Dysregulated production of Type I interferon (IFN-I) mediated by TLR7 is likely to be involved in the pathogenesis of SLE. In mice with lupus caused by i.p. injection of tetramethylpentadecane (TMPD, pristane), anti-Sm/RNP and anti-DNA autoantibodies are induced and immune complex-mediated glomerulonephritis develops. These lupus manifestations are absent in TMPD-treated mice deficient in TLR7, IRF5, or the Type I interferon receptor (IFNAR). The proposed studies look at the role of TLR7/IRF5/IRF7 and IFNAR signaling in various cell types and the mechanism(s) by which anti-Sm/RNP memory B cells undergo terminal differentiation into autoantibody-secreting plasma cells. The overall objective is to develop a strategy to selectively block IFN-I and autoantibody production. We hypothesize that chronic TLR7- mediated IFN-I production by myeloid cells increases TLR7 expression on anti-Sm/RNP memory B cells, promoting terminal differentiation. RNA-containing immune complexes formed by the secreted autoantibodies may perpetuate disease by amplifying IFN-I production. Disease activity may be reduced by targeting autoreactive memory and plasma cells and interrupting chronic IFN-I production. Using bone marrow chimeras and knockout mice, Aim 1 will define the roles of TLR7, IRF5/7, and the IFNAR as well as autoantigens released from dying cells in autoantibody and IFN-I production.
Aim 2 is to phenotype anti-Sm/RNP memory B cells and to examine how they become autoantibody-secreting plasma cells.
Aim 3 is to interrupt the "vicious cycle" of inflammation that may be central to the pathogenesis of SLE. Combination therapy aimed at eliminating pre-existing autoantibody producing plasma cells and down-modulating TLR7/IRF5/IRF7 signaling in memory B cells and APCs will be tested in TMPD-lupus with the ultimate objective of translating this strategy into humans. TMPD-induced lupus closely mimics a subset (~60%) of human lupus exhibiting the interferon signature. In view of the IRF5/7 gene polymorphisms associated with human SLE, there is reason for optimism that this two-pronged approach may be beneficial in both murine and human lupus.

Public Health Relevance

Systemic lupus erythematosus is a systemic autoimmune disease associated with kidney disease and the production of self-reactive antibodies (autoantibodies). There is considerable evidence that the disease may be caused by a defect in the regulation of interferon alpha. This project will further define how interferon is overproduced and how it promotes autoantibody production, and will test a new strategy for correcting these abnormalities.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mancini, Marie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Florida
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Xu, Yuan; Zhuang, Haoyang; Han, Shuhong et al. (2015) Mechanisms of tumor necrosis factor ? antagonist-induced lupus in a murine model. Arthritis Rheumatol 67:225-37
Reeves, Westley H (2014) Editorial: systemic lupus erythematosus: death by fire and ICE? Arthritis Rheumatol 66:6-9
Zhuang, Haoyang; Han, Shuhong; Xu, Yuan et al. (2014) Toll-like receptor 7-stimulated tumor necrosis factor ? causes bone marrow damage in systemic lupus erythematosus. Arthritis Rheumatol 66:140-51
Pawar, Rahul D; Goilav, Beatrice; Xia, Yumin et al. (2014) Serum autoantibodies in pristane induced lupus are regulated by neutrophil gelatinase associated lipocalin. Clin Immunol 154:49-65
Wallet, M A; Calderon, N l; Alonso, T R et al. (2013) Triclosan alters antimicrobial and inflammatory responses of epithelial cells. Oral Dis 19:296-302
George, Eva V; Pharm, John; Houston, Courtney et al. (2013) Breast implant-associated ALK-negative anaplastic large cell lymphoma: a case report and discussion of possible pathogenesis. Int J Clin Exp Pathol 6:1631-42
Xu, Yuan; Lee, Pui Y; Li, Yi et al. (2012) Pleiotropic IFN-dependent and -independent effects of IRF5 on the pathogenesis of experimental lupus. J Immunol 188:4113-21
Barker, Tolga T; Lee, Pui Y; Kelly-Scumpia, Kindra M et al. (2011) Pathogenic role of B cells in the development of diffuse alveolar hemorrhage induced by pristane. Lab Invest 91:1540-50
Lee, Pui Y; Kumagai, Yutaro; Xu, Yuan et al. (2011) IL-1* modulates neutrophil recruitment in chronic inflammation induced by hydrocarbon oil. J Immunol 186:1747-54
Li, Yi; Lee, Pui Y; Reeves, Westley H (2010) Monocyte and macrophage abnormalities in systemic lupus erythematosus. Arch Immunol Ther Exp (Warsz) 58:355-64

Showing the most recent 10 out of 44 publications