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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044731-18
Application #
8733517
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mancini, Marie
Project Start
1997-09-30
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
18
Fiscal Year
2014
Total Cost
$319,043
Indirect Cost
$98,543
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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