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Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus–like inflammation
Purvi Mande, … , John E. Harris, Ann Marshak-Rothstein
Purvi Mande, … , John E. Harris, Ann Marshak-Rothstein
Published June 11, 2018
Citation Information: J Clin Invest. 2018;128(7):2966-2978. https://doi.org/10.1172/JCI98219.
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Research Article Autoimmunity Dermatology

Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus–like inflammation

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Abstract

Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9–/– autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific Tbet+, IFN-γ+, and FasL-expressing Th1 cells as well as autoantibody-producing B cells. Unexpectedly, contrary to what occurs in most models of SLE, they also developed skin lesions that are very similar to those of human cutaneous lupus erythematosus (CLE) as far as clinical appearance, histological changes, and gene expression. FasL was a key effector mechanism in the skin, as the transfer of FasL-deficient DO11gld T cells completely failed to elicit overt skin lesions. FasL was also upregulated in human CLE biopsies. Overall, our model provides a relevant system for exploring the pathophysiology of CLE as well as the negative regulatory role of TLR9.

Authors

Purvi Mande, Bahar Zirak, Wei-Che Ko, Keyon Taravati, Karen L. Bride, Tia Y. Brodeur, April Deng, Karen Dresser, Zhaozhao Jiang, Rachel Ettinger, Katherine A. Fitzgerald, Michael D. Rosenblum, John E. Harris, Ann Marshak-Rothstein

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Figure 2

TLR9-deficiency promotes development of Th1 and TFH cells.

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TLR9-deficiency promotes development of Th1 and TFH cells.
sdLN suspensi...
sdLN suspensions from DO11-injected TLR9WT, TLR9KO, TLR7KO, and TLR7/9DKO Ii-TGO mice at 4 weeks after T cell injection were analyzed for (A) percentages of DO11 (KJ126+) T cells in the CD4+ gate, (B) percentages of cytokine-producing cells in the KJ126+ gate, (C) percentages of FasL-expressing cells in the KJ126+ gate, and (D) percentages of TFH cells in the KJ126+ gate. Data are shown as mean ± SEM and are representative of 5 independent experiments with n = 15 mice per group. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, 1-way ANOVA with Šidák’s multiple-comparison test (A–C) and 2-tailed Student’s t test (D).
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