UMass Chan Medical School Faculty Publications
UMMS Affiliation
Department of Medicine, Division of Rheumatology; Department of Medicine, Division of Infectious Diseases and Immunology; Department of Dermatology; UMass Metabolic Network
Publication Date
2018-06-11
Document Type
Article
Disciplines
Dermatology | Immune System Diseases | Immunity | Immunopathology | Rheumatology | Skin and Connective Tissue Diseases
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-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.
Keywords
Autoimmune diseases, Autoimmunity, Dermatology, Innate immunity, Th1 response
Rights and Permissions
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
10.1172/JCI98219
Source
J Clin Invest. 2018 Jun 11. pii: 98219. doi: 10.1172/JCI98219. [Epub ahead of print] Link to article on publisher's site
Related Resources
Journal/Book/Conference Title
The Journal of clinical investigation
PubMed ID
29889098
Repository Citation
Mande P, Zirak B, Ko W, Taravati K, Bride KL, Brodeur TB, Deng AC, Dresser KA, Jiang Z, Ettinger R, Fitzgerald KA, Rosenblum MD, Harris JE, Marshak-Rothstein A. (2018). Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus-like inflammation. UMass Chan Medical School Faculty Publications. https://doi.org/10.1172/JCI98219. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1581
Included in
Dermatology Commons, Immune System Diseases Commons, Immunity Commons, Immunopathology Commons, Rheumatology Commons, Skin and Connective Tissue Diseases Commons