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)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Mancini, Marie
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University of Florida
Internal Medicine/Medicine
Schools of Medicine
United States
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Han, Shuhong; Zhuang, Haoyang; Shumyak, Stepan et al. (2018) Liver X Receptor Agonist Therapy Prevents Diffuse Alveolar Hemorrhage in Murine Lupus by Repolarizing Macrophages. Front Immunol 9:135
Han, Shuhong; Zhuang, Haoyang; Shumyak, Stepan et al. (2017) A Novel Subset of Anti-Inflammatory CD138+ Macrophages Is Deficient in Mice with Experimental Lupus. J Immunol 199:1261-1274
Zhuang, Haoyang; Han, Shuhong; Lee, Pui Y et al. (2017) Pathogenesis of Diffuse Alveolar Hemorrhage in Murine Lupus. Arthritis Rheumatol 69:1280-1293
Zhuang, Haoyang; Han, Shuhong; Li, Yi et al. (2016) A Novel Mechanism for Generating the Interferon Signature in Lupus: Opsonization of Dead Cells by Complement and IgM. Arthritis Rheumatol 68:2917-2928
Shumyak, Stepan; Yang, Li-Jun; Han, Shuhong et al. (2016) ""Lupoid hepatitis"" in SLE patients and mice with experimental lupus. Clin Immunol 172:65-71
Han, Shuhong; Zhuang, Haoyang; Xu, Yuan et al. (2015) Maintenance of autoantibody production in pristane-induced murine lupus. Arthritis Res Ther 17:384
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
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
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

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