. Rev. Rheumatol. 6, 339–347 (2010).
Lateef, A. & Petri, M. Unmet medical needs in systemic lupus erythematosus. Arthritis Res. Ther. 14 (suppl. 4), S4 (2012).
Rönnblom, L. & Alm, G.V. A pivotal role for the natural interferon α-producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus. J. Exp. Med. 194, F59–F63 (2001).
Rowland, S.L. et al. Early, transient depletion of plasmacytoid dendritic cells ameliorates autoimmunity in a lupus model. J. Exp. Med. 211, 1977–1991 (2014).
Gilliet, M., Cao, W. & Liu, Y.J. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat. Rev. Immunol. 8, 594–606 (2008).
Siegal, F.P. et al. The nature of the principal type 1 interferon-producing cells in human blood. Science 284, 1835–1837 (1999).
Båve, U. et al. FcγRIIa is expressed on natural IFN-α-producing cells (plasmacytoid dendritic cells) and is required for the IFN-α production induced by apoptotic cells combined with lupus IgG. J. Immunol. 171, 3296–3302 (2003).
Honda, K., Takaoka, A. & Taniguchi, T. Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity 25, 349–360 (2006).
Kawai, T. & Akira, S. Signaling to NF-κB by Toll-like receptors. Trends Mol. Med. 13, 460–469 (2007).
Swiecki, M. & Colonna, M. The multifaceted biology of plasmacytoid dendritic cells. Nat. Rev. Immunol. 15, 471–485 (2015).
Atta, A.M., Santiago, M.B., Guerra, F.G., Pereira, M.M. & Sousa Atta, M.L. Autoimmune response of IgE antibodies to cellular self-antigens in systemic lupus erythematosus. Int. Arch. Allergy Immunol. 152, 401–406 (2010).
Charles, N., Hardwick, D., Daugas, E., Illei, G.G. & Rivera, J. Basophils and the T helper 2 environment can promote the development of lupus nephritis. Nat. Med. 16, 701–707 (2010).
Dema, B. et al. Autoreactive IgE is prevalent in systemic lupus erythematosus and is associated with increased disease activity and nephritis. PLoS ONE 9, e90424 (2014).
Dema, B. et al. Immunoglobulin E plays an immunoregulatory role in lupus. J. Exp. Med. 211, 2159–2168 (2014).
Allen, J.E. & Maizels, R.M. Diversity and dialogue in immunity to helminths. Nat. Rev. Immunol. 11, 375–388 (2011).
Galli, S.J., Tsai, M. & Piliponsky, A.M. The development of allergic inflammation. Nature 454, 445–454 (2008).
Lit, L.C. et al. Elevated gene expression of Th1/Th2 associated transcription factors is correlated with disease activity in patients with systemic lupus erythematosus. J. Rheumatol. 34, 89–96 (2007).
Masutani, K. et al. Predominance of Th1 immune response in diffuse proliferative lupus nephritis. Arthritis Rheum. 44, 2097–2106 (2001).
Elkayam, O., Tamir, R., Pick, A.I. & Wysenbeek, A. Serum IgE concentrations, disease activity, and atopic disorders in systemic lupus erythematosus. Allergy 50, 94–96 (1995).
Morton, S., Palmer, B., Muir, K. & Powell, R.J. IgE and non-IgE mediated allergic disorders in systemic lupus erythematosus. Ann. Rheum. Dis. 57, 660–663 (1998).
Wozniacka, A., Sysa-Jedrzejowska, A., Robak, E., Samochocki, Z. & Zak-Prelich, M. Allergic diseases, drug adverse reactions and total immunoglobulin E levels in lupus erythematosus patients. Mediators Inflamm. 12, 95–99 (2003).
Livingston, B., Bonner, A. & Pope, J. Differences in autoantibody profiles and disease activity and damage scores between childhood- and adult-onset systemic lupus erythematosus: a meta-analysis. Semin. Arthritis Rheum. 42, 271–280 (2012).
Durrani, S.R. et al. Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children. J. Allergy Clin. Immunol. 130, 489–495 (2012).
Gill, M.A. et al. Counterregulation between the FcɛRI pathway and antiviral responses in human plasmacytoid dendritic cells. J. Immunol. 184, 5999–6006 (2010).
Novak, N. et al. Characterization of FcɛRI-bearing CD123 blood dendritic cell antigen-2 plasmacytoid dendritic cells in atopic dermatitis. J. Allergy Clin. Immunol. 114, 364–370 (2004).
Henault, J. et al. Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes. Immunity 37, 986–997 (2012).
Sasai, M., Linehan, M.M. & Iwasaki, A. Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3. Science 329, 1530–1534 (2010).
Nossent, H., Berden, J. & Swaak, T. Renal immunofluorescence and the prediction of renal outcome in patients with proliferative lupus nephritis. Lupus 9, 504–510 (2000).
