title: Epicutaneous application of toll-like receptor 7 agonists leads to systemic autoimmunity in wild-type mice: a new model of systemic Lupus erythematosus.
abstract: OBJECTIVE
  To examine whether topical treatment of wild-type mice with Toll-like receptor 7 (TLR-7) agonists leads to lupus-like autoimmunity.
  
  
  METHODS
  Wild-type FVB/N, BALB/c, and C57BL/6 mice were treated with the topical TLR-7 agonist imiquimod or R848 administered to the ear 3 times weekly. During treatment, the mice were monitored for serum autoantibody and creatinine levels as well as histopathology of the kidneys, spleens, livers, hearts, and skin. Immunologic abnormalities were analyzed by immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, and fluorescence-activated cell sorting. The role of plasmacytoid dendritic cells (PDCs) in the development of autoimmune disease was validated by in vivo treatment with an anti-PDC antibody. Diseased mice underwent ultraviolet B irradiation, to evaluate skin photosensitivity. The disease-causing effect of topical application of imiquimod was compared with that of systemic (intraperitoneal) administration. TLR-7- and TLR-9-deficient mice were used to validate the role of TLR-7.
  
  
  RESULTS
  Wild-type mice of different genetic backgrounds developed systemic autoimmune disease following 4 weeks of topical treatment with imiquimod or R848, with elevated levels of autoantibodies to double-stranded DNA and multiple organ involvement, including glomerulonephritis, hepatitis, carditis, and photosensitivity. Expression of Ifna and Mx1, the interferon-α-stimulated gene, was up-regulated in the organs of imiquimod-treated mice. However, disease caused by intraperitoneal injection of imiquimod was less severe than that induced by topical application. In vivo depletion of PDCs by a specific antibody protected mice against the autoimmunity induced by topical administration of imiquimod, suggesting a role of PDCs. Furthermore, TLR-7-deficient mice, but not TLR-9-deficient mice, were protected against autoimmunity.
  
  
  CONCLUSIONS
  This protocol provides a novel model of inducible systemic lupus erythematosus in wild-type mice and underscores the skin as the primary organ that allows TLR-7 agonists to induce SLE.
authors.affiliation: Kochi University, Nankoku, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Yokogawa
authors.forename: Mikiro
authors.initials: M
authors.lastname: Takaishi
authors.forename: Kimiko
authors.initials: K
authors.lastname: Nakajima
authors.forename: Reiko
authors.initials: R
authors.lastname: Kamijima
authors.forename: Chisa
authors.initials: C
authors.lastname: Fujimoto
authors.forename: Sayo
authors.initials: S
authors.lastname: Kataoka
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Terada
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Sano
mesh_terms: D000279:Administration, Cutaneous; D000634:Aminoquinolines; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D007093:Imidazoles; D000077271:Imiquimod; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced* / Q000276:immunology; D051379:Mice; D012867:Skin / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists*
chemical_list: D000634:Aminoquinolines; D001323:Autoantibodies; D007093:Imidazoles; D051199:Toll-Like Receptor 7; D000077271:Imiquimod; C402365:resiquimod