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.
|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|
|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|
|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 Î± antagonist-induced lupus in a murine model. Arthritis Rheumatol 67:225-37|
|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|
|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 Î± 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|
|Weinstein, Jason S; Delano, Matthew J; Xu, Yuan et al. (2013) Maintenance of anti-Sm/RNP autoantibody production by plasma cells residing in ectopic lymphoid tissue and bone marrow memory B cells. J Immunol 190:3916-27|
|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|
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