Systemic lupus erythematosus in humans and spontaneous mouse models is characterized by autoantibodies to nuclear and cytoplasmic materials that contain RNA, DNA or both, and considerable evidence indicates a direct pathologic role of these autoantibodies. Until recently the mechanisms involved in autoantibody production were to a large extend unclear, however, the emerging knowledge of a diverse array of mammalian sensors for nucleic acids, and the demonstration that these sensors are principal participants in lupus pathogenesis, have now provided a more concise definition of the mechanisms by which this disease is initiated and propagated. Among the innate immune cells implicated in the pathogenesis of lupus is the plasmacytoid dendritic cell (pDC) which constitute a small (<1%), but distinct population of cells that is thought to be activated by nucleic acid-containing immune complex stimulation of endosomal TLRs resulting in the production of disease-promoting type I interferons. Although investigation of the role of pDCs in SLE was previously not possible because of the absence of adequate animal models, recently an ENU mutation in the Slc15a4 gene, called feeble, was discovered that resulted in defective TLR7/9-induced type I interferon production in specifically pDCs. This proposal will utilize this unique model to define the role of pDCs and the production of type I interferons by these cells in animal models of lupus. We will also seek to identify pharmacologic inhibitors of SLC15A4 by high throughput screening. The insights gained from these studies are likely to provide a better understanding of the mechanisms by which innate sensors and cells promote disease, and reveal novel targets for therapeutic intervention.

Public Health Relevance

Plasmacytoid dendritic cells (pDCs) have been implicated, but not proven to play a major role in SLE presumably through their capacity to produce large quantities of type I IFNs. This proposal, consisting of two aims, will use a novel mouse strain with impaired SLC15A4, a proton-dependent histidine transporter in the endosome, to address this issue and will also seek to identify small molecule inhibitors of SLC15A4 by high-throughput screening. These studies should have a major impact on our understanding of the pathophysiology of lupus and in identifying a new approach for intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AR065384-01
Application #
8598770
Study Section
Special Emphasis Panel (ZRG1-MOSS-Q (02))
Program Officer
Mancini, Marie
Project Start
2013-07-01
Project End
2015-04-30
Budget Start
2013-07-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$241,613
Indirect Cost
$114,113
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kono, Dwight H; Baccala, Roberto; Theofilopoulos, Argyrios N (2013) TLRs and interferons: a central paradigm in autoimmunity. Curr Opin Immunol 25:720-7