Satoskar, A.A. et al. Discrepancies in glomerular and tubulointerstitial/vascular immune complex IgG subclasses in lupus nephritis. Lupus 20, 1396–1403 (2011).
Jego, G. et al. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 19, 225–234 (2003).
Seth, S. et al. CCR7 essentially contributes to the homing of plasmacytoid dendritic cells to lymph nodes under steady-state as well as inflammatory conditions. J. Immunol. 186, 3364–3372 (2011).
Sharp, G.C. et al. Association of antibodies to ribonucleoprotein and Sm antigens with mixed connective-tissue disease, systematic lupus erythematosus and other rheumatic diseases. N. Engl. J. Med. 295, 1149–1154 (1976).
Mouchess, M.L. et al. Transmembrane mutations in Toll-like receptor 9 bypass the requirement for ectodomain proteolysis and induce fatal inflammation. Immunity 35, 721–732 (2011).
Kulczycki, A. Jr. & Metzger, H. The interaction of IgE with rat basophilic leukemia cells. II. Quantitative aspects of the binding reaction. J. Exp. Med. 140, 1676–1695 (1974).
Bruhns, P. et al. Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses. Blood 113, 3716–3725 (2009).
Fitzsimmons, C.M., Falcone, F.H. & Dunne, D.W. Helminth allergens, parasite-specific IgE, and its protective role in human immunity. Front. Immunol. 5, 61 (2014).
Means, T.K. et al. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115, 407–417 (2005).
Pellegrino, M.G. et al. HIV type 1-specific IgE in serum of long-term surviving children inhibits HIV type 1 production in vitro. AIDS Res. Hum. Retroviruses 18, 363–372 (2002).
Russi, J.C. et al. Evaluation of immunoglobulin E-specific antibodies and viral antigens in nasopharyngeal secretions of children with respiratory syncytial virus infections. J. Clin. Microbiol. 31, 819–823 (1993).
Smith-Norowitz, T.A. et al. Long term persistence of IgE anti-influenza virus antibodies in pediatric and adult serum post vaccination with influenza virus vaccine. Int. J. Med. Sci. 8, 239–244 (2011).
Secord, E.A. et al. IgE against HIV proteins in clinically healthy children with HIV disease. J. Allergy Clin. Immunol. 98, 979–984 (1996).
Hochberg, M.C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40, 1725 (1997).
Tan, E.M. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25, 1271–1277 (1982).
Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9, 847–856 (2008).
Cohen, E.S. et al. A novel IgE-neutralizing antibody for the treatment of severe uncontrolled asthma. MAbs 6, 756–764 (2014).
Oganesyan, V., Gao, C., Shirinian, L., Wu, H. & Dall'Acqua, W.F. Structural characterization of a human Fc fragment engineered for lack of effector functions. Acta Crystallogr. D Biol. Crystallogr. 64, 700–704 (2008).
Agley, C.C., Velloso, C.P., Lazarus, N.R. & Harridge, S.D. An image analysis method for the precise selection and quantitation of fluorescently labeled cellular constituents: application to the measurement of human muscle cells in culture. J. Histochem. Cytochem. 60, 428–438 (2012).
Karnell, J.L. et al. CD19 and CD32b differentially regulate human B cell responsiveness. J. Immunol. 192, 1480–1490 (2014).
Peng, L., Oganesyan, V., Wu, H., Dall'Acqua, W.F. & Damschroder, M.M. Molecular basis for antagonistic activity of anifrolumab, an anti-interferon-α receptor 1 antibody. MAbs 7, 428–439 (2015).
Finch, D.K. et al. Whole-molecule antibody engineering: generation of a high-affinity anti-IL-6 antibody with extended pharmacokinetics. J. Mol. Biol. 411, 791–807 (2011).
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).
Author information
Authors and Affiliations
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.
Corresponding author
Ethics declarations
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.
Integrated supplementary information
Supplementary Figure 1 Aggregated IgE blocks interferon responses in pDCs.
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.
Supplementary Figure 2 IgED binds to DNA.
(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
Supplementary Figure 3 DNA-IgED triggers cytokines through TLR9.
(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.
Supplementary Figure 4 Deposition of IgE autoantibodies in LN.
(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.
Supplementary Figure 5 pDCs are required for DNA-IgED–dependent formation of B cells and PCs.
(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.
Supplementary Figure 6 Synergistic stimulation of pDCs by ICs containing IgE and IgG.
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.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–6 (PDF 987 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni.3326
This article is cited by
-
Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis
Journal of Neuroinflammation (2021)
-
Autoantibody-dependent amplification of inflammation in SLE
Cell Death & Disease (2020)
-
Autoimmunity and organ damage in systemic lupus erythematosus
Nature Immunology (2020)
-
Characterizing the BCR repertoire in immune-mediated diseases
Nature Reviews Rheumatology (2020)
-
Stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria
Allergy, Asthma & Clinical Immunology (2019)