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.
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.
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|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|
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|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|
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|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|
|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|
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