Department of Medicine, Division of Rheumatology; Department of Medicine, Division of Infectious Diseases and Immunology; Department of Dermatology; UMass Metabolic Network
Dermatology | Immune System Diseases | Immunity | Immunopathology | Rheumatology | Skin and Connective Tissue Diseases
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-gamma+, 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.
Autoimmune diseases, Autoimmunity, Dermatology, Innate immunity, Th1 response
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Copyright © 2018, American Society for Clinical Investigation. The JCI is an open access journal. Publisher PDF posted as allowed by the publisher's policy posted at https://www.jci.org/kiosks/terms.
DOI of Published Version
J Clin Invest. 2018 Jun 11. pii: 98219. doi: 10.1172/JCI98219. [Epub ahead of print] Link to article on publisher's site
The Journal of clinical investigation
Mande, Purvi; Zirak, Bahar; Ko, Wei-Che; Taravati, Keyon; Bride, Karen L.; Brodeur, Tia Bumpus; Deng, April C.; Dresser, Karen A.; Jiang, Zhaozhao; Ettinger, Rachel; Fitzgerald, Katherine A.; Rosenblum, Michael D.; Harris, John E.; and Marshak-Rothstein, Ann, "Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus-like inflammation" (2018). University of Massachusetts Medical School Faculty Publications. 1581.