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 doublestranded DNA and multiple organ involvement, including glomerulonephritis, hepatitis, carditis, and photosensitivity. Expression of Ifna and Mx1, the interferon-␣-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.Conclusion. 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.

4. Laryngoscope, 126:E103-E109, 2016.

Please cite this paper as: Fujimoto et al. (2012) Induction and maintenance of anti‐influenza antigen‐specific nasal secretory IgA levels and serum IgG levels after influenza infection in adults. Influenza and Other Respiratory Viruses 6(6), 396–403. Objectives  To determine the induction and changes in anti‐influenza virus secretory IgA (s‐IgA) levels in nasal washes and serum IgG levels in patients with influenza. Methods  The study recruited 16 patients with influenza aged 35·6 ± 9·6 years in 2007/2008 and 2008/2009 seasons. Nasal washes and serum were obtained throughout the first year. Anti‐viral s‐IgA levels and neutralization activities in nasal washes, and serum anti‐viral IgG levels and hemagglutination inhibition (HI) titers were measured. Results  Anti‐viral(H1N1) s‐IgA to total IgA ratio and neutralizing antibody titer were low in nasal washes of all patients, whereas serum levels of anti‐viral IgG and HI titers varied widely at day 1·4 ± 1·0 postinfection. Both nasal s‐IgA and serum IgG levels later increased significantly, reaching peak levels at day 9·6 ± 3·3 postinfection. The induced nasal s‐IgA then returned toward the initial levels within 300 days, although the levels at day 143 ± 70 were 3·03‐fold of the initial. Individual serum IgG levels also returned toward the initial levels within 300 days, although the mean levels remained high probably because of re‐infection in a subgroup of patients. Although influenza A (H3N2) was a minor epidemic subtype in both flu seasons, a significant rise in nasal anti‐viral (H3N2) s‐IgA levels and a slightly increase in serum IgG levels were noted. Conclusion  Low levels of nasal anti‐viral s‐IgA and neutralizing antibody were noted compared with a wide range of serum anti‐viral IgG and HI titers at the onset of infection. Elevated s‐IgA and IgG returned toward the initial levels within 300 days of infection with minor exceptions.

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