(Verbatim) - Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease caused by immune complex deposition in target organs, such as the kidney, and characterized by the production of marker autoantibodies, including anti-double stranded (ds) DNA, anti-Sm, and anti-ribosomal P. It is not known why these autoantibodies are so highly specific for SLE or how they are generated. The pathogenesis of SLE involves an interplay between endogenous (genetic) and exogenous (environmental) factors. Our laboratory is interested in the role of exogenous factors. We have reported that the isoprenoid alkane, pristane, induces both autoimmune disease (nephritis) and a variety of autoantibodies characteristic of SLE in non-autoimmune mice. These include anti-dsDNA, -Sm, -ribosomal P and others. Autoantibody production is highly dependent on IL-6 and IFNgamma and/or IL-12. Microbial stimulation is a co-factor. Unexpectedly, the injection of pristane in NZB X NZW F1 mice altered the autoantibody phenotype from anti-DNA/chromatin and anti-RNA helicase A (Th2 cytokine dependent) to anti-nRNP/Sm and Su (Th1 dependent). At the same time, IL-12 production increased, IL-4 decreased, and renal disease was accelerated dramatically. We hypothesize that pristane causes a defect in antigen presenting cells (APCs), mimicking genetic defects predisposing to SLE. Further, we hypothesize that differences in the cytokines induced by pristane may account for inter-strain differences in the autoantibodies produced.
Four specific aims are proposed.
Aim 1 is to identify the cells producing IL-6 and IL-12, which appear to drive the autoimmune process, using a combination of depletion experiments, mixing studies, and immunohistochemistry.
Aim 2 is to define the role of microbial stimulation by treating mice in germ-free conditions with pristane.
Aim 3 is to determine how pristane alters the immune function of APCs. These studies focus on a) identifying cellular receptors for pristane that appear to transmit a signal promoting lupus susceptibility and b) determining the mechanism.
Aim 4 is to examine the basis for the exquisite antigen-selectivity of autoantibody responses in pristane treated mice. We will look at the role of CD40-CD40 ligand interactions and germinal center formation. Finally, exploratory studies will begin to define how cytokines influence autoantibody phenotypes. These studies may provide a basis for understanding how defective APC function can predispose to SLE, the role of exogenous """"""""triggers"""""""" in the disease process, and the mechanisms for generating different autoantibody phenotypes under the influence of different cytokines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044731-08
Application #
6692146
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Gretz, Elizabeth
Project Start
1997-09-30
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
8
Fiscal Year
2004
Total Cost
$310,384
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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
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 ? 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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